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S-adenosylmethionine treatment in alcoholic cirrhosis

S-腺苷甲硫氨酸治疗酒精性肝硬化

基本信息

批准号：
10247836
负责人：
Suthat Liangpunsakul
金额：
$ 35.3万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247836
关键词：
Abstinence Alcohol abuse Alcohol consumption Alcohol-Induced Disorders Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcoholic steatohepatitis Alcohols Area Biological Biological Markers CYP2E1 gene Catalytic Domain Cells Child Cirrhosis Complex Complication DNA Data Diglycerides Disease Dose Double-Blind Method Dropout Endotoxemia Endotoxins Enzymes Fatty Acids Fibrosis Genes Health Hepatic Human Immune Immunologic Markers Indiana Inflammation Inflammatory Injury Intestinal permeability Knock-out Lead Lipopolysaccharides Liver Liver diseases Los Angeles Mammals Medical center Messenger RNA Methionine Mitochondria Morbidity - disease rate NMR Spectroscopy National Institute on Alcohol Abuse and Alcoholism Oral Oral Administration Oxidative Stress Oxidative Stress Induction Pathogenesis Pathologic Patients Placebos Process Proteins Public Health Randomized Research Research Design Research Institute Research Personnel Risk Risk Factors Role S-Adenosylmethionine Sample Size Scientist Secondary to Series Serum Spain Supplementation Techniques Triglycerides United States University Hospitals Violence dimer double-blind placebo controlled trial effective therapy endoplasmic reticulum stress extracellular vesicles human disease immune activation improved inclusion criteria insight liquid chromatography mass spectrometry macrophage metabolic phenotype metabolomics methionine adenosyltransferase mortality novel novel strategies personalized medicine placebo controlled study placebo group pre-clinical predicting response primary endpoint problem drinker randomized placebo controlled study response secondary endpoint survival outcome treatment response

项目摘要

Project Summary Alcoholic cirrhosis is a leading cause of morbidity and mortality in the US. One of the key drivers in its pathogenesis is the reduction in hepatic methionine adenosyltransferase 1A (MAT1A) expression resulting in the reduction in hepatic S-adenosylmethionine (SAMe) levels. The reduction in SAMe level leads to several adverse intracellular consequences, which include promoting the inflammatory cascades in immune cells such as macrophages by lipopolysaccharides (LPS), oxidative stress and endoplasmic reticulum (ER) stress. There is extensive preclinical evidence that support the use of SAMe in alcoholic liver disease but human trials using SAMe in alcoholic cirrhosis have not provided clear evidence of efficacy. One large trial conducted in Spain by one of the co-investigators (Dr. José Mato) showed SAMe treatment (1200 mg in divided doses for two years) reduced the mortality of less advanced alcoholic cirrhotics but this was done as a post-hoc analysis and no mechanism was investigated. A shorter (six months) trial done in the U.S. was negative but the dropout rate was very high and abstinence was required to stay in the trial, which may have obscured the SAMe effect since placebo group had marked improvement likely due to abstinence. This application involves two academic centers in the United States (Cedars-Sinai Medical Center in Los Angeles and Indiana University Hospital), a research institute in Spain (CIC bioGUNE), and NIAAA intramural liver research scientist (Dr. Bin Gao) to examine SAMe in humans with alcoholic cirrhosis. We propose a randomized double-blind placebo controlled trial to determine the efficacy of SAMe and its mechanistic effects in patients with alcoholic cirrhosis in the real world setting by encouraging but not requiring abstinence. In addition, we aim to investigate the underlying mechanism(s) of SAMe and use novel metabolomics to follow response to treatment and examine if baseline metabolomics profiles correlate with response to SAMe. Two specific aims are proposed: Aim 1: we will perform a randomized double-blind placebo controlled study between SAMe (1,200 mg/day given in two divided dose) and placebo, in patients with alcoholic cirrhosis (Child class A and B) for 24 months. The primary endpoint will be the mortality of any causes between groups. The key secondary endpoints are the changes in intestinal permeability, serum endotoxin, markers of immune cell activations, and liver-specific mortality. Complementary metabolomics using liquid-chromatography-mass spectrometry (LC-MS) and NMR spectroscopy at baseline and NMR at the end of the trial will assess response to treatment and whether certain profiles predict response to SAMe. Aim 2: we will determine the effect of SAMe treatment on oxidative stress, and ER-stress induced mitochondrial DNA and cytochrome P450 2E1 enriched microparticles. Our application is novel and relevant to an un-met need area of research where no proven effective treatments are available. In addition, our proposal may unveil novel mechanistic insights on the effect of SAMe in alcoholic cirrhosis and the use of metabolomics in personalized treatment of these patients.

项目总结