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Treating Nonalcoholic Fatty Liver Disease From the Outside In?
Flynn CR
(2019) Cell Mol Gastroenterol Hepatol 7: 682-683
MeSH Terms: Animals, Hepatocytes, Intracellular Signaling Peptides and Proteins, Mice, Non-alcoholic Fatty Liver Disease, Oligonucleotides, Antisense, Protein-Serine-Threonine Kinases
Added April 15, 2019
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7 MeSH Terms
Glycine -methyltransferase deletion in mice diverts carbon flux from gluconeogenesis to pathways that utilize excess methionine cycle intermediates.
Hughey CC, Trefts E, Bracy DP, James FD, Donahue EP, Wasserman DH
(2018) J Biol Chem 293: 11944-11954
MeSH Terms: Animals, Carbon, Citric Acid Cycle, Energy Metabolism, Fatty Liver, Gene Deletion, Gluconeogenesis, Glucose, Glycine N-Methyltransferase, Liver, Male, Metabolic Flux Analysis, Methionine, Mice, Mice, Knockout, S-Adenosylmethionine
Show Abstract · Added March 26, 2019
Glycine -methyltransferase (GNMT) is the most abundant liver methyltransferase regulating the availability of the biological methyl donor, -adenosylmethionine (SAM). Moreover, GNMT has been identified to be down-regulated in hepatocellular carcinoma (HCC). Despite its role in regulating SAM levels and association of its down-regulation with liver tumorigenesis, the impact of reduced GNMT on metabolic reprogramming before the manifestation of HCC has not been investigated in detail. Herein, we used H/C metabolic flux analysis in conscious, unrestrained mice to test the hypothesis that the absence of GNMT causes metabolic reprogramming. GNMT-null (KO) mice displayed a reduction in blood glucose that was associated with a decline in both hepatic glycogenolysis and gluconeogenesis. The reduced gluconeogenesis was due to a decrease in liver gluconeogenic precursors, citric acid cycle fluxes, and anaplerosis and cataplerosis. A concurrent elevation in both hepatic SAM and metabolites of SAM utilization pathways was observed in the KO mice. Specifically, the increase in metabolites of SAM utilization pathways indicated that hepatic polyamine synthesis and catabolism, transsulfuration, and lipogenesis pathways were increased in the KO mice. Of note, these pathways utilize substrates that could otherwise be used for gluconeogenesis. Also, this metabolic reprogramming occurs before the well-documented appearance of HCC in GNMT-null mice. Together, these results indicate that GNMT deletion promotes a metabolic shift whereby nutrients are channeled away from glucose formation toward pathways that utilize the elevated SAM.
© 2018 Hughey et al.
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MeSH Terms
Alcohol Use and Cardiovascular Disease Risk in Patients With Nonalcoholic Fatty Liver Disease.
VanWagner LB, Ning H, Allen NB, Ajmera V, Lewis CE, Carr JJ, Lloyd-Jones DM, Terrault NA, Siddique J
(2017) Gastroenterology 153: 1260-1272.e3
MeSH Terms: Adolescent, Adult, Age Factors, Alcohol Drinking, Binge Drinking, Chi-Square Distribution, Coronary Artery Disease, Cross-Sectional Studies, Echocardiography, Doppler, Female, Humans, Linear Models, Logistic Models, Longitudinal Studies, Male, Middle Aged, Multidetector Computed Tomography, Multivariate Analysis, Non-alcoholic Fatty Liver Disease, Odds Ratio, Prognosis, Protective Factors, Risk Assessment, Risk Factors, Time Factors, Underage Drinking, United States, Young Adult
Show Abstract · Added September 11, 2017
BACKGROUND & AIMS - Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD.
METHODS - We analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation <51 Hounsfield Units after exclusions. Drinkers reported 1-21 (men) or 1-14 (women) standard drinks/week at years 15, 20, or 25. Nondrinkers reported no alcohol use at years 15, 20, and 25.
RESULTS - Of the 570 participants with NAFLD (mean age, 50 years; 54% black; 46% female), 332 (58%) were drinkers; significantly higher proportions of drinkers were white, male, and with higher levels of education compared with nondrinkers (P < .05 for all). Higher proportions of drinkers had obesity, diabetes, and metabolic syndrome compared with nondrinkers (P < .01). There was no difference in liver attenuation between groups (P = .12). After multivariable adjustment, there was no association between alcohol use and CVD risk factors (diabetes, hypertension, hyperlipidemia) or subclinical CVD measures (coronary artery calcification, early transmitral velocity/late (atrial) transmitral velocity (E/A) ratio, global longitudinal strain).
CONCLUSIONS - In a population-based sample of individuals with NAFLD in midlife, prospectively assessed alcohol use is not associated with significant differences in risk factors for CVD or markers of subclinical CVD. In contrast to general population findings, alcohol use may not reduce the risk of CVD in patients with NAFLD.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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28 MeSH Terms
Testosterone Levels in Pre-Menopausal Women are Associated With Nonalcoholic Fatty Liver Disease in Midlife.
Sarkar M, Wellons M, Cedars MI, VanWagner L, Gunderson EP, Ajmera V, Torchen L, Siscovick D, Carr JJ, Terry JG, Rinella M, Lewis CE, Terrault N
(2017) Am J Gastroenterol 112: 755-762
MeSH Terms: Adult, Body Mass Index, Diabetes Mellitus, Follow-Up Studies, Humans, Insulin Resistance, Intra-Abdominal Fat, Lipoproteins, HDL, Middle Aged, Multidetector Computed Tomography, Non-alcoholic Fatty Liver Disease, Premenopause, Prevalence, Risk Factors, Testosterone, Triglycerides, Waist Circumference, Young Adult
Show Abstract · Added September 11, 2017
OBJECTIVES - Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown.
METHODS - Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987-1988) were associated with prevalent NAFLD at Year 25 (2010-2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression.
RESULTS - Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04-1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05-1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22-119%).
CONCLUSIONS - Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.
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18 MeSH Terms
Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.
Jacobson IM, Washington MK, Buti M, Thompson A, Afdhal N, Flisiak R, Akarca US, Tchernev KG, Flaherty JF, Aguilar Schall R, Myers RP, Subramanian GM, McHutchison JG, Younossi Z, Marcellin P, Patel K
(2017) Clin Gastroenterol Hepatol 15: 1087-1094.e2
MeSH Terms: Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Alanine Transaminase, Antiviral Agents, Biopsy, Clinical Trials, Phase III as Topic, Fatty Liver, Female, Hepatitis B e Antigens, Hepatitis B, Chronic, Histocytochemistry, Humans, Liver, Male, Middle Aged, Tenofovir, Young Adult
Show Abstract · Added March 14, 2018
BACKGROUND & AIMS - Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate.
METHODS - We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level.
RESULTS - Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P = .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P = .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P = .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level.
CONCLUSIONS - HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. ClinicalTrials.gov registration numbers: NCT00117676 and NCT00116805.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Nonalcoholic fatty liver disease and measures of early brain health in middle-aged adults: The CARDIA study.
VanWagner LB, Terry JG, Chow LS, Alman AC, Kang H, Ingram KH, Shay C, Lewis CE, Bryan RN, Launer LJ, Jeffrey Carr J
(2017) Obesity (Silver Spring) 25: 642-651
MeSH Terms: Brain, Female, Health Behavior, Humans, Intra-Abdominal Fat, Liver, Magnetic Resonance Spectroscopy, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Organ Size, Prevalence, Risk Factors, Tomography, X-Ray Computed
Show Abstract · Added April 6, 2017
OBJECTIVE - To assess associations between nonalcoholic fatty liver disease (NAFLD) and measures of brain health in a population-based sample of adults.
METHODS - Participants from the CARDIA study (Y25 exam; age 43-55 years) with concurrent computed tomography quantification of liver fat, visceral adipose tissue (VAT), and brain magnetic resonance (MR) images were included (n = 505). NAFLD was identified after exclusion of other causes of liver fat. Total tissue volume (TTV) and gray matter cerebral blood flow (GM-CBF) were estimated using 3T brain MR images.
RESULTS - NAFLD prevalence was 18%. NAFLD was associated with lower TTV and GM-CBF after adjusting for intracranial volume, demographics, and health behaviors (P < 0.04 for all). In models with additional adjustment for cardiovascular risk factors, the association of NAFLD with GM-CBF remained significant (P = 0.04) but was attenuated after adjustment for VAT (P = 0.06) and eliminated with BMI (P = 0.20). NAFLD was not associated with TTV after adjustment for cardiovascular risk factors (P = 0.10) or additional adjustment for VAT (P = 0.14) or BMI (P = 0.05).
CONCLUSIONS - NAFLD is negatively associated with early brain health as assessed by MR measures of structure (TTV) and perfusion (GM-CBF). BMI and VAT attenuated this relationship, providing insight into the potential metabolic role of liver fat in brain health and disease.
© 2017 The Obesity Society.
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14 MeSH Terms
Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans.
Liu W, Anstee QM, Wang X, Gawrieh S, Gamazon ER, Athinarayanan S, Liu YL, Darlay R, Cordell HJ, Daly AK, Day CP, Chalasani N
(2016) Aging (Albany NY) 9: 26-40
MeSH Terms: Adult, Alleles, Case-Control Studies, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Lipase, Liver, Male, Membrane Proteins, Middle Aged, Non-alcoholic Fatty Liver Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription, Genetic
Show Abstract · Added April 13, 2017
The increased expression of leads to hepatosteatosis in mice. This study aims to investigate the genetic control of hepatic transcription and to explore its impact on NAFLD risk in humans. Through a locus-wide expression quantitative trait loci (eQTL) mapping in two human liver sample sets, a PNPLA3 intronic SNP, rs139051 A>G was identified as a significant eQTL ( = 6.6×10) influencing transcription, with the A allele significantly associated with increased PNPLA3 mRNA. An electrophoresis mobility shift assay further demonstrated that the A allele has enhanced affinity to nuclear proteins than the G allele. The impact of this eQTL on NAFLD risk was further tested in three independent populations. We found that rs139051 did not independently affect the NAFLD risk, whilst rs738409 did not significantly modulate transcription but was associated with NAFLD risk. The A-G haplotype associated with higher transcription of the disease-risk rs738409 G allele conferred similar risk for NAFLD compared to the G-G haplotype that possesses a lower transcription level. Our study suggests that the pathogenic role of in NAFLD is independent of the gene transcription in humans, which may be attributed to the high endogenous transcription level of gene in human livers.
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16 MeSH Terms
The effect of high intensity statin use on liver density: A post hoc analysis of the coronary artery calcification treatment with zocor [CATZ] study.
Sarkar S, Terry JG, Ikizler TA, Crouse JR, Carr JJ, Hung AM
(2016) Obes Res Clin Pract 10: 613-615
MeSH Terms: Adult, Aged, Coronary Artery Disease, Disease Progression, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Liver, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Plaque, Atherosclerotic, Radiography, Abdominal, Simvastatin, Tomography, X-Ray Computed, Treatment Outcome, Young Adult
Added September 29, 2016
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17 MeSH Terms
CC-chemokine receptor 7 (CCR7) deficiency alters adipose tissue leukocyte populations in mice.
Orr JS, Kennedy AJ, Hill AA, Anderson-Baucum EK, Hubler MJ, Hasty AH
(2016) Physiol Rep 4:
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Diet, High-Fat, Fatty Liver, Interleukins, Macrophage Activation, Macrophages, Mice, Mice, Inbred C57BL, Obesity, Receptors, CCR7, Tumor Necrosis Factor-alpha
Show Abstract · Added April 6, 2017
The mechanism by which macrophages and other immune cells accumulate in adipose tissue (AT) has been an area of intense investigation over the past decade. Several different chemokines and their cognate receptors have been studied for their role as chemoattractants in promoting recruitment of immune cells to AT However, it is also possible that chemoattractants known to promote clearance of immune cells from tissues to regional lymph nodes might be a critical component to overall AT immune homeostasis. In this study, we evaluated whether CCR7 influences AT macrophage (ATM) or T-cell (ATT) accumulation. CCR7 and littermate wild-type (WT) mice were placed on low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks. CCR7 deficiency did not impact HFD-induced weight gain, hepatic steatosis, or glucose intolerance. Although lean CCR7 mice had an increased proportion of alternatively activated ATMs, there were no differences in ATM accumulation or polarization between HFD-fed CCR7 mice and their WT counterparts. However, CCR7 deficiency did lead to the preferential accumulation of CD8 ATT cells, which was further exacerbated by HFD feeding. Finally, expression of inflammatory cytokines/chemokines, such as Tnf, Il6, Il1β, Ccl2, and Ccl3, was equally elevated in AT by HFD feeding in CCR7 and WT mice, while Ifng and Il18 were elevated by HFD feeding in CCR7 but not in WT mice. Together, these data suggest that CCR7 plays a role in CD8ATT cell egress, but does not influence ATM accumulation or the metabolic impact of diet-induced obesity.
© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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13 MeSH Terms
Nonalcoholic Fatty Liver Disease and Incident Cardiac Events: The Multi-Ethnic Study of Atherosclerosis.
Zeb I, Li D, Budoff MJ, Katz R, Lloyd-Jones D, Agatston A, Blumenthal RS, Blaha MJ, Blankstein R, Carr J, Nasir K
(2016) J Am Coll Cardiol 67: 1965-6
MeSH Terms: Age Distribution, Aged, Aged, 80 and over, Comorbidity, Coronary Artery Disease, Ethnic Groups, Female, Humans, Incidence, Kaplan-Meier Estimate, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Predictive Value of Tests, ROC Curve, Risk Assessment, Severity of Illness Index, Sex Distribution, United States
Added September 29, 2016
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19 MeSH Terms