Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in ... more Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for tr...
A 68-year-old man was diagnosed with chronic hepatitis C genotype 1b 5 years ago. He had no evide... more A 68-year-old man was diagnosed with chronic hepatitis C genotype 1b 5 years ago. He had no evidence of advanced liver disease (eg, thrombocytopenia). Liver ultrasound showed no signs of cirrhosis, such as nodularity. Vibration-controlled transient elastography (VCTE) performed prior to treatment was negative for signficant fibrosis at 6.7 kPa. Hepatitis C was cured, based on viral load, with simeprevir and sofosbuvir for 12 weeks. He presents for follow-up. Laboratory studies and VCTE were performed (Table 1).
Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased su... more Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2-receptor antagonist [H2B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74–0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26–0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.
Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased su... more Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2‐receptor antagonist [H2B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non‐random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of o...
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes... more Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) and clinical factors including diabetes, obesity, and older age increase a patient's risk for NASH, advanced fibrosis, and worse outcomes. Despite substantial investigation and identification of some common variants associated with NAFLD and advanced fibrosis, the genetics and functional mechanisms remain poorly understood. This study aimed to identify genetic variants by whole‐exome sequencing of NAFLD phenotypes to provide novel insights into mechanisms behind NAFLD pathogenesis ...
The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortalit... more The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0-1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, he...
Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of n... more Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and non-invasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water ((2) H2 O, 50 ml aliquots) 2-3 times daily for 3 to 5 weeks prior to a clinically indicated liver-biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on (2) H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advanci...
The American journal of gastroenterology, Jan 20, 2016
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has bee... more The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has been implicated in NAFLD pathogenesis because it has roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. We evaluated the association of VitD levels, hepatic gene expression for VitD metabolizing genes, and NAFLD histological severity. Two adult cohorts, controls (n=39) and NAFLD (n=244), who underwent liver biopsy were compared. Two-sided t-tests or Wilcoxon's rank-sum tests for continuous predictors and chi-squared tests or Fisher's exact tests for categorical variables were used to analyze the association of VitD and NAFLD. Generalized linear models were used to analyze the association of VitD levels and VitD metabolizing genes with histological severity of NAFLD while adjusting for potential confounders and correcting for multiple comparisons. NAFLD patients were more likely than controls to have higher HbA1c (6.5±1.2 vs 5.9±1.0; P...
Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and ... more Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcri...
Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and sec... more Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were incr...
American journal of physiology. Gastrointestinal and liver physiology, Jan 15, 2015
TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that... more TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline conte...
The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) alon... more The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling. PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated. Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in he...
Session - Steatosis and Steatohepatitis / Q03 Alcohol: Clinical and ExperimentalThis journal supp... more Session - Steatosis and Steatohepatitis / Q03 Alcohol: Clinical and ExperimentalThis journal suppl. entitled: 2011 DDW Abstract SupplementBACKGROUND: NAFLD, the liver manifestation of the metabolic syndrome, increases the risk for cardiovascular disease. Modest alcohol consumption is advocated for cardiovascular health, but whether it benefits or worsens NAFLD is unclear. We used gene expression analysis to determine if modest alcohol consumption potentiated or antagonized the changes in liver gene expression that accompany fibrosis progression in NAFLD. METHODS: 85 patients with biopsy-proven NAFLD who had completed alcohol questionnaires were selected from our repository on the basis of fibrosis stage (early:F0-1 vs. advanced:F3-4) and alcohol exposure (unexposed: none within 2 years vs. exposed: <2 drinks/day) to generate 4 study groups: early fibrosis/unexposed, early fibrosis/exposed, advanced fibrosis/unexposed, advanced fibrosis/exposed. Total RNA was extracted from frozen liver biopsies. Adequate RNA was obtained from 72 samples, hybridized to Affymetrix HG U133A 2.0 arrays, and resultant data analyzed via an empirical Bayes method after normalization. In unexposed patients, linear modeling was done using the R package limma to identify differentially expressed genes in livers with advanced fibrosis (n=19) versus early fibrosis (n=20). Significance was set at a False Discovery Rate of 5% after Benjamini-Hochberg correction. The Wilcoxon rank-sum test with multiple testing threshold q<.05 was then used to compare expression in exposed and unexposed patients with advanced fibrosis in order to assess antagonism or potentiation by alcohol exposure. Permutation analysis was also performed to confirm the findings. RESULTS: In the 39 non-drinking (unexposed) patients, 585 genes were found to be differentially expressed in patients with advanced fibrosis vs. early fibrosis, identifying a group of fibrosis-associated genes. In the 13 alcohol-exposed patients with advanced fibrosis, expression of only one of these genes (COL16A1) was potentiated, whereas the fibrosis-associated pattern of 338 other genes (including genes associated with extracellular matrix (COL1A2, FBN1); PDGF signaling (STAT1); oxidoreductases (ALDH1A3, KDM5A); integrin cell surface interactions (LAMA2); and vascular development (CXCL12,VEGFC, TGFB2) was antagonized. Histology demonstrated that the alcohol-exposed patients were more likely to have early fibrosis than unexposed patients (62.5% vs. 51.2%; p=.002). They were also younger (47±2 vs. 53±2 years; p=0.015) and more likely to be male (51.5% vs. 20.5%; p=.002). Race, BMI, diabetes mellitus, hypertension, and triglyceride levels did not differ significantly by exposure. CONCLUSIONS: In this cohort of NAFLD patients, alcohol exposure was associated with less advanced fibrosis and generally attenuated the changes in liver gene expression that accompanied fibrosis progression in non-drinkers
Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in ... more Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for tr...
A 68-year-old man was diagnosed with chronic hepatitis C genotype 1b 5 years ago. He had no evide... more A 68-year-old man was diagnosed with chronic hepatitis C genotype 1b 5 years ago. He had no evidence of advanced liver disease (eg, thrombocytopenia). Liver ultrasound showed no signs of cirrhosis, such as nodularity. Vibration-controlled transient elastography (VCTE) performed prior to treatment was negative for signficant fibrosis at 6.7 kPa. Hepatitis C was cured, based on viral load, with simeprevir and sofosbuvir for 12 weeks. He presents for follow-up. Laboratory studies and VCTE were performed (Table 1).
Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased su... more Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2-receptor antagonist [H2B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74–0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26–0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.
Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased su... more Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2‐receptor antagonist [H2B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non‐random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of o...
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes... more Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous disease with highly variable outcomes. Patients with simple steatosis typically experience a benign course, whereas those with more advanced liver injury, nonalcoholic steatohepatitis (NASH), and advanced stage fibrosis suffer increased risk for complications such as cirrhosis, hepatic decompensation, and liver cancer. Genetic variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) and clinical factors including diabetes, obesity, and older age increase a patient's risk for NASH, advanced fibrosis, and worse outcomes. Despite substantial investigation and identification of some common variants associated with NAFLD and advanced fibrosis, the genetics and functional mechanisms remain poorly understood. This study aimed to identify genetic variants by whole‐exome sequencing of NAFLD phenotypes to provide novel insights into mechanisms behind NAFLD pathogenesis ...
The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortalit... more The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0-1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, he...
Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of n... more Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and non-invasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water ((2) H2 O, 50 ml aliquots) 2-3 times daily for 3 to 5 weeks prior to a clinically indicated liver-biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on (2) H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advanci...
The American journal of gastroenterology, Jan 20, 2016
The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has bee... more The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is complex. Vitamin D (VitD) has been implicated in NAFLD pathogenesis because it has roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. We evaluated the association of VitD levels, hepatic gene expression for VitD metabolizing genes, and NAFLD histological severity. Two adult cohorts, controls (n=39) and NAFLD (n=244), who underwent liver biopsy were compared. Two-sided t-tests or Wilcoxon's rank-sum tests for continuous predictors and chi-squared tests or Fisher's exact tests for categorical variables were used to analyze the association of VitD and NAFLD. Generalized linear models were used to analyze the association of VitD levels and VitD metabolizing genes with histological severity of NAFLD while adjusting for potential confounders and correcting for multiple comparisons. NAFLD patients were more likely than controls to have higher HbA1c (6.5±1.2 vs 5.9±1.0; P...
Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and ... more Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcri...
Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and sec... more Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease and second indication for liver transplantation in the Western world. Effective therapy is still not available. Previously we showed a critical role for caspase-2 in the pathogenesis of nonalcoholic steatohepatitis (NASH), the potentially progressive form of NAFLD. An imbalance between free coenzyme A (CoA) and acyl-CoA ratio is known to induce caspase-2 activation. We aimed to evaluate CoA metabolism and the effects of supplementation with CoA precursors, pantothenate and cysteine, in mouse models of NASH. CoA metabolism was evaluated in methionine-choline deficient (MCD) and Western diet mouse models of NASH. MCD diet-fed mice were treated with pantothenate and N-acetylcysteine or placebo to determine effects on NASH. Liver free CoA content was reduced, pantothenate kinase (PANK), the rate-limiting enzyme in the CoA biosynthesis pathway, was down-regulated, and CoA degrading enzymes were incr...
American journal of physiology. Gastrointestinal and liver physiology, Jan 15, 2015
TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that... more TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-α increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high-fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline conte...
The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) alon... more The ductular reaction (DR) involves mobilisation of reactive-appearing duct-like cells (RDC) along canals of Hering, and myofibroblastic (MF) differentiation of hepatic stellate cells (HSC) in the space of Disse. Perivascular cells in stem cell niches produce pleiotrophin (PTN) to inactivate the PTN receptor, protein tyrosine phosphatase receptor zeta-1 (PTPRZ1), thereby augmenting phosphoprotein-dependent signalling. We hypothesised that the DR is regulated by PTN/PTPRZ1 signalling. PTN-GFP, PTN-knockout (KO), PTPRZ1-KO, and wild type (WT) mice were examined before and after bile duct ligation (BDL) for PTN, PTPRZ1 and the DR. RDC and HSC from WT, PTN-KO, and PTPRZ1-KO mice were also treated with PTN to determine effects on downstream signaling phosphoproteins, gene expression, growth, and migration. Liver biopsies from patients with DRs were also interrogated. Although quiescent HSC and RDC lines expressed PTN and PTPRZ1 mRNAs, neither PTN nor PTPRZ1 protein was demonstrated in he...
Session - Steatosis and Steatohepatitis / Q03 Alcohol: Clinical and ExperimentalThis journal supp... more Session - Steatosis and Steatohepatitis / Q03 Alcohol: Clinical and ExperimentalThis journal suppl. entitled: 2011 DDW Abstract SupplementBACKGROUND: NAFLD, the liver manifestation of the metabolic syndrome, increases the risk for cardiovascular disease. Modest alcohol consumption is advocated for cardiovascular health, but whether it benefits or worsens NAFLD is unclear. We used gene expression analysis to determine if modest alcohol consumption potentiated or antagonized the changes in liver gene expression that accompany fibrosis progression in NAFLD. METHODS: 85 patients with biopsy-proven NAFLD who had completed alcohol questionnaires were selected from our repository on the basis of fibrosis stage (early:F0-1 vs. advanced:F3-4) and alcohol exposure (unexposed: none within 2 years vs. exposed: <2 drinks/day) to generate 4 study groups: early fibrosis/unexposed, early fibrosis/exposed, advanced fibrosis/unexposed, advanced fibrosis/exposed. Total RNA was extracted from frozen liver biopsies. Adequate RNA was obtained from 72 samples, hybridized to Affymetrix HG U133A 2.0 arrays, and resultant data analyzed via an empirical Bayes method after normalization. In unexposed patients, linear modeling was done using the R package limma to identify differentially expressed genes in livers with advanced fibrosis (n=19) versus early fibrosis (n=20). Significance was set at a False Discovery Rate of 5% after Benjamini-Hochberg correction. The Wilcoxon rank-sum test with multiple testing threshold q<.05 was then used to compare expression in exposed and unexposed patients with advanced fibrosis in order to assess antagonism or potentiation by alcohol exposure. Permutation analysis was also performed to confirm the findings. RESULTS: In the 39 non-drinking (unexposed) patients, 585 genes were found to be differentially expressed in patients with advanced fibrosis vs. early fibrosis, identifying a group of fibrosis-associated genes. In the 13 alcohol-exposed patients with advanced fibrosis, expression of only one of these genes (COL16A1) was potentiated, whereas the fibrosis-associated pattern of 338 other genes (including genes associated with extracellular matrix (COL1A2, FBN1); PDGF signaling (STAT1); oxidoreductases (ALDH1A3, KDM5A); integrin cell surface interactions (LAMA2); and vascular development (CXCL12,VEGFC, TGFB2) was antagonized. Histology demonstrated that the alcohol-exposed patients were more likely to have early fibrosis than unexposed patients (62.5% vs. 51.2%; p=.002). They were also younger (47±2 vs. 53±2 years; p=0.015) and more likely to be male (51.5% vs. 20.5%; p=.002). Race, BMI, diabetes mellitus, hypertension, and triglyceride levels did not differ significantly by exposure. CONCLUSIONS: In this cohort of NAFLD patients, alcohol exposure was associated with less advanced fibrosis and generally attenuated the changes in liver gene expression that accompanied fibrosis progression in non-drinkers
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