Characterizing Alcohol's Effects on Repair of Liver Injury

表征酒精对肝损伤修复的影响

• 批准号: 7944184
• 负责人: ANNA MAE ELIZABETH DIEHL
• 金额: $ 98.16万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944184
• 关键词: Accounting; Aftercare; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animals; Benefits and Risks; Cardiovascular Diseases; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Protocols; DNA; Data; Disease; Environmental Risk Factor; Epigenetic Process; Event; Evolution; Exposure to; Fibrosis; Freezing; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic Polymorphism; Haplotypes; Health Benefit; Hepatic; Hepatitis C virus; Housing; Hypermethylation; Individual; Injury; Knowledge; Learning; Link; Liver; Liver Fibrosis; Liver diseases; Mediating; Methylation; Modification; Molecular Profiling; Pathway Analysis; Patients; Plasma; Population; Predisposition; Process; Public Health; Recommendation; Reporting; Research; S-Adenosylmethionine; Sampling; Specific qualifier value; Supplementation; Time; Tissue Banks; Tissues; Transplantation; Work; alcohol effect; alcohol response; base; biobank; chronic alcohol ingestion; cohort; drinking; genetic profiling; insight; liver biopsy; liver transplantation; non-alcoholic fatty liver; novel; promoter; public health relevance; repaired; repository; response; social

DESCRIPTION (provided by applicant): Heavy habitual consumption of alcohol leads to progressive injury and fibrosis in several tissues, including the liver. However, many heavy drinkers do not develop advanced liver fibrosis (i.e., cirrhosis) despite years of alcohol abuse. More modest consumption of alcohol (< 2drinks/day) has actually been associated with certain health benefits, such as protection from cardiovascular disease. The effects of modest alcohol consumption on the liver have been difficult to predict, however, because evidence suggests that this inhibits fibrosis progression in some types of liver injury (e.g., nonalcoholic fatty liver disease - NAFLD) but accelerates the evolution of cirrhosis in others (e.g., chronic hepatitis C - HCV). Research is needed to clarify the mechanisms that account for the diverse hepatic responses to alcohol. This project is grounded in the HYPOTHESIS that alcohol consumption provokes epigenetic events that modify liver repair responses that are specified by the underlying genetic profile. Our Specific Aims are: 1) to determine if a) there are liver gene expression and/or epigenetic signatures for advanced liver fibrosis and b) alcohol consumption influences this fibrogenic profile; 2) to identify gene polymorphisms that associate with susceptibility to alcohol-related alterations in the fibrogenic profile; 3) to determine the effects of SAMe deficiency and SAMe supplementation on epigenetic modifications and the liver gene expression profile for advanced liver fibrosis in individuals with alcohol-induced cirrhosis. We will take advantage of large well-annotated bio-repositories that house frozen liver samples, serum/plasma, DNA, and clinical information from patients with NAFLD, chronic HCV, and alcoholic liver disease (ALD). The largest and most comprehensive tissue collection was obtained from > 1000 patients with NAFLD and includes sizeable sub-populations who are either non-drinkers or social drinkers. Therefore, initial work in Aims 1 & 2 will focus on characterizing the liver gene expression, epigenetic signature and haplotype profiles of these groups. Parallel liver gene expression and epigenetic analyses will be conducted in non- drinking and modest drinkers with chronic HCV, our next largest cohort. Because liver biopsies are not generally indicated in patients with ALD, analysis will be restricted to cirrhotic ALD samples that were acquired at the time of liver transplantation or during an already approved and funded clinical protocol that is investigating the effects of SAMe on liver fibrosis. In aggregate, these studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous. PUBLIC HEALTH RELEVANCE: These studies will provide novel information about how alcohol induces epigenetic events that modulate hepatic expression of genes that regulate liver fibrosis, and identify gene polymorphisms that influence these responses. Such knowledge will help to guide recommendations about the risk/benefits of alcohol use, particularly in individuals with underlying liver disease. This has important public health implications given the fact that social use of alcohol is virtually ubiquitous.

描述(申请人提供)：大量习惯性饮酒会导致几种组织的进行性损伤和纤维化，包括肝脏。然而，尽管酗酒多年，许多酗酒者并没有发展为晚期肝纤维化(即肝硬变)。更适度的饮酒(每天2杯)实际上与某些健康益处有关，比如预防心血管疾病。然而，适量饮酒对肝脏的影响一直难以预测，因为有证据表明，这抑制了某些类型的肝损伤(例如，非酒精性脂肪性肝病)的纤维化进展，但加速了其他类型的肝硬变(例如，慢性丙型肝炎)的演变。需要研究来澄清解释肝脏对酒精的不同反应的机制。这个项目基于这样一个假设，即饮酒会引发表观遗传事件，从而改变由潜在基因特征指定的肝脏修复反应。我们的具体目标是：1)确定是否有进展性肝纤维化的肝脏基因表达和/或表观遗传学特征，以及b)饮酒是否影响这种纤维化特征；2)确定与酒精性纤维化相关改变的易感性相关的基因多态；3)确定相同的缺乏和相同的补充对酒精性肝硬化症患者的表观遗传修饰和肝脏基因表达谱的影响。我们将利用大型的注释良好的生物储存库，其中存储了来自NAFLD、慢性丙型肝炎和酒精性肝病(ALD)患者的冷冻肝脏样本、血清/血浆、DNA和临床信息。最大和最全面的组织收集来自&gt；1000名NAFLD患者，其中包括相当大的不饮酒者或社交饮酒者。因此，AIMS 1和AIMS 2的初步工作将集中于表征这些群体的肝脏基因表达、表观遗传学特征和单倍型特征。平行的肝脏基因表达和表观遗传学分析将在不饮酒和适度饮酒的慢性丙型肝炎患者中进行，这是我们的下一个最大的队列。由于ALD患者一般不进行肝活检，因此分析将仅限于在肝移植时或在已经批准和资助的临床方案中获得的肝硬化性ALD样本，该临床方案正在调查同样的检查对肝纤维化的影响。总而言之，这些研究将提供关于酒精如何诱导调控肝纤维化基因表达的表观遗传事件的新信息，并确定影响这些反应的基因多态。这些知识将有助于指导关于饮酒风险/益处的建议，特别是在患有潜在肝病的个人中。鉴于酒精在社会上的使用几乎无处不在，这对公共卫生具有重要的影响。 公共卫生相关性：这些研究将提供关于酒精如何诱导表观遗传事件的新信息，这些事件调节肝脏调节肝纤维化基因的表达，并确定影响这些反应的基因多态。这些知识将有助于指导关于饮酒风险/益处的建议，特别是在患有潜在肝病的个人中。鉴于酒精在社会上的使用几乎无处不在，这对公共卫生具有重要的影响。

项目成果

Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression.

• DOI: 10.1038/s41467-022-32788-x
• 发表时间: 2022-09-03
• 期刊: Nature communications
• 影响因子: 16.6

Sex and Menopause Modify the Effect of Single Nucleotide Polymorphism Genotypes on Fibrosis in NAFLD.

• DOI: 10.1002/hep4.1668
• 发表时间: 2021-04
• 期刊: Hepatology communications
• 影响因子: 5.1
• 作者: Wegermann K;Garrett ME;Zheng J;Coviello A;Moylan CA;Abdelmalek MF;Chow SC;Guy CD;Diehl AM;Ashley-Koch A;Suzuki A
• 通讯作者: Suzuki A