Food Science and Biotechnology (2024) 33:3153–3166

https://doi.org/10.1007/s10068-024-01664-3

INVITED REVIEW

Fatty acids and epigenetics in health and diseases

Min‑Yu Chung1 · Byung Hee Kim2

Received: 4 March 2024 / Revised: 8 July 2024 / Accepted: 17 July 2024 / Published online: 25 July 2024
© The Korean Society of Food Science and Technology 2024

Abstract
Lipids are crucial for human health and reproduction and include diverse fatty acids (FAs), notably polyunsaturated FAs
(PUFAs) and short-chain FAs (SCFAs) that are known for their health benefits. Bioactivities of PUFAs, including ω-6 and
ω-3 FAs as well as SCFAs, have been widely studied in various tissues and diseases. Epigenetic regulation has been suggested
as a significant mechanism affecting the progression of various diseases, including cancers and metabolic and inflammatory
diseases. Epigenetics encompasses the reversible modulation of gene expression without altering the DNA sequence itself,
mediated by mechanisms such as DNA methylation, histone acetylation, and chromatin remodeling. Bioactive FAs have
been demonstrated to regulate gene expression via epigenetic modifications that are potentially important for modulating
metabolic control and disease risk. This review paper discusses the evidence in support of bioactive FAs, including ω-6 and
ω-3 FAs and SCFAs, eliciting various disease prevention via epigenetic regulation including methylation or acetylation.
Graphical abstract
Diseases/disorders

Obesity/
Long-chain fatty acids Metabolic syndrome

Inflammation Short-chain fatty acids

Omega-6
fatty acids
Acetate,
Cancers Propionate,
Omega-3 Butyrate,
fatty acids Nonalcoholic fatty Valerate
liver diseases

Conjugated Cardiovascular
linoleic acids diseases

Brain disorders
Potential negative health benefits have been reported,
or the evidence is inconclusive

Potential health benefits have been reported

Keywords Disease · Epigenetics · Polyunsaturated fatty acid · Regulation · Short-chain fatty acid

Introduction them, triglycerides are the most common type of lipid found
in the body and in foods. Each triglyceride molecule consists
Human lipids are required to maintain health. Lipids that of glycerol and three attached fatty acids (FAs). FAs vary
are solid at room temperature are fats, and liquids are oils. in the number, arrangement, and configuration of double
Lipids are a diverse group of chemical compounds; among bonds along the hydrocarbon chain (Lehninger Principles of
Biochemistry). The carbon atoms in unsaturated FAs con-
* Byung Hee Kim tain less hydrogen than those of saturated FAs because of
bhkim@sookmyung.ac.kr some unfilled bonds or double bonds. Monounsaturated FAs
Min‑Yu Chung (MUFAs) contain at least 12 carbon atoms with single dou-
chungmy@gangseo.ac.kr ble bonds, whereas polyunsaturated FAs (PUFAs) have two
1 or more double bonds (de Roos et al., 2009; Karapanagio-
Department of Food and Nutrition, Gangseo University,
Seoul 07661, Republic of Korea tidis et al., 2007). Omega-6 (ω-6) and omega-3 (ω-3) are two
2 major classes of PUFAs, and they are considered essential
Department of Food and Nutrition, Sookmyung Women’s
University, Seoul 04310, Republic of Korea

Vol.:(0123456789)
3154 M.-Y. Chung, B.H. Kim

FAs that indicate that FAs should be obtained from foods of enzymes responsible for attaching acetyl groups to the
since they cannot be synthesized or produced by humans. ε-amino group of lysine residues on both histone and non-
Short-chain FAs (SCFAs) contain fewer than six carbon histone proteins. Histone deacetylases (HDAC) catalyze the
atoms, while medium-chain FAs are 6–12 carbons long, and removal of acetyl groups (Berndsen and Denu 2008; Gong
long-chain FAs contain 14 or more carbon atoms. SCFAs are and Miller, 2013; Hodawadekar and Marmorstein, 2007;
microbial metabolites that are formed in the large intestine Marmorstein and Zhou, 2014; Wang et al., 2014). Acety-
by the fermentation of soluble fibers and proteins, and are lation leads to the transformation of condensed chromatin
excreted through feces (Morrison and Preston, 2016; Rios- into a more relaxed structure, making it more accessible and
Covian et al., 2016). SCFAs exhibit several health benefits. facilitating gene expression, whereas deacetylation causes
For example, SCFAs can be absorbed and transported to the chromatin compaction, making genes less accessible for
liver where they suppress cholesterol synthesis, contribut- transcription (Berndsen and Denu, 2008; Liu and Xu, 2004).
ing to decreased serum cholesterol levels (Hara et al. 1999). After being first defined by Waddington (1942), the
Indeed, a meta-analysis by Brown et al. revealed that a diet term ‘epigenetics’ has been increasingly used and has been
rich in soluble fiber elicits small but significant reductions actively studied to investigate its significant role in tumor
in serum cholesterol levels, particularly in the form most development and metastasis (Lee and Kim, 2022). Numerous
related to atherosclerosis and coronary heart disease (Brown studies have demonstrated that changes in histone acetyla-
et al., 1999). Since SCFAs are the products from micro- tion can lead to cancer. Overexpression and increased activ-
bial fermentation that can be absorbed in the large intestine ity of HDACs have been demonstrated to cause tumor devel-
(Bergman, 1990), to achieve health beneficial effect, daily opment and metastasis by regulating histone acetylation and
consumption of foods rich in soluble fiber is important. expression of oncogenes, including p300 and CREBP-bind-
FAs can modify epigenetic landmarks, including histone ing protein (CBP) (Cohen et al., 2011; Sugiura et al. 2021).
acetylation, deacetylation, and methylation, thereby modu- Additionally, HDAC1 catalyzes the deacetylation of H3K27
lating the expression of genes involved in several pathways. at the STAT1 promoter, leading to an immunosuppressive
These pathways are associated with lipid metabolism, insu- environment that promotes the progression of glioma stem-
lin sensitivity, and cancer, and there have been many studies like cells (Sugiura et al., 2021). HDAC Administration has
on epigenetic regulation by functional FAs (Arents et al., approved HDAC inhibitors for cancer treatment drug by the
1991; Goldberg et al., 2007; Li and Li, 2006). The purpose US FDA (Jones et al., 2016). Beyond research on cancer,
of this review paper is to summarize evidence of the crucial studies reveal that epigenetic modifications like DNA meth-
role of bioactive FAs including ω-6 and ω-3 FAs and SCFAs ylation and histone acetylation influence the expression of
in various diseases progression via epigenetic regulation. genes associated with obesity and type 2 diabetes including
INS, GLUT4, ADIPOq, FTO, and C/EBPβ (Kuroda et al.,
2009; Toperoff et al., 2012; Yokomori et al., 1999; Zheng
Epigenetic modifications et al., 2011; Bouchard et al. 2012). Obesity and high-fat diets
can induce epigenetic modifications within adipose tissue,
Epigenetic regulation has been suggested as a significant leading to increased expression of genes encoding inflamma-
mechanism affecting the progression of various diseases, tory cytokines and chemokines (Jung and Kang, 2021), indi-
including cancers and metabolic and inflammatory diseases. cating that inflammation-induced metabolic diseases can be
Epigenetics refers to the phenomenon in which gene expres- epigenetically regulated in overweight or obese individuals.
sion changes reversibly through DNA methylation, histone In addition to DNA methylation and histone acetyla-
acetylation, and chromatin folding without changing the tion/deacetylation, the gut microbiota is critical for epige-
DNA sequence (Lillycrop and Burdge, 2015; Weinhold, netic regulation. In the folate metabolic pathway, folate is
2006). metabolized to tetrahydrofolate, 5-methyltetrahydrofolate
DNA methylation is a process mediated by DNA methyl- (5-MTHF), and 5-formyltetrahydrofolate. The most effective
transferase (DNMT) enzymes, involving the covalent addi- and stable form, 5-MTHF, plays a crucial role in methyla-
tion of a methyl group to the C-5 position of cytosine nucle- tion (Liu et al., 2022) because it serves as a methyl donor
otides. This leads to the production of 5-methylcytosine (Jin by converting homocysteine to methionine in the presence
et al., 2011; Shimizu et al., 2019) that is a methylated form of methionine synthase (MS) and vitamin B12 as a cofactor
of the DNA base cytosine that regulates gene transcription. (Shane, 2008). Homocysteine and S-adenosylhomocysteine
Histone modification involves the covalent attachment (SAH) are important products of SAM methylation by DNA
of functional groups to amino acids, mostly on the N-ter- methyltransferases. SAM-subtracted DNA methylation is
minal histone tails, and includes acetylation, methylation, predominantly directed towards CpG dinucleotides, where
and phosphorylation (Bowman and Poirier, 2015). His- cytosine is converted to 5-methylcytosin. These CpGs tend
tone acetyltransferases (HATs) constitute a diverse group to occur on islands that are abundant in the promoter regions
Epigenetic regulation of fatty acids 3155

of genes that are regulated in their expression by methylation beneficial to the innate immune system in mice (de la Rocha
(Muskiet and Kemperman, 2006). Hence, folate deficiency et al., 2022).
(and other vitamins working as co-factors) or abnormal
metabolism caused by the gut microbiota is associated with Inflammation and cancers
several abnormal conditions, including reductions in DNA
methylation, and this can promote tumor cell proliferation LA intake likely exhibits a negative relationship, as previ-
and growth in the intestinal mucosa (Zheng and Cantley, ously mentioned. LA has also been demonstrated to increase
2019; Rossi et al., 2011). Diet or dietary modifications can the risk of colon cancer (Zock and Katan, 1998). An LA diet
cause dramatic effects on the composition of the gut micro- increases the risk of colon cancer through cytochrome P450
biota, and this act as critical regulators of health and disease (CYP) monooxygenase that converts LA to epoxy octadece-
(Licciardi et al., 2011), therefore, the role of SCFAs, metab- noic acids that are known to act as potent promoters of colon
olites of the gut microbiota, and bioactive FAs is important. tumorigenesis (Zhang et al., 2023). Chronic intake of diet
high in ω-6 PUFA activates FXR expression via CpG dem-
ethylation thereby increasing the genes whose products are
Epigenetic regulation of long‑chain FAs involved in the regulation of bile acid homoeostasis. Mean-
in diseases progression while, the chronic intake of ω-6 PUFA diet caused decreased
adenomatous polyposis Coli (APC) expression through CpG
Omega‑6 FAs hypermethylation, leading to COX-2-mediated inflammation
and thus together contributing to exacerbate colon cancer
Linoleic acid (LA) is an essential FA and an important com- (Romagnolo et al., 2019). In a cross-sectional study using
ponent of human diet. As the major ω-6 FAs, LA is found in young women, the authors found that ω-6 PUFA intake posi-
various plant oils (e.g., corn oil, soybean oil, palm oil) and tively related with truncal fat, and women with greater trun-
butter fat (Mercola and D'Adamo, 2023). Arachidonic acid cal adiposity had lower methylation levels of TNFα promoter
(AA), a derivative of LA, is found in breast milk; therefore, in peripheral white blood cells and higher plasma TNFα
it is added to infant formulas to mimic breast milk (Brenna concentrations (Hermsdorff et al., 2013). Linear regression
et al., 2007). In the first chapter, ω-6 FAs LA, and AA are model in this study suggest that TNFα promoter methylation
discussed in various diseases progression in terms of epige- correlated with ω-6 PUFA intake (Hermsdorff et al., 2013).
netic regulation. The pro-inflammatory property of AA are well known.
AA induces DNA hypermethylation in human and mouse
Obesity and metabolic disorders cultured cells that was observed in PPAR-α and sirtuin 1
as important mediators of FA metabolism and β-oxidation
LA intake has a negative effect on obesity prevention. In a (Silva-Martinez et al., 2016). The AA-induced DNA meth-
cross-sectional study using young women, ω-6 PUFA intake ylation profiles were similar to those described for palmitic
positively associated with truncal fat, body mass index acid, atherosclerosis, diabetes, obesity, and autism (Silva-
(BMI), and waist circumference (Hermsdorff et al., 2013). Martinez et al., 2016). Collectively, ω-6 PUFA including
Some studies have demonstrated that higher ω-6 PUFA may LA and AA could exacerbate the proinflammatory state and
increase the risk of obesity via epigenetic changes particu- further inflammation-related diseases including cancers or
larly in later generations. For example, Massiera et al. found metabolic diseases. Epigenetic mechanisms regulated by ω-6
that diet greater in LA and low in ω-3 FA (α-linolenic acid), PUFA in various diseases states are summarized in Table 1.
and this are similar to the diet common in the US (Ailhaud
et al., 2006; Massiera et al., 2010), change gene expressions, Omega‑3 FAs
and this lead to increase in obesity prevalence. In their study,
exposure to Western diet for four generations caused up to -3 PUFA has long been actively studied to have a number of
two-fold changes in the expression of 22 genes associated health benefits including protection against cardiovascular
with increased adiposity, angiogenesis, and inflammation, diseases (Dyerberg et al., 1975, 1978), anti-inflammatory
as well as an accumulative increase in fat mass over genera- activity (Smith and Guentzel, 2010), anti-obesity activity
tions (Massiera et al. 2010). AA causes gene-specific DNA (Makhoul et al., 2011), improvement of endothelial func-
methylation. Paternal or maternal exposure to AA induces tion (Tousoulis et al., 2014), reduction of blood pressure
cumulative weight gain in offspring generations without an (Cicero et al., 2009), and anti-cancer activity in skin and
increase in liver fat and with decreased hepatic Scd1 pro- oral (Nikolakopoulou et al., 2013). However, the epige-
moter methylation (de la Rocha et al., 2022). This study also netic mechanisms underlying these processes have not been
found that AA exposure across generations was potentially clearly defined.
3156 M.-Y. Chung, B.H. Kim

Table 1  Epigenetic mechanism regulated by ω-6 fatty acids in various disease states
Fatty acids Diseases/states Epigenetic mechanism References

Linoleic acid (LA) Inflammatory states, ↑ FXR expression via CpG demethylation Romagnolo et al. (2019)
cancers ↓ APC expression via CpG hypermethylation Romagnolo et al. (2019)
↓ TNFα promoter methylation Hermsdorff et al. (2013)
Arachidonic acid (AA) Weight gain ↓ hepatic Scd1 promoter methylation de la Rocha et al. (2022)
Inflammation ↑ PPAR-α and sirtuin 1 hypermethylation Silva-Martinez et al. (2016)

Docosahexaenoic acid (DHA) and eicosapentaenoic acid diet during five-year follow-up. They found that the Med-
(EPA) have unique biological effects compared to other Diet with nuts favored hypermethylation of cg01081346 in
FAs, indicating that their unique physical and biochemical CPT1B/CHKB-CPT 1 B genes, and the MedDiet + EVOO
properties are likely attributable to their longer chin length induced hypomethylation of CG17071192 in GNAS/GNA-
and higher number and position of double bonds (Deckel- SAS genes GNAS/GNASAS. Both diets are associated with
baum et al., 2006; Seo et al., 2005). Female Wistar rats were intermediate metabolism and improved expression of genes
fed either a control diet or an experimental diet containing involved in diabetes and inflammatory pathways (Arpon
EPA, DHA, and alpha-linolenic acid (ALA) for two months, et al., 2017). This indicates that diet rich in ω-3 PUFA con-
mated, and continued on their diets during pregnancy. On tribute to the regulation of methylation thereby contributing
gestation days–18–20, the rat placenta and fetal liver were to prevent inflammation and related diseases progression.
isolated, and increased global DNA methylation, decreased Anti-inflammatory effects of ω-3 PUFA via epigenetic regu-
H2A and H2B acetylation, and decreased HAT activity were lation have been widely studied in a number of diseases.
detected in the placenta and fetal liver. In parallel, DNA- Rats fed with higher ω-3 PUFA diet exhibited lower tumor
binding ability of PPAR-α was decreased in fetal liver, incidence compared to non-treated group, and this was asso-
indicating that ω-3 PUFA including DHA, EPA, and ALA ciated to DNA methylation (Huang et al., 2016).
modify DNA methylation and HAT activity and acetylation
thereby preventing the development of fatty liver and pla- Cancers
centa (Ramaiyan and Talahalli, 2018). Another ω-3 PUFA
docosapentaenoic acid (DPA) is a long-chain FA and found Two of the most studied epigenetic modifications, DNA
in fish, red meat and milk of ruminant animals in our diet. methylation and histone acetylation, drive and maintain the
Although the health benefits of DPA have not been exten- cancer phenotype. While DNA methyltransferase (DNMT)
sively studied, evidence exists regarding its effects on liver dysregulation promotes localized hypermethylation of CpG-
health. In the second chapter, ω-3 FAs ALA, EPA, DHA, rich regions, activated histone deacetylases (HDAC) deacet-
and DPA are discussed in various diseases progression in ylate histone tails. These modifications cause the chromatin
terms of epigenetic regulation. conformation to close, suppressing the transcription and
silencing of tumor suppressor genes (Ceccarelli et al., 2020).
Inflammatory state The anticancer properties of EPA are mediated through the
inhibition of HDAC1 and DNMTa, 3A, and 3 B expression,
Higher ω-3 PUFA is associated with lower methylation at thereby promoting the expression of tumor suppressor genes
IL6 promoter, thereby reducing IL-6 gene expression (Ma in hepatocarcinoma cells (Ceccarelli et al., 2020).
et al., 2016). Indeed, Ma et al. found that higher methylation Combined treatment with DHA and butyrate significantly
of IL6 promoter cg01770232 was associated with higher decreased the methylation of pro-apoptotic Bcl2l11, Cideb,
IL-6 plasma concentrations (p = 0.03) and greater IL-6 Dapk1, Ltbr, and Tnfrsf25 genes in HCT-116 colon cancer
gene expression (p = 0.0005). Higher circulating total ω-3 cells compared to untreated controls, suggesting that apop-
PUFA was associated with lower cg01770232 methylation tosis induction by DHA and butyrate is partly mediated
(p = 0.007) and lower IL-6 concentration (p = 0.02) that was through changes in the methylation state of apoptosis-related
analyzed using the data in the Genetics of Lipid Lowering genes (Cho et al., 2014). The anti-CRC effects of EPA and
Drugs and Diet Network (GOLDN) study and the Encyclo- DHA via DNA methylation have been demonstrated in vitro
pedia of DNA Elements (ENCODE) consortium (Ma et al., (Moradi Sarabi et al., 2019). ALA also regulates cancer-
2016). In PREDIMED study, Arpon et al. demonstrated the related epigenetic modifiers by targeting key signaling path-
effect of the Mediterranean diet on DNA methylation. In this ways related to transcriptional regulation, miRNA involve-
study, two diets 1) MedDiet with extra virgin olive oil and ment, stem cell pluripotency, and cellular senescence in
2) MedDiet with nuts) were compared to a low-fat control cancer epigenetics (Ulhe et al., 2023).
Epigenetic regulation of fatty acids 3157

Obesity and metabolic disorders EPA, it was most effective in increasing hepatic DHA levels
and preventing the progression of steatosis by reducing FAS
ω-3 PUFAs have anti-obesity effect by reducing triacylglyc- and fibrosis markers (Hong et al., 2019).
erol (TG) concentration (Dunbar, 2014 – Tousoulis et al., Kaur et al. (2011) demonstrated that DPA treatment
2014), and higher EPA and DHA is associated with attenu- (equivalent to EPA and DHA) significantly reduced SREBP-
ation in TG and C-reactive protein (Makhoul et al., 2011). 1c, 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A reductase
Tremblay et al. investigated the effects of n-3 PUFA supple- (HMG-CoA reductase), Acetyl Coenzyme A Carboxylase
mentation in overweight and obese subjects on DNA methyl- (ACC-1), and FA Synthase (FASn) levels in rat liver cells,
ation-mediated biological pathways (Tremblay et al., 2017). suggesting the possibility of DPA preventing fatty liver.
Genome-wide DNA methylation analysis indicates that fol- However, the epigenetic regulation of DPA has not yet been
lowing 6-month ω-3 PUFA supplementation differentially studied; thus, further studies are warranted.
methylated 308CpG sites. Epigenetic modifications can
influence pathways involved in inflammatory and immune Cardiovascular diseases
responses, lipid metabolism, type 2 diabetes, and cardiovas-
cular diseases (Tremblay et al., 2017). Shen et al. has studied EPA and DHA decrease the risk of cardiovascular disease
of the effects of ω-3 PUFA on leptin promoter and thereby (CVD) (Mozaffarian et al., 2005; Willett, 2007). A num-
regulating leptin gene transcription in obesity. Higher ω-3 ber of studies have demonstrated that ω-3-mediated CVD
PUFA diet induced methylation of CpG island and the protective effect was also mediated via epigenetic modifica-
binding of methyl-CpG binding domain protein 2 (MBD2) tions. In a study by Trembly et al., researchers investigated
and DNA methyltrnasferases (DNMTs) at leptin promoter. the effects of ω-3 fatty acid supplementation on overweight
This was accompanied by hypoacetylation of H3 and H4 and obese individuals. They compared genome-wide DNA
and increased binding of histone deacetylases (HDACs) 1, methylation profiles of blood leukocytes before and after a
2, and 6 to the leptin promoter (Shen et al., 2014). This 6-week intervention with 3 g of ω-3 FAs daily (Tremblay
study suggests that obesity inhibits enzymes that catalyze et al., 2017). The study also revealed correlations between
DNA methylation and histone modification, contributing to changes in DNA methylation profiles of blood leukocytes,
the maintenance of leptin levels within the normal range, particularly at CpG sites within AKT3, ATF1, HDAC4, and
thereby preventing or treating obesity (Shen et al., 2014). IGFBP5 genes, and variations in plasma triglyceride, glu-
In vitro evidence further support that ω-3 PUFA attenuates cose, and cholesterol levels following ω-3 fatty acid supple-
lipid accumulation via HAT inhibition in 3T3-L1 adipocytes mentation (Trembly et al., 2017). This suggests a potential
(Chung et al., 2020). CBP/p300 causes acetylation of sterol insight into the metabolic pathways following ω-3 PUFA
regulatory element-binding protein (SRECP-1c), a transcrip- consumption in patients with CVD. Epigenetic mechanisms
tion factor involved in lipid accumulation, thereby promot- regulated by ω-3 PUFA in various diseases states are sum-
ing the expression of FA synthase, glycerol-3-phosphoate marized in Table 2.
acyltransferase, etc. (Wang et al., 2015; Yang et al., 2001).
Chung et al. demonstrated that treatment with EPA and ω‑6 to ω ‑3 ratio
DHA significantly inhibited in vitro HAT activity, thereby
regulating lipid metabolism-associated gene expression. Essential lipids play important roles in human health. Con-
Similarly, in a study using goat mammary epithelial cells, sume adequate amounts of PUFAs is important, and more
DHA affected lipid metabolism via genome-wide H3K9ac importantly, sources of food which contain favorable ratios
changes, thereby regulating the PDK4-AMPK-SREBP1 of ω-3 PUFA (ALA) to ω-6 PUFA (LA). Increased ratio of
signaling axis, suggesting that DHA regulates mammary ω-6 to ω-3 is associated with increased chronic inflammatory
cell functions through epigenetic changes (Wu et al., 2023). diseases including NAFLD, CVD, obesity, and inflamma-
tory bowel diseases, rheumatoid arthritis, and Alzheimer’s
Nonalcoholic fatty liver diseases disease (Patterson et al., 2012).
While increased levels of ω-6 PUFA and ω-6/ω-3 PUFA
A high dietary intake of sucrose/fructose, cholesterol ratio were recently demonstrated in the cancerous tissues of
and saturated fat is associated with fatty liver in humans colorectal cancer patients (Serini et al., 2016), decreased ω-6
(Abdelmalek et al., 2010; Tiniakos et al., 2010), and high PUFA and ω-6/ω-3 PUFA ratio provide different results. In
fat high calories diet caused nonalcoholic fatty liver diseases the study conducted by Isaac et al., female rats fed a control
(NAFLD) via DNA methylation and histone modifications or different diets containing various ω-6/ω-3 ratio or pro-
(Zaiou et al., 2021), On the other hand, ω-3 PUFAs may con- tein levels for 30 days prior to mating and during pregnancy
tribute to the protection of NAFLD development. Although (Isaac et al., 2018). A low ω-6/ω-3 ratio (~ 1.7) with pro-
DHA was more effective in reducing hepatic FAS levels than tein deficiency in the maternal diet group exhibited higher
3158 M.-Y. Chung, B.H. Kim

Table 2  Epigenetic mechanism regulated by ω-3 fatty acids in various disease states
Fatty acids Diseases/states Epigenetic mechanism References

EPA/DHA/ALA Fatty liver ↑ global DNA methylation Ramaiyan and Talahalli (2018)
↓ H2A and H2B and acetylation Ramaiyan and Talahalli (2018)
↓ IL-6 promoter methylation Ma et al. (2016)
EPA Cancers Inhibition of HDAC1 and DNMT Ceccarelli et al. (2020)
DHA&Butyrate Cancers ↓ methylation of apoptosis-related genes Cho et al. (2014)
EPA&DHA Cancer DNA methylation Moradi Sarabi et al. (2019)
ALA Cancers MicroRNA involvement Ulhe et al. (2023)
EPA&DHA Obesity and metabolic disorders Methylation of leptin promoter, Shen et al. (2014)
hypoacetylation of H3 and H4, increased
HDACs binding
EPA/DHA Obesity and metabolic disorders Inhibition of HAT activity Chung et al. (2020)

levels of H3K9Ac in neurons, H3K4Me2 in astrocytes, and demonstrate the role of CLA in various diseases via epige-
LIF mRNA levels than those in the control diet group. This netic modifications.
emphasizes the importance of dietary ω-3 availability for
the brain, even under a protein-deficient condition, inducing
histone modifications and increasing LIF gene transcription, Epigenetic regulation of SCFAs in diseases
involved in neural cell differentiation and reactivity (Isaac progression
et al., 2018).
SCFAs containing fewer than six carbons are produced
through the fermentation of dietary fiber, carbohydrates,
Conjugated linoleic acid
peptides, and glycoprotein precursors (Frank et al., 2007).
The human gut produces three main short-chain fatty acids
Conjugated LAs (CLAs) are positional and configurational
(SCFAs): acetate (C2), propionate (C3), and butyrate (C4),
isomers of LA (n-6) in which two double bonds are conju-
and these all been have found to reduce allergic (Roberfroid
gated (Ma et al., 1999). CLAs mainly consist of two isomers:
et al., 2010; Sandin et al., 2009; Thompson-Chagoyan et al.,
cis-9,trans-11 (c9,t11)-CLA and trans-10,cis-12 (t10,c12)-
2011) or inflammatory bowel disease (D'Argenio and Maz-
CLA. Various health benefits of CLAs have been reported,
zacca, 1999; Huda-Faujan et al., 2010) patients compared
including anti-cancer, anti-atherosclerotic, and anti-diabetic
to healthy controls. These results suggest that major SCFAs
properties, fat mass reduction, bone mass improvement, and
can be used as markers of disease risk. SCFAs are potential
immune-modulating functions (Dilzer and Park, 2012; Park
histone deacetylase 3 (HDAC3) inhibitors (Li et al. 2018;
and Pariza, 2007). CLAs are naturally found in dairy and
Shakespear et al., 2011; Silva et al. 2018). Similarly, valproic
ruminant fats (Kim et al., 2010; Rule et al., 2002).
acid (VPA), an eight-carbon SCFA, has been used to treat
epilepsy for the last 50 years (Blaheta and Cinatl, 2002).
Obesity The mechanism beyond this is not clearly understood, but
it has been demonstrated to enhance the level of the inhibi-
The anti-obesity effects of CLA have been previously stud- tory neurotransmitter gamma-aminobutyric acid in the brain
ied (Woo et al., 2016). Chaplin et al. studied if CLA-medi- (Johannessen, 2000; Rosenberg, 2007). In recent years, VPA
ated lipid metabolism is regulated via epigenetic modula- has HDAC HDAC-inhibitory activity, resulting in differenti-
tion, including DNA methylation, in adult mice (Chaplin ation, cell death, and apoptosis in malignant cells (Gottlicher
et al., 2017). In their experiment, mice fed a high-fat diet et al. 2001; Kramer et al. 2003; Phiel et al. 2001).
(43% energy from fat) supplemented with 6 mg CLA/day or SCFA concentrations vary in the gut and circulation.
CLA + calcium (12 g/kg calcium) were compared to dietary Estimates for concentrations of major SCFA acetate, pro-
control groups. Chaplin et al. found that gene expression pionate and butyrate range from 70–140 mM in the proxi-
and methylation degree of CpG sites in promoter sequences mal colon, 20–70 mM in the distal colon (Correa-Oliveira
of genes such as adiponectin (Adipoq), stearoyl-CoA et al., 2016) to as low as 0.16–25.05 μM in circulation.
desaturase (Scd1), and FA synthase (Fasn) were altered The ratio of acetate:propionate:butyrate in the gut is about
by CLA + calcium, indicating a healthier metabolic pro- 60:20:20, though the relative concentrations of propionate
file (Chaplin et al., 2017). Further studies are warranted to and butyrate are far lower in the circulation, with butyrate
Epigenetic regulation of fatty acids 3159

circulating at ~ 0.16 μM and propionate circulating at ~ 0.62 leads to increase the binding of hypoxia-inducible factor
μΜ compared to ~ 25 μM for acetate (Parada Venegas et al., 1α (HIF1α) to the hypoxia response element (HRE) of the
2019). Among SCFA, sodium butyrate has been the most IL22 promoter. As a part of this effect, butyrate increases
widely studied as an HDAC inhibitor; however, the mecha- H3K9 acetylation and suppresses H3K9 trimethylation at
nism by which SCFA inhibit HDAC is not fully understood the HRE site of the IL22 promoter (Stein and Riber—Yang
(Stein and Riber, 2023). An in vitro study demonstrated that et al., 2020). Likely, butyrate-mediated anti-inflammatory
sodium butyrate increased histone acetylation by inhibiting activity through downregulation of TNF-α and STAT1, and
HDAC activity in rat hepatoma and HeLa cells (Boffa et al., upregulation of anti-inflammatory IL-19 that are attributed
1978; Sealy and Chalkley, 1978). Since then, it has been to via H3K9 acetylation modulation (Patnala et al., 2017).
suggested that SCFA acts as a GPCR activator (He et al. SCFA reduced production of LPS-induced production of
2020). These actions affect a wide range of cellular pro- proinflammatory ILs and TNF-α in murine macrophage cells
cesses including proliferation, differentiation, chemotaxis, (Liu et al., 2012; Vinolo et al., 2012). As an HDAC inhibi-
gene expression, epigenetic remodeling, cytokine produc- tor, butyrate increases histone H3K9ac at the promoters of
tion, and apoptosis (Correa-Oliveira et al., 2016). Il2, Nos2, and Il12b in macrophages; these effects were not
Many studies have demonstrated the clinical health ben- observed with propionate or acetate (Chang et al. 2014).
efits of SCFAs that are naturally produced in the human gut, One evidence indicates that sodium acetate alleviated
non-toxic, and well tolerated at very high concentrations arsenic-induced sexual dysfunction as well as biochemical
(Parada Venegas et al., 2019). In randomized controlled or and histological alterations (Besong et al., 2023), and this
clinical trials using SCFAs, SCFAs treatment effects were were accompanied acetate-driven downregulation of HDAC
approved in inflammatory bowel and gastrointestinal disor- activity, and similarly, acetate also reduced arsenic-mediated
ders (Demehri et al., 2016; Hustoft et al., 2017; Mazzawi male reproductive toxicity via suppression of HDAC and
et al. 2019), diabetes and obesity (Canfora et al. 2017; van uric acid-driven NFκB-Inos-NO-involved responses (Besong
der Beek et al. 2018; Zhao et al. 2018), cancer (Hague et al. et al., 2023).
1995), prematurity (Underwood et al., 2009), neurological Valerate has been studied as a potential inhibitor of auto-
disease (Erny et al. 2015), and psychosocial stress (Burokas immune and inflammatory diseases (Luu et al., 2019). They
et al., 2017). The preventive effects of SCFA on epigenetic found that valerate that possesses HDAC inhibitory activ-
regulation have been demonstrated in various disease mod- ity, contributes to the suppression of IL-17A expression,
els. In the third chapter, SCFA acetate, propionate, butyrate, leading to the amelioration of autoimmune inflammation in
and valerate (C5) are discussed in various disease progres- the central nervous system. Taken together, butyrate likely
sions in terms of epigenetic regulation. plays a crucial role in suppressing inflammation via various
mechanisms, and acetate, propionate, and valerate exert anti-
Inflammatory states inflammatory effects via HDAC inhibition.

The anti-inflammatory effects and the redirection of the Cancers

innate immune response regulated by SCFAs have been
widely studied. SCFA, including butyrate and propion- HDAC removes acetyl groups from amino acids on histones
ate, exert their effects through toll-like receptor responses and is known to be a critical target for cancer cells via the
in vitro, thereby regulating NF-κB and TNF-α that are simi- induction of apoptosis and/or cell cycle arrest (Akimova
lar to the small-molecule HDAC inhibitor, trichostatin A et al., 2012). Therefore, HDAC inhibition has been recog-
(TSA) (Lin et al., 2015). An in vitro study also found that nized as a preventive strategy against inflammation-related
butyrate attenuated the production of proinflammatory mole- diseases, including cancer. As a natural HDAC inhibitor,
cules, such as NO, IL-6, and IL-12, in bone marrow-derived SCFA also play a role in the expression of various anti-
macrophages and macrophages from the lamina propria of inflammatory genes within immune cells (Kim, 2018; Park
the colon. Similarly, oral administration of butyrate to mice et al. 2015), mimicking the action of valproic acid, such as
decreased the levels of these proinflammatory molecules inhibition of tight junction degradation and translocation of
in colon lamina propria macrophages that likely occurred NFκB (Wang et al., 2011).
through the inhibition of HDACs (Chang et al., 2014). Direct evidence of the anticarcinogenic effects of SCFAs
Butyrate also promotes the production of IL-22, an anti- has been demonstrated in various experimental models,
inflammatory cytokine, by G-protein receptor 41-medi- including humans. Propionate plays a crucial role in reduc-
ated signaling and HDAC inhibition that were observed in ing cell proliferation, inducing apoptosis, and suppressing
mice fed butyrate in drinking water, as well as in CD4 + T tumor progression that is attributed to significant activation
cells and innate lymphoid cells. The mechanism beyond it of FFAR2 in colorectal adenocarcinoma (Bindels et al.,
was attributed to butyrate-mediated histone modification 2013, 2012). Butyrate and valerate also can cause increased
3160 M.-Y. Chung, B.H. Kim

production of certain effector molecules including CD25, oral supplementation with acetate affects body weight man-
IFN-γ, and TNF-α among CAR T-cells and cytotoxic T cells agement and remains controversial owing to the lack and
(CTLs), leading to significant increases in anti-tumor reac- inconsistency of data (Hernandez et al., 2019).
tivity and thereby improving therapeutic outcomes in cancer In a study conducted by Remely et al., methylation of the
patients (Luu et al. 2021). Taken together, SCFAs are likely promoter region of FFAR3 was analyzed and compared in
to exert their anti-carcinogenic effects through their anti- patients with obesity and type 2 diabetes and their controls
inflammatory activity. Hence, further studies are warranted (lean control group) with four-month intervention. They
to investigate the role of SCFA-mediated epigenetic regula- found decreased butyryl-CoA:acetate CoA transferase gene
tion in cancer prevention. and significantly lower methylation of the FFAR3 promoter
in obese and diabetic patients, and this was increased during
Obesity and metabolic disorders the intervention, indicating a significant correlation between
FFAR3 methylation and BMI, as well as LINE-3, a marker
Several studies have demonstrated the protective effects of of global methylation (Remely et al., 2014).
SCFAs against obesity and diabetes via epigenetic modula-
tion; however, the mechanisms underlying these effects vary. Brain diseases
Rumberger et al. investigated that both butyrate and propi-
onate stimulated lipolysis in mouse adipocytes, mimicking A cross-sectional study of elderly individuals found that
the action of the HDAC inhibitor trichostatin A (Rumberger brain amyloid deposition and endothelial dysfunction posi-
et al., 2014). In a streptozotocin-mediated type 2 diabetes tively correlated with blood acetate levels and negatively
rat model, intraperitoneal injection of sodium butyrate correlated with butyrate levels (Marizzoni et al., 2020). In a
(i.p. injection) significantly reduced plasma glucose levels, study conducted by Xiang, the authors investigated the fecal
insulin resistance, and liver steatosis that were mediated by microbiome and levels of SCFAs in the serum and brain of
HDAC inhibition and histone H3 hyperacetylation in the a rat model of chronic unpredictable mild stress (CUMS)
liver (Khan and Jena, 2016). Similarly, sodium butyrate (oral and found significantly decreased butyrate in the brains of
administration) significantly decreased obesity, improved CUMS rats (Li et al., 2021). This suggests that SCFAs are
glucose tolerance, and reduced fat deposition in the skeletal detected not only in the gut but also in blood circulation,
muscle of mice fed a high-fat diet, likely through sodium playing a role in brain function, development, and inflamma-
butyrate-mediated HDAC inhibition. In this study, H3K9 tion. Stein and Riber demonstrated that oral sodium butyrate
acetylation was increased at the promoters of Adipor1 decreased beta-amyloid levels and improved cognitive mem-
and Adipor2 that encode adiponectin receptors, and Ucp2 ory in a mouse model of early Alzheimer’s disease (Stein
(uncoupling protein 2) and Ucp3, thereby increasing mito- and Riber, 2023).
chondrial thermogenesis and β-oxidation in HFD-fed mice Sodium butyrate-mediated preventive effects against
with sodium butyrate administration (Hong et al., 2016). brain diseases are likely attributable to its ability to modu-
Another line of evidence indicates that sodium butyrate late histone acetylation. In primary cortical astrocyte cul-
decreases glucose level and Hba1c, favoring insulin sensi- tures, sodium butyrate increases brain-derived neurotrophic
tivity, thereby reducing the risk of diabetes development in factor (BDNF) and glial cell line-derived neurotrophic fac-
juvenile diabetic rats (Khan and Jena, 2014), and similarly in tor (GDNF) transcription, accompanied by an increase in
a high-fat diet-induced obese mouse model (Henagan et al., histone H3 acetylation at the GDNF promoter (Wu et al.,
2015). 2008). In another study, sodium butyrate partially prevented
Acetate-containing foods include dairy products, dried apoptotic cell death caused by the mitochondrial toxin
pasta, bread, liquid eggs, salt substitutes, coffee, processed 1-methyl-4-phenylpyridinium, likely due to a significant
meat, smoked/frozen fish, ethanol, and vinegar (Israel increase in histone H3 acetylation in human neuroblastoma-
et al., 1994; Lim et al., 2016). Sodium acetate supple- derived and rat mesencephalon-derived cell lines (Kidd and
mentation significantly suppresses HFD-induced weight Schneider, 2010). Additionally, in a study using a preseni-
gain compared to that in HFD control mice (Kondo et al., lin-1 and presenilin-2 conditional double-knockout mouse
2009; Lu et al., 2016). The prevention of weight gain was model, butyrate significantly increased neurogenesis in the
attributed to the action of acetate through binding to the subgranular zone of the dentate gyrus, restored contextual
G-protein-coupled receptors GPR43 (FFAR2) and GPR41 memory, and reversed dysregulated histone acetylation in
(FFAR3) that are characterized by increases in adipose tis- the hippocampus and cortex (Cao et al., 2018). Several
sue and reductions in the colon. These factors contribute to pieces of evidence have been found in a study on Parkinson’s
increased TG hydrolysis and FFA oxidation (through UCP-2 disease. In a mouse model of Parkinson’s disease, butyrate
and CPT-1 gene expression) in the adipose tissue and liver prevented the DNA damage caused by α-synuclein, pos-
(Kondo et al. 2009; Lu et al., 2016). However, long-term sibly by upregulating DNA repair genes, and in cell lines
Epigenetic regulation of fatty acids 3161

Table 3  Epigenetic mechanism regulated by SCFA in various disease states

Fatty acids Diseases/states Epigenetic mechanism References

Acetate Inflammatory states, diabetes, obesity HDAC inhibition, Parada Venegas et al. (2019), Canfora et al.
GPR43/GPR41 activation (2017), Zhao et al. (2018), and Besong et al.
(2023)
Propionate Inflammatory states, cancers HDAC inhibition, FFAR2 activation Parada Venegas et al. (2019), Bindels et al.
(2012, 2013)
Obesity Histone acetylation Rumberger et al. (2014)
Butyrate Inflammatory states, cancers ↑Histone acetylation, HDAC inhibition Chang et al. (2014)
Inflammatory states ↑ H3K9 acetylation Yang et al. (2020), Pantnala et al. (2017), and
↓H3K9 trimethylation at IL22 promoter Chang et al. (2014)
Obesity and metabolic disorders HDAC inhibition, H3 hyperacetylation Rumberger et al. (2014) and Khan and Jena
(2016
Obesity and metabolic disorders ↑ H3K9 acetylation at the promoter of Hong et al. (2016)
Adipor1 and Adipor2
Brain diseases ↑ histone H3 acetylation at GDNF promoter Wu et al. (2008), Kidd and Schneider (2010),
and Sharma et al. (2015)
Valerate Inflammatory states HDAC inhibition Luu et al. (2019)

it rescued the decrease in histone H3 acetylation that was physiology and disease susceptibility. It would be worth-
mediated by α-synuclein (Paiva et al., 2017). Additionally, while to conduct additional studies on the effects of epige-
sodium butyrate (i.p.) attenuated motor deficits, increased netic modifications induced by various functional/bioactive
dopamine levels in the striatum, lowered oxidative stress, FA on gene function in various tissues.
and increased striatal global histone H3 acetylation levels
Acknowledgements This work was supported by a National Research
in a rat model of 6-hydroxydopamine-induced experimental Foundation of Korea (NRF) grant funded by the Korean government
Parkinson’s disease (Sharma et al., 2015). The epigenetic (MSIT) [No. 2019R1F1A1053604].
mechanisms regulated by SCFAs in various disease states
are summarized in Table 3. Declarations
In conclusion, the sensitivity of epigenetic regulation to
Conflict of interest On behalf of all authors, the corresponding author
environmental factors, such as diet, highlights its dynamic states that there is no conflict of interest.
and potentially reversible nature (Lillycrop and Burdge,
2015; Weinhold, 2006). Growing evidence suggests that
alterations in epigenetic modifications, including increased
DNA methylation and histone acetylation triggered by vari- References
ous factors, contribute to the progression of certain diseases,
and there is an increasing interest in foods that can alleviate Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson
these effects. RJ, Diehl AM Nonalcoholic Steatohepatitis Clinical Research
Network. Increased fructose consumption is associated with
The field of food research finds epigenetics particularly fibrosis severity in patients with nonalcoholic fatty liver disease.
attractive due to its potential to elucidate how dietary com- Hepatology. 51: 1961-1971 (2010)
ponents, such as FAs, can induce reversible modifications in Ailhaud G, Massiera F, Weoill P, Legrand P, Alessandri JM, Guesnet
gene expression. This review paper summarizes the evidence P. Temporal changes in dietary fats: role of n-6 polyunsaturated
fatty acids in excessive adipose tissue development and relation-
that FAs affect epigenetic processes during the progression ship to obesity. Progress in Lipid Research. 45: 203-236 (2006)
of various diseases. A number of studies have demonstrated Akimova T, Beier UH, Liu Y, Wang L, Hancock WW. Histone/protein
that ω-3 PUFA majorly regulated DNA methylation as well deacetylases and T-cell immune responses. Blood. 119: 2443-
as histone modifications, leading to various disease progres- 245 (2012)
Arents G, Burlingame RW, Wang BC, Love WE, Moudrianakis EN.
sion whereas the studies from ω-6 PUFA were inconclusive. The nucleosomal core histone octamer at 3.1 A resolution: a
Alterations in dietary fat consumption can induce epigenetic tripartite protein assembly and a left-handed superhelix. Proceed-
regulation of specific genes. SFA also regulate epigenetic ings of the National Academy of Sciences of the United States of
changes in transcription and metabolism that indirectly or America. 88: 10148-10152 (1991)
Arpon A, Milagro FI, Razquin C, Corella D, Estruch R, Fito M, Marti
directly alleviate several diseases. This review highlights A, Martinez-Gonzalez MA, Ros E, Salas-Salvado J, Riezu-Boj JI,
the importance of integrating dietary factor (fat)-micro- Martinez JA. Impact of consuming extra-virgin olive oil or nuts
bial metabolism-epigenetics to modulate cell and tissue within a Mediterranean diet on DNA methylation in peripheral
3162 M.-Y. Chung, B.H. Kim

white blood cells within the PREDIMED-Navarra randomized acid and calcium supplementation in adult mice. European Jour-
controlled trial: a role for dietary lipids. Nutrients. 10: 15 (2017) nal of Nutrition. 56: 879-891 (2017).
Bergman EN. Energy contributions of volatile fatty acids from the Cho Y, Turner ND, Davidson LA, Chapkin RS, Carroll RJ, Lupton JR.
gastrointestinal tract in various species. Physiological Reviews. Colon cancer cell apoptosis is induced by combined exposure
70: 567-590 (1990). to the n-3 fatty acid docosahexaenoic acid and butyrate through
Berndsen CE, Denu JM. Catalysis and substrate selection by histone/ promoter methylation. Experimental Biology and Medicine
protein lysine acetyltransferases. Current Opinion in Structural (Maywood, N. J.). 239: 302-310 (2014)
Biology. 18: 682-689 (2008) Cicero AF, Ertek S, Borghi C. Omega-3 polyunsaturated fatty acids:
Besong EE, Akhigbe TM, Obimma JN, Obembe OO, Akhigbe RE. their potential role in blood pressure prevention and manage-
Acetate abates arsenic-induced male reproductive toxicity by ment. Current Vascular Pharmacology. 7: 330-337 (2009)
suppressing HDAC and uric acid-driven oxido-inflammatory Cohen I, Poreba E, Kamieniarz K, Schneider R. Histone modifiers
NFkB/iNOS/NO response in rats. Biological Trace Element in cancer: friends or foes? Genes & Cancer. 2: 631-647 (2011)
Research. 1-16 (2023) Correa-Oliveira R, achi JL, Vieira A, Sato FT, Vinolo MA. Regulation
Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: physiopatho- of immune cell function by short-chain fatty acids. Clinical &
logical relevance and therapeutic prospects. Trends in Pharma- Translational Immunology. 5: e73 (2016)
cological Sciences. 34: 226-232 (2013) Chung S, Han J, Chung MY. Hypolipidemic effect of omega-3 fatty
Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin acids in 3T3-L1 preadipocytes via inhibition of histone acetyl-
JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG, Sonveaux transferase activity. Journal of the Korean Society of Food Sci-
P, Cani PD, Delzenne NM. Gut microbiota-derived propionate ence and Nutrition. 49: 1319-1327 (2020)
reduces cancer cell proliferation in the liver. British Journal of D'Argenio G, Mazzacca G. Short-chain fatty acid in the human colon.
Cancer. 107: 1337-1344 (2012). Relation to inflammatory bowel diseases and colon cancer.
Blaheta RA, Cinatl J, Jr. Anti-tumor mechanisms of valproate: a novel Advances in Experimental Medicine and Biology. 472: 149-158
role for an old drug. Medicinal Research Reviews. 22: 492-511 (1999)
(2002) de la Rocha C, Rodriguez-Rios D, Ramirez-Chavez E, Molina-Torres
Boffa LC, Vidali G, Mann RS, Allfrey VG. Suppression of histone J, de Jesus Flores-Sierra J, Orozco-Castellanos LM, Galvan-Chia
deacetylation in vivo and in vitro by sodium butyrate. Journal of JP, Sanchez AV, Zaina S, Lund G. Cumulative metabolic and
Biological Chemistry. 253: 3364-3366 (1978) epigenetic effects of paternal and/or maternal supplementation
Bouchard L, Hivert MF, Guay SP, St-Pierre J, Perron P, Brisson D. with arachidonic acid across three consecutive generations in
Placental adiponectin gene DNA methylation levels are associ- mice. Cells. 11: 1057 (2022)
ated with mothers' blood glucose concentration. Diabetes. 61: de Roos B, Mavrommatis Y, Brouwer IA. Long-chain n-3 polyun-
1272-1280 (2012) saturated fatty acids: new insights into mechanisms relating to
Bowman GD, Poirier MG. Post-translational modifications of histones inflammation and coronary heart disease. British Journal of Phar-
that influence nucleosome dynamics. Chemical Reviews. 115: macology. 158: 413-428 (2009)
2274-2295 (2015) Deckelbaum RJ, Worgall TS, Seo T. n-3 fatty acids and gene expres-
Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA, sion. The American Journal of Clinical Nutrition. 83(6 Suppl):
Arterburn LM. Docosahexaenoic and arachidonic acid concen- 1520S-1525S (2006)
trations in human breast milk worldwide. The American Journal Demehri FR, Frykman PK, Cheng Z, Ruan C, Wester T, Nordenskjold
of Clinical Nutrition. 85: 1457-1464 (2007) A, Kawaguchi A, Hui TT, Granstrom AL, Funari V, Teitelbaum
Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering DH, Group HCR. Altered fecal short chain fatty acid composition
effects of dietary fiber: a meta-analysis. The American Journal in children with a history of Hirschsprung-associated enterocol-
of Clinical Nutrition. 69: 30-42 (1999) itis. Journal of Pediatric Surgery. 51: 81-86 (2016)
Burokas A, Arboleya S, Moloney RD, Peterson VL, Murphy K, Clarke Dilzer A, Park Y. Implication of conjugated linoleic acid (CLA) in
G, Stanton C, Dinan TG, Cryan JF. Targeting the microbiota- human health. Critical Reviews in Food Science and Nutrition.
gut-brain axis: prebiotics have anxiolytic and antidepressant-like 52: 488-513 (2012)
effects and reverse the impact of chronic stress in mice. Biologi- Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma
cal Psychiatry. 82: 472-487 (2017) lipids in Greenland Eskimos. The American Journal of Clinical
Canfora EE, van der Beek CM, Jocken JWE, Goossens GH, Holst Nutrition. 28: 958-966 (1975)
JJ, Olde Damink SWM, Lenaerts K, Dejong CHC, Blaak EE. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapen-
Colonic infusions of short-chain fatty acid mixtures promote taenoic acid and prevention of thrombosis and atherosclerosis?
energy metabolism in overweight/obese men: a randomized Lancet. 2(8081): 117-119 (1978)
crossover trial. Scientific Reports. 7: 2360 (2017) Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O,
Cao T, Zhou X, Zheng X, Cui Y, Tsien JZ, Li C, Wang H. Histone David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch
Deacetylase Inhibitor Alleviates the Neurodegenerative Pheno- T, Schwierzeck V, Utermohlen O, Chun E, Garrett WS, McCoy
types and Histone Dysregulation in Presenilins-Deficient Mice. KD, Diefenbach A, Staeheli P, Stecher B, Amit I, Prinz M. Host
Frontiers in Aging Neuroscience. 15: 137 (2018) microbiota constantly control maturation and function of micro-
Ceccarelli V, Ronchetti S, Marchetti MC, Calvitti M, Riccardi C, Grig- glia in the CNS. Nature Neuroscience. 18: 965–977 (2015)
nani F, Vecchini A. Molecular mechanisms underlying eicosap- Fernando W, Martins IJ, Morici M, Bharadwaj P, Rainey-Smith SR,
entaenoic acid inhibition of HDAC1 and DNMT expression and Lim WLF, Martins RN. Sodium butyrate reduces brain amyloid-
activity in carcinoma cells. Biochimica et Biophysica Acta-Gene beta levels and improves cognitive memory performance in an
Regulatory Mechanisms. 1863: 194481 (2020) Alzheimer's disease transgenic mouse model at an early disease
Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabo- stage. Journal of Alzheimer's Disease. 74: 91-99 (2020)
lite butyrate regulates intestinal macrophage function via histone Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N,
deacetylase inhibition. Proceedings of the National Academy of Pace NR. Molecular-phylogenetic characterization of microbial
Sciences of the United States of America. 111: 2247-2252 (2014) community imbalances in human inflammatory bowel diseases.
Chaplin A, Palou A, Serra F. Methylation analysis in fatty-acid-related Proceedings of the National Academy of Sciences of the United
genes reveals their plasticity associated with conjugated linoleic States of America. 104: 13780-13785 (2007)
Epigenetic regulation of fatty acids 3163

Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes in progeny neural cells and favors leukemia inhibitory factor
shape. Cell. 128: 635-638 (2007) genetranscription. The Journal of Nutritional Biochemistry. 55:
Gong F, Miller KM. Mammalian DNA repair: HATs and HDACs make 229-242 (2018)
their mark through histone acetylation. Mutation Research. 750: Israel Y, Orrego H, Carmichael FJ. Acetate-mediated effects of etha-
23-30 (2013) nol. Alcohol, Clinical and Experimental Research. 18: 144-148
Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, (1994)
Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic Jin B, Li Y, Robertson KD. DNA methylation: superior or subordi-
acid defines a novel class of HDAC inhibitors inducing differ- nate in the epigenetic hierarchy? Genes & Cancer. 2: 607-617
entiation of transformed cells. EMBO J. 20: 6969-6978 (2001) (2011)
Hague A, Elder DJ, Hicks DJ, Paraskeva C. Apoptosis in colorectal Johannessen CU. Mechanisms of action of valproate: a commentatory.
tumour cells: induction by the short chain fatty acids butyrate, Neurochemistry International. 37: 103-110 (2000)
propionate and acetate and by the bile salt deoxycholate. Inter- Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for ther-
national Journal of Cancer. 60: 400-406 (1995) apy. Nature Reviews Genetics. 17: 630-641 (2016)
Hara H, Haga S, Aoyama Y, Kiriyama S. Short-chain fatty acids sup- Jung BC, Kang S. Epigenetic regulation of inflammatory factors in
press cholesterol synthesis in rat liver and intestine. The Journal adipose tissue. Biochimica et Biophysica Acta - Molecular and
of Nutrition. 129: 942-948 (1999) Cell Biology of Lipids. 1866: 159019 (2021)
He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Karapanagiotidis IT, Bell MV, Little DC, Yakupitiyage A. Replacement
Li X, Zhang S, Zhu L. Short-chain fatty acids and their associa- of dietary fish oils by alpha-linolenic acid-rich oils lowers omega
tion with signalling pathways in inflammation, glucose and lipid 3 content in tilapia flesh. Lipids. 42: 547-559 (2007)
metabolism. International Journal of Molecular Sciences. 21: Kaur G, Sinclair AJ, Cameron-Smith D, Barr DP, Molero-Navajas JC,
6356 (2020) Konstantopoulos N. Docosapentaenoic acid (22:5n-3) down-reg-
Henagan TM, Stefanska B, Fang Z, Navard AM, Ye J, Lenard NR, ulates the expression of genes involved in fat synthesis in liver
Devarshi PP. Sodium butyrate epigenetically modulates high-fat cells. Prostaglandins, Leukotrienes and Essential Fatty Acids.
diet-induced skeletal muscle mitochondrial adaptation, obesity 85: 155-161 (2011)
and insulin resistance through nucleosome positioning. British Khan S, Jena G. Sodium butyrate reduces insulin-resistance, fat accu-
Journal of Pharmacology. 172: 2782-2798 (2015) mulation and dyslipidemia in type-2 diabetic rat: a comparative
Hermsdorff HH, Mansego ML, Campion J, Milagro FI, Zulet MA, study with metformin. Chemico-Biological Interactions. 254:
Martinez JA. TNF-alpha promoter methylation in peripheral 124-134 (2016)
white blood cells: relationship with circulating TNFalpha, trun- Khan S, Jena GB. Protective role of sodium butyrate, a HDAC inhibi-
cal fat and n-6 PUFA intake in young women. Cytokine. 64: tor on beta-cell proliferation, function and glucose homeostasis
265-271 (2013) through modulation of p38/ERK MAPK and apoptotic pathways:
Hernandez MAG, Canfora EE, Jocken JWE, Blaak EE. The short-chain study in juvenile diabetic rat. Chemico-Biological Interactions.
fatty acid acetate in body weight control and insulin sensitivity. 213: 1-12 (2014)
Nutrients. 11: 1943 (2019) Kidd SK, Schneider JS. Protection of dopaminergic cells from
Hodawadekar SC, Marmorstein R. Chemistry of acetyl transfer by his- ­MPP+-mediated toxicity by histone deacetylase inhibition. Brain
tone modifying enzymes: structure, mechanism and implications Research. 1354: 172-178 (2010)
for effector design. Oncogene. 26: 5528-5540 (2007) Kim CH. Microbiota or short-chain fatty acids: which regulates dia-
Hong J, Jia Y, Pan S, Jia L, Li H, Han Z, Cai D, Zhao R. Butyrate betes? Cellular and Molecular Immunology. 15: 88-91 (2018)
alleviates high fat diet-induced obesity through activation of Kim JH, Pan JH, Park HG, Yoon HG, Kwon OJ, Kim TW, Shin DH,
adiponectin-mediated pathway and stimulation of mitochondrial Kim YJ. Functional comparison of esterified and free forms of
function in the skeletal muscle of mice. Oncotarget. 7: 56071- conjugated linoleic acid in high-fat-diet-induced obese C57BL/6J
56082 (2016) mice. Journal of Agricultural and Food Chemistry. 58: 11441-
Hong L, Zahradka P, Cordero-Monroy L, Wright B, Taylor CG. Dietary 11447 (2010)
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) Kondo T, Kishi M, Fushimi T, Kaga T. Acetic acid upregulates the
operate by different mechanisms to modulate hepatic steato- expression of genes for fatty acid oxidation enzymes in liver
sis and hyperinsulemia in fa/fa Zucker rats. Nutrients. 11: 917 to suppress body fat accumulation. Journal of Agricultural and
(2019) Food Chemistry. 57: 5982-5986 (2009)
Huang Q, Wen J, Chen G, Ge M, Gao Y, Ye X, Liu C, Cai C. Omega-3 Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J,
polyunsaturated fatty acids inhibited tumor growth via preventing Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher
the decrease of genomic DNA methylation in colorectal cancer M. The histone deacetylase inhibitor valproic acid selectively
rats. Nutrition and Cancer. 68: 113-119 (2016) induces proteasomal degradation of HDAC2. EMBO J. 22: 3411-
Huda-Faujan N, Abdulamir AS, Fatimah AB, Anas OM, Shuhaimi M, 3420 (2003)
Yazid AM, Loong YY. The impact of the level of the intestinal Kuroda A, Rauch TA, Todorov I, Ku HT, Al-Abdullah IH, Kandeel
short chain Fatty acids in inflammatory bowel disease patients F, Mullen Y, Pfeifer GP, Ferreri K. Insulin gene expression is
versus healthy subjects. The Open Biochemistry Journal. 4: regulated by DNA methylation. PLoS One. 4: e6953 (2009)
53-58 (2010) Lee JE, Kim MY. Cancer epigenetics: Past, present and future. Semi-
Hustoft TN, Hausken T, Ystad SO, Valeur J, Brokstad K, Hatlebakk JG, nars in Cancer Biology. 83: 4-14 (2022)
Lied GA. Effects of varying dietary content of fermentable short- Li H, Xiang Y, Zhu Z, Wang W, Jiang Z, Zhao M, Cheng S, Pan F, Liu
chain carbohydrates on symptoms, fecal microenvironment, and D, Ho RCM, Ho CSH. Rifaximin-mediated gut microbiota regu-
cytokine profiles in patients with irritable bowel syndrome. Neu- lation modulates the function of microglia and protects against
rogastroenterology & Motility. 29: e12969 (2017) CUMS-induced depression-like behaviors in adolescent rat. Jour-
Isaac AR, da Silva EAN, de Matos RJB, Augusto RL, Moreno nal of Neuroinflammation. 18: 254 (2021)
GMM, Mendonca IP, de Souza RF, Cabral-Filho PE, Rod- Li M, van Esch B, Wagenaar GTM, Garssen J, Folkerts G, Henricks
rigues CG, Goncalves-Pimentel C, Rodrigues MCA, da Sil- PAJ. Pro- and anti-inflammatory effects of short chain fatty acids
veira Andrade-da-Costa BL. Low omega-6/omega-3 ratio in on immune and endothelial cells. European journal of pharma-
a maternal protein-deficient diet promotes histone-3 changes cology. 831: 52-59 (2018)
3164 M.-Y. Chung, B.H. Kim

Li RW, Li C. Butyrate induces profound changes in gene expression Marmorstein R, Zhou MM. Writers and readers of histone acetyla-
related to multiple signal pathways in bovine kidney epithelial tion: structure, mechanism, and inhibition. Cold Spring Harbor
cells. BMC Genomics. 7: 234 (2006) Perspectives in Biology. 6: a018762 (2014)
Licciardi PV, Ververis K, Karagiannis TC. Histone deacetylase inhi- Massiera F, Barbry P, Guesnet P, Joly A, Luquet S, Moreilhon-Brest
bition and dietary short-chain Fatty acids. ISRN Allergy. 2011: C, Mohsen-Kanson T, Amri EZ, Ailhaud G. A Western-like fat
869647 (2011) diet is sufficient to induce a gradual enhancement in fat mass over
Lillycrop KA, Burdge GC. Maternal diet as a modifier of offspring generations. Journal of Lipid Research. 51: 2352-2361 (2010)
epigenetics. Journal of Developmental Origins of Health and Mazzawi T, Hausken T, Hov JR, Valeur J, Sangnes DA, El-Salhy M,
Disease. 6: 88-95 (2015) Gilja OH, Hatlebakk JG, Lied GA. Clinical response to fecal
Lim J, Henry CJ, Haldar S. Vinegar as a functional ingredient to microbiota transplantation in patients with diarrhea-predominant
improve postprandial glycemic control-human intervention irritable bowel syndrome is associated with normalization of
findings and molecular mechanisms. Molecular Nutrition & fecal microbiota composition and short-chain fatty acid levels.
Food Research. 60: 1837-1849 (2016) Scandinavian Journal of Gastroenterology. 54: 690-699 (2019)
Lin MY, de Zoete MR, van Putten JP, Strijbis K. Redirection of Mercola J, D'Adamo CR. Linoleic acid: a narrative review of the effects
epithelial immune responses by short-chain fatty acids through of increased intake in the standard American diet and associa-
inhibition of histone deacetylases. Frontiers in Immunology. tions with chronic disease. Nutrients. 15: 3129 (2023)
6: 554 (2015) Moradi Sarabi M, Mohammadrezaei Khorramabadi R, Zare Z, Eftekhar
Liu C, Xu D. Inhibition of histone deacetylases. Methods in Molecu- E. Polyunsaturated fatty acids and DNA methylation in colorectal
lar Biology. 287: 87-97 (2004) cancer. World Journal of Clinical Cases. 7: 4172-4185 (2019)
Liu H, Liao C, Wu L, Tang J, Chen J, Lei C, Zheng L, Zhang C, Liu Morrison DJ, Preston T. Formation of short chain fatty acids by the
YY, Xavier J, Dai L. Ecological dynamics of the gut microbi- gut microbiota and their impact on human metabolism. Gut
ome in response to dietary fiber. ISME J. 16: 2040-2055 (2022) Microbes. 7: 189-200 (2016)
Liu L, Li L, Min J, Wang J, Wu H, Zeng Y, Chen S, Chu Z. Butyrate Mozaffarian D, Ascherio A, Hu FB, Stampfer MJ, Willett WC, Siscov-
interferes with the differentiation and function of human ick DS, Rimm EB. Interplay between different polyunsaturated
monocyte-derived dendritic cells. Cellular immunology. 277: fatty acids and risk of coronary heart disease in men. Circulation.
66-73 (2012) 111: 157-164 (2005)
Lu Y, Fan C, Li P, Lu Y, Chang X, Qi K. Short chain fatty acids Muskiet FA, Kemperman RF. Folate and long-chain polyunsaturated
prevent high-fat-diet-induced obesity in mice by regulating fatty acids in psychiatric disease. The Journal of Nutritional Bio-
G protein-coupled receptors and gut microbiota. Scientific chemistry. 17: 717-727 (2006)
Reports. 6: 37589 (2016) Nikolakopoulou Z, Nteliopoulos G, Michael-Titus AT, Parkinson EK.
Luu M, Pautz S, Kohl V, Singh R, Romero R, Lucas S, Hofmann J, Omega-3 polyunsaturated fatty acids selectively inhibit growth in
Raifer H, Vachharajani N, Carrascosa LC, Lamp B, Nist A, neoplastic oral keratinocytes by differentially activating ERK1/2.
Stiewe T, Shaul Y, Adhikary T, Zaiss MM, Lauth M, Steinhoff Carcinogenesis. 34: 2716-2725 (2013)
U, Visekruna A. The short-chain fatty acid pentanoate sup- Paiva I, Pinho R, Pavlou MA, Hennion M, Wales P, Schutz AL, Rajput
presses autoimmunity by modulating the metabolic-epigenetic A, Szego EM, Kerimoglu C, Gerhardt E, Rego AC, Fischer A,
crosstalk in lymphocytes. Nature Communications. 10: 760 Bonn S, Outeiro TF. Sodium butyrate rescues dopaminergic
(2019) cells from alpha-synuclein-induced transcriptional deregulation
Luu M, Riester Z, Baldrich A, Reichardt N, Yuille S, Busetti A, and DNA damage. Human Molecular Genetics. 26: 2231-2246
Klein M, Wempe A, Leister H, Raifer H, Picard F, Muham- (2017)
mad K, Ohl K, Romero R, Fischer F, Bauer CA, Huber M, Parada Venegas D, De la Fuente MK, Landskron G, Gonzalez MJ,
Gress TM, Lauth M, Danhof S, Bopp T, Nerreter T, Mulder IE, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA.
Steinhoff U, Hudecek M, Visekruna A. Microbial short-chain Short chain fatty acids (SCFAs)-mediated gut epithelial and
fatty acids modulate CD8(+) T cell responses and improve immune regulation and its relevance for inflammatory bowel
adoptive immunotherapy for cancer. Nature Communications. diseases. Frontiers in Immunology. 10: 277 (2019)
12: 4077 (2021) Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim
Ma DW, Wierzbicki AA, Field CJ, Clandinin MT. Conjugated linoleic CH. Short-chain fatty acids induce both effector and regulatory
acid in canadian dairy and beef products. Journal of Agricultural T cells by suppression of histone deacetylases and regulation of
and Food Chemistry. 47: 1956-1960 (1999) the mTOR-S6K pathway. Mucosal Immunology. 8: 80-93 (2015)
Ma Y, Smith CE, Lai CQ, Irvin MR, Parnell LD, Lee YC, Pham LD, Park Y, Pariza MW. Mechanisms of body fat modulation by conjugated
Aslibekyan S, Claas SA, Tsai MY, Borecki IB, Kabagambe EK, linoleic acid (CLA). Food Research International. 40: 311-323
Ordovas JM, Absher DM, Arnett DK. The effects of omega-3 (2007)
polyunsaturated fatty acids and genetic variants on methylation Patnala R, Arumugam TV, Gupta N, Dheen ST. HDAC inhibitor
levels of the interleukin-6 gene promoter. Molecular Nutrition & sodium butyrate-mediated epigenetic regulation enhances neuro-
Food Research. 60: 410-419 (2016) protective function of microglia during ischemic stroke. Molecu-
Makhoul Z, Kristal AR, Gulati R, Luick B, Bersamin A, O'Brien D, lar Neurobiology. 54: 6391-6411 (2017)
Hopkins SE, Stephensen CB, Stanhope KL, Havel PJ, Boyer B. Patterson E, Wall R, Fitzgerald GF, Ross RP, Stanton C. Health impli-
Associations of obesity with triglycerides and C-reactive protein cations of high dietary omega-6 polyunsaturated Fatty acids.
are attenuated in adults with high red blood cell eicosapentaenoic Journal of Nutrition and Metabolism. 2012: 539426 (2012)
and docosahexaenoic acids. European Journal of Clinical Nutri- Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS.
tion. 65: 808-817 (2011) Histone deacetylase is a direct target of valproic acid, a potent
Marizzoni M, Cattaneo A, Mirabelli P, Festari C, Lopizzo N, Nicolosi anticonvulsant, mood stabilizer, and teratogen. Journal of Bio-
V, Mombelli E, Mazzelli M, Luongo D, Naviglio D, Coppola L, logical Chemistry. 276: 36734-36741 (2001)
Salvatore M, Frisoni GB. Short-chain fatty acids and lipopolysac- Ramaiyan B, Talahalli RR. Dietary unsaturated fatty acids modulate
charide as mediators between gut dysbiosis and amyloid pathol- maternal dyslipidemia-induced DNA methylation and histone
ogy in Alzheimer's disease. Journal of Alzheimer's Disease. 78: acetylation in placenta and fetal liver in rats. Lipids. 53: 581-
683-697 (2020) 588 (2018)
Epigenetic regulation of fatty acids 3165

Remely M, Aumueller E, Merold C, Dworzak S, Hippe B, Zan- Silva LG, Ferguson BS, Avila AS, Faciola AP. Sodium propionate and
ner J, Pointner A, Brath H, Haslberger AG. Effects of short sodium butyrate effects on histone deacetylase (HDAC) activity,
chain fatty acid producing bacteria on epigenetic regulation of histone acetylation, and inflammatory gene expression in bovine
FFAR3 in type 2 diabetes and obesity. Gene. 537: 85-92 (2014) mammary epithelial cells. Journal of Animal Science. 96: 5244-
Rios-Covian D, Ruas-Madiedo P, Margolles A, Gueimonde M, de 5252 (2018)
Los Reyes-Gavilan CG, Salazar N. Intestinal short chain fatty Smith KL, Guentzel JL. Mercury concentrations and omega-3 fatty
acids and their link with diet and human health. Frontiers in acids in fish and shrimp: Preferential consumption for maximum
Microbiology. 7: 185 (2016) health benefits. Marine Pollution Bulletin. 60: 1615-1618 (2010)
Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Stein RA, Riber L. Epigenetic effects of short-chain fatty acids from
Rowland I, Wolvers D, Watzl B, Szajewska H, Stahl B, Guarner the large intestine on host cells. Microlife. 4: uqad032 (2023)
F, Respondek F, Whelan K, Coxam V, Davicco MJ, Leotoing L, Sugiura M, Sato H, Kanesaka M, Imamura Y, Sakamoto S, Ichikawa
Wittrant Y, Delzenne NM, Cani PD, Neyrinck AM, Meheust. A T, Kaneda A. Epigenetic modifications in prostate cancer. Inter-
prebiotic effects: metabolic and health benefits. British Journal national Journal of Urology. 28: 140-149 (2021)
of Nutrition 104:1–63 (2010) Thompson-Chagoyan OC, Fallani M, Maldonado J, Vieites JM, Khanna
Romagnolo DF, Donovan MG, Doetschman TC, Selmin OI. n-6 S, Edwards C, Dore J, Gil A. Faecal microbiota and short-chain
Linoleic acid induces epigenetics alterations associated with fatty acid levels in faeces from infants with cow's milk protein
colonic inflammation and cancer. Nutrients. 11: 171 (2019) allergy. International Archives of Allergy and Immunology. 156:
Rosenberg G. The mechanisms of action of valproate in neuropsy- 325-332 (2011)
chiatric disorders: can we see the forest for the trees? Cellular Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease:
and Molecular Life Sciences. 64: 2090-2103 (2007) pathology and pathogenesis. Annual Review of Pathology:
Rossi M, Amaretti A, Raimondi S. Folate production by probiotic Mechanisms of Disease. 5: 145-171 (2010)
bacteria. Nutrients. 3: 118-134 (2011) Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B,
Rule DC, Broughton KS, Shellito SM, Maiorano G. Comparison of Wainstein J, Friedlander Y, Levy-Lahad E, Glaser B, Hellman
muscle fatty acid profiles and cholesterol concentrations of A. Genome-wide survey reveals predisposing diabetes type
bison, beef cattle, elk, and chicken. Journal of Animal Science. 2-related DNA methylation variations in human peripheral blood.
80: 1202-1211 (2002) Human Molecular Genetics. 21: 371-383 (2012)
Rumberger JM, Arch JR, Green A. Butyrate and other short-chain Tousoulis D, Plastiras A, Siasos G, Oikonomou E, Verveniotis A, Kok-
fatty acids increase the rate of lipolysis in 3T3-L1 adipocytes. kou E, Maniatis K, Gouliopoulos N, Miliou A, Paraskevopoulos
PeerJ. 2: e611 (2014) T, Stefanadis C. Omega-3 PUFAs improved endothelial func-
Sandin A, Braback L, Norin E, Bjorksten B. Faecal short chain fatty tion and arterial stiffness with a parallel antiinflammatory effect
acid pattern and allergy in early childhood. Acta Paediatrica. in adults with metabolic syndrome. Atherosclerosis. 232: 10-16
98: 823-827 (2009) (2014)
Sealy L, Chalkley R. The effect of sodium butyrate on histone modi- Tremblay BL, Guenard F, Rudkowska I, Lemieux S, Couture P, Vohl
fication. Cell. 14: 115-121 (1978) MC. Epigenetic changes in blood leukocytes following an
Seo T, Blaner WS, Deckelbaum RJ. Omega-3 fatty acids: molecular omega-3 fatty acid supplementation. Clinical Epigenetics. 9: 43
approaches to optimal biological outcomes. Current Opinion (2017)
in Lipidology. 16: 11-18 (2005) Ulhe A, Sharma N, Mahajan A, Patil R, Hegde M, Bhalerao S, Mali
Serini S, Ottes Vasconcelos R, Fasano E, Calviello G. Epigenetic A. Decoding the therapeutic landscape of alpha-linolenic acid: a
regulation of gene expression and M2 macrophage polarization network pharmacology and bioinformatics investigation against
as new potential omega-3 polyunsaturated fatty acid targets in cancer-related epigenetic modifiers. Journal of Biomolecular
colon inflammation and cancer. Expert Opinion on Therapeutic Structure and Dynamics. 1-26 (2023)
Targets. 20: 843-858. (2016) Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA,
Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ. His- Marcobal A, Tancredi DJ, Bevins CL, Sherman MP. A rand-
tone deacetylases as regulators of inflammation and immunity. omized placebo-controlled comparison of 2 prebiotic/probiotic
Trends in Immunology. 32: 335-343 (2011) combinations in preterm infants: impact on weight gain, intes-
Shane B. Folate and vitamin B12 metabolism: overview and inter- tinal microbiota, and fecal short-chain fatty acids. Journal of
action with riboflavin, vitamin B6, and polymorphisms. Food Pediatric Gastroenterology and Nutrition. 48: 216-225 (2009)
and Nutrition Bulletin. 29(2 Suppl): S5-16; discussion S17-19 van der Beek CM, Canfora EE, Kip AM, Gorissen SHM, Olde Damink
(2008) SWM, van Eijk HM, Holst JJ, Blaak EE, Dejong CHC, Lenaerts
Sharma S, Taliyan R, Singh S. Beneficial effects of sodium butyrate in K. The prebiotic inulin improves substrate metabolism and pro-
6-OHDA induced neurotoxicity and behavioral abnormalities: motes short-chain fatty acid production in overweight to obese
Modulation of histone deacetylase activity. Behavioural Brain men. Metabolism. 87: 25-35 (2018)
Research. 291: 306-314 (2015) Vinolo MA, Rodrigues HG, Festuccia WT, Crisma AR, Alves VS,
Shen W, Wang C, Xia L, Fan C, Dong H, Deckelbaum RJ, Qi K. Epi- Martins AR, Amaral CL, Fiamoncini J, Hirabara SM, Sato FT,
genetic modification of the leptin promoter in diet-induced obese Fock RA, Malheiros G, dos Santos MF, Curi R Tributyrin attenu-
mice and the effects of N-3 polyunsaturated fatty acids. Scientific ates obesity-associated inflammation and insulin resistance in
Reports. 4: 5282 (2014) high-fat-fed mice. American Journal of Physiology-Endocrinol-
Shimizu H, Masujima Y, Ushiroda C, Mizushima R, Taira S, Ohue- ogy and Metabolism. 303: E272-282 (2012)
Kitano R, Kimura I. Dietary short-chain fatty acid intake Wang Y, Viscarra J, Kim SJ, Sul HS. Transcriptional regulation of
improves the hepatic metabolic condition via FFAR3. Scientific hepatic lipogenesis. Nature Reviews Molecular Cell Biology. 16:
Reports. 9: 16574 (2019) 678-689 (2015)
Silva-Martinez GA, Rodriguez-Rios D, Alvarado-Caudillo Y, Vaquero Wang Z, Leng Y, Tsai LK, Leeds P, Chuang DM. Valproic acid attenu-
A, Esteller M, Carmona FJ, Moran S, Nielsen FC, Wickstrom- ates blood-brain barrier disruption in a rat model of transient
Lindholm M, Wrobel K, Wrobel K, Barbosa-Sabanero G, Zaina focal cerebral ischemia: the roles of HDAC and MMP-9 inhibi-
S, Lund G. Arachidonic and oleic acid exert distinct effects on tion. Journal of Cerebral Blood Flow & Metabolism. 31: 52-57
the DNA methylome. Epigenetics. 11: 321-334 (2016) (2011)
3166 M.-Y. Chung, B.H. Kim

Wang Z, Qin G, Zhao TC. HDAC4: mechanism of regulation and bio- eicosanoid pathway mediates colon cancer-promoting effects of
logical functions. Epigenomics. 6: 139-150 (2014) dietary linoleic acid. FASEB J. 37: e23009 (2023)
Weinhold B. Epigenetics: the science of change. Environmental Health Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu
Perspectives. 114: A160-167 (2006) C, Ma J, Yu L, Xu C, Ren Z, Xu Y, Xu S, Shen H, Zhu X, Shi
Willett WC. The role of dietary n-6 fatty acids in the prevention of Y, Shen Q, Dong W, Liu R, Ling Y, Zeng Y, Wang X, Zhang
cardiovascular disease. Journal of Cardiovascular Medicine Q, Wang J, Wang L, Wu Y, Zeng B, Wei H, Zhang M, Peng Y,
(Hagerstown). 8 Suppl 1: S42-45 (2007) Zhang C. Gut bacteria selectively promoted by dietary fibers
Woo H, Chung MY, Kim J, Kong D, Min J, Choi HD, Choi IW, Kim alleviate type 2 diabetes. Science. 359: 1151-1156 (2018)
IH, Noh SK, Kim BH. Conjugated linoleic triacylglycerols Zheng S, Rollet M, Pan YX. Maternal protein restriction during preg-
exhibit superior lymphatic absorption than free conjugate lin- nancy induces CCAAT/enhancer-binding protein (C/EBPbeta)
oleic acids and have antiobesity properties. Journal of Medicinal expression through the regulation of histone modification at its
Food. 19: 486-494 (2016) promoter region in female offspring rat skeletal muscle. Epige-
Wu J, Luo J, He Q, Xia Y, Tian H, Zhu L, Li C, Loor JJ. Docosahex- netics. 6: 161-170 (2011)
aenoic acid alters lipid metabolism processes via H3K9ac epi- Zheng Y, Cantley LC. Toward a better understanding of folate metabo-
genetic modification in dairy goat. Journal of Agricultural and lism in health and disease. Journal of Experimental Medicine.
Food Chemistry. 71: 8527-8539 (2023) 216: 253-266 (2019)
Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD. Zock PL, Katan MB. Linoleic acid intake and cancer risk: a review
Decreased lipid synthesis in livers of mice with disrupted Site-1 and meta-analysis. The American Journal of Clinical Nutrition.
protease gene. Proceedings of the National Academy of Sciences 68: 142-153 (1998)
of the United States of America. 98: 13607-13612 (2001)
Yokomori N, Tawata M, Onaya T. DNA demethylation during the dif- Publisher's Note Springer Nature remains neutral with regard to
ferentiation of 3T3-L1 cells affects the expression of the mouse jurisdictional claims in published maps and institutional affiliations.
GLUT4 gene. Diabetes. 48: 685-690 (1999)
Zaiou M, Amrani R, Rihn B, Hajri T. Dietary patterns influence target Springer Nature or its licensor (e.g. a society or other partner) holds
gene expression through emerging epigenetic mechanisms in exclusive rights to this article under a publishing agreement with the
nonalcoholic fatty liver disease. Biomedicines. 9: 1256 (2021) author(s) or other rightsholder(s); author self-archiving of the accepted
Zhang J, Yang J, Duval C, Edin ML, Williams A, Lei L, Tu M, Pour- manuscript version of this article is solely governed by the terms of
mand E, Song R, Graves JP, DeGraff LM, Wong JJ, Wang Y, such publishing agreement and applicable law.
Sun Q, Sanidad KZ, Wong S, Han Y, Zhang Z, Lee KSS, Park
Y, Xiao H, Liu Z, Decker EA, Cui W, Zeldin DC, Zhang G. CYP