Genetic Factors in Determining Susceptibility to Alcohol Dependence and Development of Alcohol-induced Liver Disease

1981 ◽  
Vol 10 (2) ◽  
pp. 307-314
Author(s):  
W.J. JENKINS ◽  
H.C. THOMAS
Keyword(s):  
Liver Disease ◽  
Alcohol Dependence ◽  
Genetic Factors

Pathophysiology of Nonalcoholic Fatty Liver Disease: Lifestyle-Gut-Gene Interaction

2016 ◽  
Vol 34 (Suppl. 1) ◽  
pp. 3-10 ◽  
Author(s):  
Arianna Mazzotti ◽  
Maria Turchese Caletti ◽  
Anna Simona Sasdelli ◽  
Lucia Brodosi ◽  
Giulio Marchesini
Keyword(s):  
Liver Disease ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Genetic Factors ◽  
De Novo Lipogenesis ◽  
Primary Role ◽  
Nonalcoholic Fatty Liver ◽  
Increased Risk

Background: The accumulation of fat droplets in the hepatic parenchyma is driven by several factors, synergistically acting to increase triglyceride flow to the liver (diet and metabolic factors, endotoxemia from gut microbiota, genetic factors). Key Messages: In the presence of unhealthy lifestyles and behavioral factors, leading to enlarged adipose tissue and insulin resistance (IR), both lipolysis and de novo lipogenesis are expected to increase the risk of hepatic lipid depots, in association with high calorie (either high-fat or high-carbohydrate) diets. The gut microbiota may also be involved via obesity, IR and hepatic inflammation generated by gut-derived toxic factors. Finally, several data also support a primary role of genetic factors. A few gene polymorphisms have also been associated with the risk of nonalcoholic fatty liver disease development and nonalcoholic steatohepatitis progression to more fibrosis and advanced liver disease. In a few cases (e.g., patatin-like phospholipase domain-containing 3/adiponutrin), steatosis carries a high risk of both liver disease and cardiovascular morbidity/mortality; in other cases (e.g., transmembrane 6 superfamily 2 human gene), dissociation has been observed between the increased risk of liver disease versus cardiovascular disease. Conclusions: A variable interplay between the genetic background and the metabolic milieu is the likely physiopathologic mechanism involved in individual cases, which must be considered for implementing effective treatment strategies.

scholarly journals Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial

2018 ◽  
Vol 212 (6) ◽  
pp. 362-369 ◽  
Author(s):  
Kirsten C. Morley ◽  
Andrew Baillie ◽  
Isabel Fraser ◽  
Ainsley Furneaux-Bate ◽  
Glenys Dore ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcohol Dependence ◽  
Controlled Trial ◽  
Heavy Drinking ◽  
Randomised Clinical Trial ◽  
Effective Treatment Option ◽  
Double Blind ◽  
Significant Treatment ◽  
Double Blind Placebo ◽  
Specialist Services

BackgroundThere are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD).AimsTo conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125).MethodPatients (n= 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (≥5 drinks per day in men and ≥4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent.ResultsThere was a significant effect of baclofen (composite groups) on time to lapse (χ2= 6.44,P<0.05, Cohen'sd= 0.56) and relapse (χ2= 4.62,P<0.05,d= 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%;P<0.05). There was one serious adverse event (overdose) directly related to medication (75 mg).ConclusionsBaclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services.Declaration of interestNone.

scholarly journals Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in nonalcoholic fatty liver disease

2021 ◽  
Author(s):  
Taekyeong Yoo ◽  
Sae Kyung Joo ◽  
Hyo Jung Kim ◽  
Hyun Young Kim ◽  
Hyungtai Sim ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Genetic Factors ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Causal Genes ◽  
Disease Specific

AbstractBackground & AimsNonalcoholic fatty liver disease (NAFLD) poses an impending clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype.MethodsWe recruited 125 Korean biopsy-proven NAFLD patients and healthy individuals and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed SNPs. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean NAFLD individuals was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models.ResultsThe NAFLD-specific eQTL screening yielded 242 loci. Among them, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in NAFLD patients homozygous for the non-reference allele of rs2291702, compared to no-NAFLD subjects with the same genotype (P = 4.79 × 10−6). This change was replicated in an additional 162 individuals, yielding a combined P-value of 8.05 × 10−8 from a total of 245 NAFLD patients and 48 controls.Knockdown of AGXT2 induced palmitate-overloaded hepatocyte death by increasing ER stress, and exacerbated NAFLD diet-induced liver fibrosis in mice. However, overexpression of AGXT2 reversely attenuated liver fibrosis and steatosis as well.ConclusionsWe implicate a new molecular role of AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD.Lay summaryElucidating causal genes for NAFLD has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 biopsy-proven NAFLD and no-NAFLD Korean individuals and an additional 162 individuals for replication, we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of NAFLD causal genes that act on the basis of genotype.

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