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13 pages, 24856 KiB

Open AccessCommunication

The Novel Inhibitory Effect of YM976 on Adipocyte Differentiation

by Hee Jung Kim, Dong-Hoon Kim and Sung Hee Um

Cells 2023, 12(2), 205; https://doi.org/10.3390/cells12020205 - 4 Jan 2023

Cited by 3 | Viewed by 2723

Abstract

The pyrimidine derivative YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) exerts anti-inflammatory and anti-asthmatic effects. Considering that accumulation of lipids in adipose tissue is accompanied by inflammation, we investigated whether YM976 affects adipocyte differentiation. We found that YM976 significantly decreased lipid accumulation without cytotoxicity [...] Read more.

The pyrimidine derivative YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) exerts anti-inflammatory and anti-asthmatic effects. Considering that accumulation of lipids in adipose tissue is accompanied by inflammation, we investigated whether YM976 affects adipocyte differentiation. We found that YM976 significantly decreased lipid accumulation without cytotoxicity and reduced the expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) as well as their lipogenic regulators including fatty acid synthase (FASN) and fatty acid-binding protein 4 (FABP4) in 3T3-L1 cells induced for differentiation. YM976 mainly inhibited the early stage of adipocyte differentiation. Furthermore, intracellular cAMP level was elevated by YM976 resulting in increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Conversely, decreasing the levels of AMPK or treatment with Compound C, an AMPK inhibitor, lessened the suppressive effects of YM976 on PPARγ transcriptional activity and adipogenesis. Thus, our results suggest YM976 as a novel potential compound for controlling lipid accumulation and formation of adipocytes in obesity. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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YM976 inhibits adipocyte differentiation. (A) The chemical structure of YM976. (B) 3T3-L1 cells were induced to differentiate for six days and treated with Veh or various concentrations of YM976. Microscopic image after staining with Oil Red O. Scale bar = 100 µm. (C) Quantification of Oil Red O staining by spectrophotometry. (D) The mRNA expression of PPARγ, C/EBPα, FASN, and FABP4 in cells after treatment with various concentrations of YM976 was analyzed by qRT-PCR. (E) Protein levels of PPARγ, C/EBPα, and C/EBPβ were analyzed by Western blot. (F) The effect of YM976 on cell viability. In (C–E), n = 3 per group. Images and blots are representative of three independent experiments. Values indicate mean ± SD. * p < 0.05; ** p < 0.01. Data were assessed by one-way ANOVA with Dunnett’s post hoc test. Full article ">Figure 2
The inhibitory effect of YM976 occurs in the early stage of adipocyte differentiation. 3T3-L1 cells were induced for differentiation and then treated with Veh or 10 µM of YM976 at the indicated time points. (A) Cells were stained with Oil Red O and analyzed by microscopy. Scale bar = 100 µm. (B) Quantification of Oil Red O staining by spectrophotometry. (C) The mRNA expression of PPARγ, C/EBPα, and C/EBPβ was analyzed by qRT-PCR. (D) Protein levels of PPARγ, C/EBPα, and C/EBPβ were analyzed by Western blot. In (B,C), n = 3 per group. Images and blots are representative of three independent experiments. Values indicate mean ± SD. * p < 0.05; ** p < 0.01. Data were assessed using Student’s t-test. Full article ">Figure 3
YM976 increases the level of cAMP and decreases the expression of adipogenic genes. Cells were treated with Veh or YM976 at the indicated days. (A) Intracellular cAMP level was analyzed by ELISA. (B) The mRNA expression levels of PPARγ, C/EBPα, and FASN after treatment with YM976 were determined by qRT-PCR. (C) Protein levels of PPARγ, C/EBPα, and FASN were analyzed by Western blot. (D) Expression levels of indicated protein were assessed by immunoblotting. In (A,B), n = 3 per group. In (C,D), blots are representative of three independent experiments. Values indicate mean ± SD. * p < 0.05; ** p < 0.01. Data were assessed by one-way ANOVA with Dunnett’s post hoc test. Full article ">Figure 4
AMPKα depletion attenuates the inhibitory effect of YM976 on adipocyte differentiation. Cells were transfected with si-NS or si-AMPKα and then treated with Veh or 10 µM YM976. (A) Cells were stained with Oil Red O and observed with microscopy. Scale bar = 100 µm. (B) Quantification of Oil Red O staining by spectrophotometry. (C) The mRNA expression levels of PPARγ, C/EBPα, and FASN were examined by qRT-PCR. (D) Expression levels of indicated protein were assessed by immunoblotting. In (B,C), n = 3 per group. In (A,D), images and blots are representative of three independent experiments. Values indicate mean ± SD. * p < 0.05; ** p < 0.01. N.S., not significant. Data were assessed by one-way ANOVA with Tukey’s post hoc test. Full article ">Figure 5
AMPK inhibitor lessens the inhibitory effect of YM976 on adipocyte differentiation. (A–D) Cells were pre-treated with Compound C (1 µM) for 1 h and then incubated with YM976 during adipocyte differentiation for six days. (A) Cells were stained with Oil Red O and observed by microscopy. Scale bar = 100 µm. (B) Quantification of Oil Red O staining by spectrophotometry. (C) The mRNA expression levels of PPARγ, C/EBPα, and FASN were examined by qRT-PCR. (D) Levels of indicated proteins were analyzed by immunoblotting. (E) After silencing with si-NS or si-AMPKα, 3T3-L1 cells were transfected with PPARγ expression plasmid and pGL3 luciferase vector (pGL3) or PPAR-response element-binding luciferase vector (PPRE-Luc) for 24 h. Cells were then treated with Veh or YM976 for 24 h. Luciferase assay was performed to measure the transcription activity of PPARγ. (F) After pre-incubation with Veh or Compound C (1 µM) for 1 h, 3T3-L1 cells were transfected with PPARγ expression plasmid and pGL3 or PPRE-Luc or for 24 h. Cells were then treated with Veh or YM976 for 24 h. Luciferase assay was performed to measure the transcriptional activity of PPARγ. (G) Proposed model of YM976 inhibition of adipocyte differentiation. YM976 increases the levels of cAMP and AMPK phosphorylation to suppress the transcriptional expression of adipogenic genes, resultings in reduced adipogenesis. pGL3, pGL3 luciferase vector; pPPRE, peroxisome proliferator response element reporter plasmid; C.C., Compound C; N.S., not significant. In (B,C,E,F), n = 3 per group. In A and D, images and blots are representative of three independent experiments. Values indicate mean ± SD. * p < 0.05; ** p < 0.01. Data were assessed by one-way ANOVA with Tukey’s post hoc test. Full article ">

31 pages, 5010 KiB

Open AccessArticle

Fat Quality Impacts the Effect of a High-Fat Diet on the Fatty Acid Profile, Life History Traits and Gene Expression in Drosophila melanogaster

by Virginia Eickelberg, Gerald Rimbach, Yvonne Seidler, Mario Hasler, Stefanie Staats and Kai Lüersen

Cells 2022, 11(24), 4043; https://doi.org/10.3390/cells11244043 - 14 Dec 2022

Cited by 6 | Viewed by 3559

Abstract

Feeding a high-fat diet (HFD) has been shown to alter phenotypic and metabolic parameters in Drosophila melanogaster. However, the impact of fat quantity and quality remains uncertain. We first used butterfat (BF) as an example to investigate the effects of increasing dietary [...] Read more.

Feeding a high-fat diet (HFD) has been shown to alter phenotypic and metabolic parameters in Drosophila melanogaster. However, the impact of fat quantity and quality remains uncertain. We first used butterfat (BF) as an example to investigate the effects of increasing dietary fat content (3–12%) on male and female fruit flies. Although body weight and body composition were not altered by any BF concentration, health parameters, such as lifespan, fecundity and larval development, were negatively affected in a dose-dependent manner. When fruit flies were fed various 12% HFDs (BF, sunflower oil, olive oil, linseed oil, fish oil), their fatty acid profiles shifted according to the dietary fat qualities. Moreover, fat quality was found to determine the effect size of the response to an HFD for traits, such as lifespan, climbing activity, or fertility. Consistently, we also found a highly fat quality-specific transcriptional response to three exemplary HFD qualities with a small overlap of only 30 differentially expressed genes associated with the immune/stress response and fatty acid metabolism. In conclusion, our data indicate that not only the fat content but also the fat quality is a crucial factor in terms of life-history traits when applying an HFD in D. melanogaster. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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19 pages, 4261 KiB

Open AccessArticle

Dietary Choline Mitigates High-Fat Diet-Impaired Chylomicrons Assembly via UPRer Modulated by perk DNA Methylation

by Zhen-Yu Bai, Hua Zheng, Zhi Luo, Christer Hogstrand, Ling-Jiao Wang and Yu-Feng Song

Cells 2022, 11(23), 3848; https://doi.org/10.3390/cells11233848 - 30 Nov 2022

Cited by 5 | Viewed by 2330

Abstract

High-fat diets (HFD) lead to impairment of chylomicrons (CMs) assembly and adversely influence intestinal lipid homeostasis. However, the mechanisms of HFD impairing CMs assembly have yet to be fully understood. Additionally, although choline, as a lipid-lowering agent, has been widely used and its [...] Read more.

High-fat diets (HFD) lead to impairment of chylomicrons (CMs) assembly and adversely influence intestinal lipid homeostasis. However, the mechanisms of HFD impairing CMs assembly have yet to be fully understood. Additionally, although choline, as a lipid-lowering agent, has been widely used and its deficiency has been closely linked to non-alcoholic steatohepatitis (NASH), the contribution of choline by functioning as a methyl donor in alleviating HFD-induced intestinal lipid deposition is unknown. Thus, this study was conducted to determine the mechanism of HFD impairing CMs assembly and also tested the effect of choline acting as a methyl donor in this process. To this end, in this study, four diets (control, HFD, choline and HFD + choline diet) were fed to yellow catfish for 10 weeks in vivo and their intestinal epithelial cells were isolated and incubated for 36 h in fatty acids (FA) with or without choline solution combining si-perk transfection in vitro. The key findings from this study as follows: (1) HFD caused impairment of CMs assembly main by unfolded protein response (UPRer). HFD activated perk and then induced UPRer, which led to endoplasmic reticulum dysfunction and further impaired CMs assembly via protein–protein interactions between Perk and Apob48. (2) Choline inhibited the transcriptional expression level of perk via activating the −211 CpG methylation site, which initiated the subsequent ameliorating effect on HFD-impaired CMs assembly and intestinal lipid dysfunction. These results provide a new insight into direct crosstalk between UPRer and CMs assembly, and also emphasize the critical contribution of choline acting as a methyl donor and shed new light on choline-deficient diet-induced NASH. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Dietary choline alleviated HFD-induced intestinal lipid dysregulation. (A) Representative images of intestinal H&E and Oil red O stained. Scale bar, 50 μm; VM, villi height. MLT, muscular layer thickness. LDs, lipid droplets. (B,C) Relative intestinal villi height and muscular layer thickness in H&E staining. (D) Relative areas for LDs in Oil red O staining. (E) Intestinal TG content. (F) mRNA levels of the genes related to FA re-esterification and de novo FA synthesis. (G) Western blot analysis and quantification analysis for Dgat1. Data are mean ± SEM, n = 3. Labeled means without a common letter differ, p < 0.05 (2-factor ANOVA, Duncan’s post hoc test). NS, not significant (p ≥ 0.05). Full article ">Figure 2
Dietary choline improved HFD-induced impairment of CMs assembly. (A) TEM structures of intestines and the isolated fractions of CMs. Scale bar, 500 nm; LD, lipid droplet. (B,C) Relative intestinal CMs areas and individual proportion in TEM structures. (D–G) Density gradient curve and quantification analysis for CMs-TGs/or apolipoprotein in intestines and serum. (H) mRNA levels of the genes related to CMs assembly and secretion. (I) Western blot for Mtp, Apob48, and Sar1b. (J) Relative MTP activity. Data are mean ± SEM, n = 3. Labeled means without a common letter differ, p < 0.05 (2-factor ANOVA, Duncan’s post hoc test). NS, not significant (p ≥ 0.05). Full article ">Figure 3
Alleviated effects of dietary choline on HFD-induced UPRer. (A) TEM structures of the intestinal endoplasmic reticulum (ER). Scale bars, 500 nm. (B) mRNA levels of the genes related to UPRer. (C) Western blot and quantification analysis for Perk and Grp78. Data are mean ± SEM, n = 3. Labeled means without a common letter differ, p < 0.05 (2-factor ANOVA, Duncan’s post hoc test). NS, not significant (p ≥ 0.05). Full article ">Figure 4
Perk signaling regulated FA/choline-mediated CMs assembly. (A) TEM structures of the isolated fractions of IECs’ CMs under FA/choline incubation with si-perk transfection. Scale bar, 500 nm. (B,C) Density gradient curve and quantification analysis for CMs-TGs/or apolipoprotein. (D,E) Relative CMs areas and individual proportion in TEM structures. (F,G) Relative quantification analysis for CMs-TGs/or apolipoprotein. (H) The co-localization of Apob48 (red) and LDs (Bodipy 493/503, green) in IECs. Scale bars, 5 μm. (I) Quantitative analysis for relative red intensity of fluorescence in H. (J) The presence of LDs with Bodipy 493/503 staining were demonstrated by flow cytometry. Data are mean ± SEM, n = 3 independent biological experiments; different lower-case letters indicate significant differences in si-NC groups; different capital letters indicate significant differences in si-perk groups (p ≤ 0.05); asterisks indicate significant differences between si-NC and si-perk groups (* p ≤ 0.05). Full article ">Figure 5
Perk-Apob48 interaction is required for FA/choline-mediated CMs assembly. (A) Western blot analysis for Mtp, Apob48, and Sar1b in the IECs under FA and CH incubation and transfected with perk siRNA. (B) Quantification analysis for Western blot. (C) mRNA levels of apob, mtp, sar1b genes. (D) Relative MTP activity. (E) The structural protein prediction model between Perk and Apob48. (F) IP analysis of Perk-Apob48 complex. Data are mean ± SEM, n = 3 independent biological experiments; different lower-case letters indicate significant differences in si-NC groups; different capital letters indicate significant differences in si-perk groups (p ≤ 0.05); asterisks indicate significant differences between si-NC and si-perk groups (* p ≤ 0.05). Full article ">Figure 6
Choline down-regulated perk expression by controlling −211 site-specific DNA methylation. (A) mRNA levels of the genes related to DNA methyltransferase in the intestine. (B) Western blot for Dnmt1. (C) The histogram of relative methylation level of perk. (D) Heat map of relative methylation level of perk. (E) The histogram of quantitative methylation percentage of perk in the IECs under FA and CH incubation and transfected with 5-azacitidine (AZA). (F) The relative luciferase activities of perk. (G) mRNA levels of perk. (H) Western blot and quantification analysis for Perk. (I) The quantitative methylation percentage of perk −211 methylation site. (J) Site mutation analysis of perk −211 methylation site on pGl3-perk −822/+122 vectors. (K,L) Density gradient curve and quantification analysis for CMs-TGs/or apolipoprotein in the IECs under FA and CH incubation and transfected with −211 methylation site mutation. Data are mean ± SEM, n = 3 independent biological experiments; different lower-case letters indicate significant differences in −AZA groups; different capital letters indicate significant differences in +AZA groups (p ≤ 0.05); asterisks indicate significant differences between −AZA and +AZA groups (* p ≤ 0.05). Full article ">Figure 7
Graphical conclusions for the mechanism of dietary choline mitigates high-fat diet-impaired chylomicrons assembly via UPRer modulated by perk DNA methylation. Full article ">

19 pages, 4510 KiB

Open AccessFeature PaperArticle

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration

by Jun-dae Kim, Teng Zhou, Aijun Zhang, Shumin Li, Anisha A. Gupte, Dale J. Hamilton and Longhou Fang

Cells 2022, 11(22), 3643; https://doi.org/10.3390/cells11223643 - 17 Nov 2022

Cited by 3 | Viewed by 2646

Abstract

Accumulating evidence indicates that the APOA1 binding protein (AIBP)—a secreted protein—plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it [...] Read more.

Accumulating evidence indicates that the APOA1 binding protein (AIBP)—a secreted protein—plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and increases or trends increasing lipid-associated metabolites cholesterol, α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe^−/− heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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13 pages, 4918 KiB

Open AccessArticle

MiR-23b Promotes Porcine Preadipocyte Differentiation via SESN3 and ACSL4

by Meng Li, Na Zhang, Jiao Li, Wanfeng Zhang, Wei Hei, Mengting Ji, Yang Yang, Guoqing Cao, Xiaohong Guo and Bugao Li

Cells 2022, 11(15), 2339; https://doi.org/10.3390/cells11152339 - 29 Jul 2022

Cited by 8 | Viewed by 2441

Abstract

Genetic improvement of pork quality is one of the hot topics in pig germplasm innovation. Backfat thickness and intramuscular fat content are important indexes of meat quality. MiRNAs are becoming recognized as a crucial regulator of adipose development. Therefore, it is crucial to [...] Read more.

Genetic improvement of pork quality is one of the hot topics in pig germplasm innovation. Backfat thickness and intramuscular fat content are important indexes of meat quality. MiRNAs are becoming recognized as a crucial regulator of adipose development. Therefore, it is crucial to understand how miR-23b regulates fat metabolism at the molecular level. In the present study, Oil Red O staining, and Western blot were used to evaluate the effect of miR-23b on the differentiation of porcine preadipocytes. Dual-luciferase reporter gene assay, pulldown, and RIP were used to reveal the mechanism of miR-23b regulating cell differentiation. The findings demonstrated that miR-23b promotes the expression of adipogenic factors and increases the content of lipid droplets, thus promoting the differentiation of preadipocytes. Further research found that miR-23b can directly bind to the 3’UTR of SESN3 to regulate adipogenic differentiation. In addition, it was speculated that miR-23b controls cell differentiation by positively regulating the expression of ACSL4 in other ways. Here, we demonstrate that miR-23b promotes the differentiation of porcine preadipocytes by targeting SESN3 and promoting the expression of ACSL4. The present study is meaningful to the improvement of pork quality and the development of animal husbandry. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Review

Jump to: Research

20 pages, 2000 KiB

Open AccessReview

Targeting Liver X Receptors for the Treatment of Non-Alcoholic Fatty Liver Disease

by Hyejin Kim, Chaewon Park and Tae Hyun Kim

Cells 2023, 12(9), 1292; https://doi.org/10.3390/cells12091292 - 1 May 2023

Cited by 9 | Viewed by 4623

Abstract

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Structures of endogenous agonists for LXRs. Full article ">Figure 2
The control of cholesterol uptake, transport and excretion by LXRs. The fine-tuned regulation of cholesterol levels in the body is a consequence of integrated interaction among various cell types and tissues, such as macrophage, liver and intestine, and LXRs play a pivotal role in these processes, termed as reverse cholesterol transport (RCT). Some, but not all, target genes that are directly regulated by LXRs are highlighted in rectangles colored in light blue. (1) LXR agonism inhibits cholesterol uptake in the liver and macrophages via upregulating the inducible degrader of the LDL receptor (IDOL), which degrades the low-density lipoprotein receptor (LDLR). (2) In parallel, LXR activation also promotes cholesterol efflux from macrophages by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ADP-ribosylation factor-like protein 7 (ARL7), facilitating cholesterol transport to lipid-poor apolipoprotein A1 (ApoA1) or pre-β high density lipoprotein (pre-β HDL). (3) Similarly, ABCG1, another direct target of LXR, also promotes cholesterol transport to ApoA1-containing lipoprotein to form mature HDL. (4) In line with this, LXR activation in the liver suppresses cholesterol biosynthesis by transcriptional induction of E3 ubiquitin protein ligase RING finger protein 145 (RNF145) and liver-expressed, LXR-induced sequence (Lexis). (5) Moreover, hepatic LXR induces cytochrome P450 7A1 (CYP7A1) expression, which promotes cholesterol clearance via conversion of cholesterol into bile acids. (6) Bile acids derived from cholesterol are then subjected to biliary excretion through ABCG5 and ABCG8, both of which are another direct target of LXR. Full article ">

12 pages, 1114 KiB

Open AccessReview

Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis

by Michael S. Mortensen, Jimena Ruiz and Jennifer L. Watts

Cells 2023, 12(5), 804; https://doi.org/10.3390/cells12050804 - 4 Mar 2023

Cited by 81 | Viewed by 9420

Abstract

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell [...] Read more.

Ferroptosis is a form of regulated cell death that is intricately linked to cellular metabolism. In the forefront of research on ferroptosis, the peroxidation of polyunsaturated fatty acids has emerged as a key driver of oxidative damage to cellular membranes leading to cell death. Here, we review the involvement of polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs), lipid remodeling enzymes and lipid peroxidation in ferroptosis, highlighting studies revealing how using the multicellular model organism Caenorhabditis elegans contributes to the understanding of the roles of specific lipids and lipid mediators in ferroptosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Non-enzymatic lipid peroxidation. Peroxidation is initiated by cellular ROS, where hydroxyl, alkoxyl or peroxyl radicals abstract a hydrogen from a PUFA acyl group (radical electrons denoted as red circle). A PUFA peroxide is formed by reacting with molecular oxygen and abstraction of a hydrogen from an adjacent membrane PUFA. Fenton chemistry contributes to further lipid radical formation, contributing to the chain reaction of lipid radicals attacking acyl groups on nearby unsaturated phospholipid molecules. Lipid peroxidation is terminated by actions of radical-trapping antioxidants or by reduction by catalyzed by glutathione peroxidase activity. Figure created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>, accessed on 1 February 2023. Full article ">Figure 2
Structures of common fatty acids and oxygenated derivatives. (A) Stearic acid (18:0) is a saturated fatty acid. (B) Oleic acid (18:1n-9) is a monounsaturated fatty acid. The single double bond is in the cis position, creating a kink in the fatty acid that prevents tight packing of fatty acids and contributes to membrane fluidity. (C) Dihommo-γ linolenic acid (DGLA, 20:3n-6) is a polyunsaturated fatty acid. Oxygenated derivatives are produced by cytochrome P450 (CYP) enzymes, forming an epoxide. The double bond that is converted to an epoxide depends on the position-specific isoform of CYP enzymes. The epoxides can be converted into diols by epoxide hydrolase (EH) enzymes. The EH enzymes are inhibited by AUDA. (D) Arachidonic acid (AA, 20:4n-6) is a polyunsaturated fatty acid. Shown are examples of oxygenated derivatives produced by lipoxygenase (LOX) enzymes and peroxidase activity. The location of the hydroperoxide is dependent on the position-specific isoform of LOX. The hydroperoxide can be further reduced by peroxidase activity, leading to a bioactive hydroxyl derivative. Full article ">Figure 3
Dietary DGLA causes ferroptosis of germ cells and sterility in C. elegans. (A) Schematic of the C. elegans fatty acid supplementation assay. Synchronized L1 larvae are plated onto agar plates containing DGLA and dietary E. coli, and incubated at 20 degrees until they reach adulthood, when they are scored as fertile or sterile. Sterile worms lack gametes due to ferroptosis of germ cells during development. (B) Mutant strains that are more sensitive to DGLA are known as enhancers, while mutant strains that are less sensitive to DGLA are known as suppressors. Often, enhancer strains contain mutations in protective genes, such as genes encoding GPX enzymes or genes required for MUFA production. Suppressor genes include genes needed to produce membrane PUFAs, or mutants that confer increased stress responses. Full article ">

24 pages, 1125 KiB

Open AccessReview

Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway

by Yusuke Nakamura and Yasuo Shimizu

Cells 2023, 12(4), 548; https://doi.org/10.3390/cells12040548 - 8 Feb 2023

Cited by 8 | Viewed by 4637

Abstract

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient’s survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid “lysophosphatidic acid (LPA)” and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Eicosanoids pathway in fibrotic lung diseases. Arachidonic acid (AA) is freed from arachidonic acid esterified phospholipid (Ara-PL) by phospholipaseA2 (PLA2). AA is metabolized by cyclooxygenase-1 or -2 (COX1 or COX2) or by 5-lipoxygenase (5-LOX), yielding various eicosanoids. The eicosanoids manifest diverse physiological actions related to the pathogenesis of pulmonary fibrosis. Abbreviations: prostaglandin D2 (PGD2), prostaglandin H2 (PGH2), prostaglandin F2 (PGF2), prostaglandin I2 (PGI2, prostacyclin), thromboxane A2 (TXA2), 5-hydroxyeicosatetraenoic acids (5-HETE), leukotriene A4 (LTA4), leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene E4 (LTE4), lipoxin A4 (LXA4). Full article ">Figure 2
Sphingolipids pathway in fibrotic lung diseases. Sphingomyelin (SM) is metabolized by sphingomyelinase (SMase), yielding ceramide (Cer). It is later converted by ceramidase into sphingosine (Sph) and subsequently converted by sphingosine kinase 1 (Sphk1) into sphingosine-1-phosphate (S1P). S1P communicates with the inside and outside of cells via ATP-binding cassette (ABC) transporters and spinster homolog 2 (Spns2) and binds to S1P receptors to manifest physiological activity. Abbreviations: Bleomycin (BLM), Hippo/yes-associated protein (YAP), mitochondrial reactive oxygen species (mtROS). Full article ">Figure 3
LPA pathway in fibrotic lung diseases. A representative pathway for lysophosphatidic acid (LPA) production is shown here. Glycerophospholipids, such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE), are converted by phospholipase A2 (PLA2) into lysophosphatidylcholine (LPC). LPC is then converted by lysophospholipase D (lysoPLD: Autotaxin: ATX) into LPA. Another pathway involves the formation of lysoPLD/ATX from phosphatidic acid (PA). Later, the signals are transduced to the LPA receptors (LPA1/LPA2), resulting in the manifestation of physiological activity related to pulmonary fibrosis. Full article ">

30 pages, 2535 KiB

Open AccessReview

Detoxification Cytochrome P450s (CYPs) in Families 1–3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids

by Jazmine A. Eccles and William S. Baldwin

Cells 2023, 12(1), 82; https://doi.org/10.3390/cells12010082 - 24 Dec 2022

Cited by 14 | Viewed by 3476

Abstract

This manuscript reviews the CYP-mediated production of oxylipins and the current known function of these diverse set of oxylipins with emphasis on the detoxification CYPs in families 1–3. Our knowledge of oxylipin function has greatly increased over the past 3–7 years with new [...] Read more.

This manuscript reviews the CYP-mediated production of oxylipins and the current known function of these diverse set of oxylipins with emphasis on the detoxification CYPs in families 1–3. Our knowledge of oxylipin function has greatly increased over the past 3–7 years with new theories on stability and function. This includes a significant amount of new information on oxylipins produced from linoleic acid (LA) and the omega-3 PUFA-derived oxylipins such as α-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). However, there is still a lack of knowledge regarding the primary CYP responsible for producing specific oxylipins, and a lack of mechanistic insight for some clinical associations between outcomes and oxylipin levels. In addition, the role of CYPs in the production of oxylipins as signaling molecules for obesity, energy utilization, and development have increased greatly with potential interactions between diet, endocrinology, and pharmacology/toxicology due to nuclear receptor mediated CYP induction, CYP inhibition, and receptor interactions/crosstalk. The potential for diet-diet and diet-drug/chemical interactions is high given that these promiscuous CYPs metabolize a plethora of different endogenous and exogenous chemicals. Full article

(This article belongs to the Special Issue Cellular and Molecular Control of Lipid Metabolism)

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Figure 1

Figure 1
PUFAs are primarily metabolized the CYPs, lipoxygenases (LOX), and cyclooxygenases (COX) with overlapping oxylipin biosynthesis capabilities. LA = linoleic acid (18:2); AA = arachidonic acid (20:4); ALA = α-linolenic acid (18:3); EPA = eicosapentaenoic acid (20:5); DHA = docosahexaenoic acid (22:6). Full article ">Figure 2
Metabolism of linoleic acid by CYPs produces multiple oxylipins. These oxylipins may be subsequently metabolized by soluble epoxide hydrolase (sEH) or dehydrogenases. Oxylipins include 9-HODE, 13-HODE, 9-HpODE, 13-HpODE, 12,13-EpOME and others that are not shown. Full article ">Figure 3
Metabolism of arachidonic acid by CYPs produces multiple products such as the EETs that are subsequently metabolized by sEH to a corresponding DiHET. Other metabolites include but are not limited to 19-HETE, 9,10-EET, 11,12-EET, and the subsequent sEH DiHET products. Full article ">Figure 4
Metabolism of a-linolenic acid a produces multiple products such as the EpODEs that are subsequently metabolized by sEH to a corresponding DiHODEs. Other metabolites include but are not limited to HOTrEs and HpOTrEs. Recent research with CYP2B6 provides a preferred metabolism of PUFAs, especially ALA, in the 9 or 13 positions. Full article ">Figure 5
Metabolism of eicosapentaenoic acid (EPA) a produces multiple products such as the EpETEs that are subsequently metabolized by sEH to a corresponding DiHETEs and the HEPEs. Full article ">Figure 6
Metabolism of eicosapentaenoic acid (EPA) a produces multiple products such as the EpETEs that are subsequently metabolized by sEH to a corresponding DiHETEs and the HEPEs. Full article ">

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