Elucidating dietary fructose and alcohol interactions during liver cancer development

阐明肝癌发展过程中膳食果糖和酒精的相互作用

基本信息

批准号：
10627856
负责人：
Cholsoon Jang
金额：
$ 35.33万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627856
关键词：
Acetate-CoA Ligase Acetates Acetyl Coenzyme A Alcohol consumption Alcoholism Alcohols Antibiotic Therapy Antibiotics Biochemical Blood Carbon Catabolism Catalogs Cause of Death Charge Chronic Circulation Cirrhosis Consumption Data Development Environment Ethanol Ethanol Metabolism Event Exposure to Fatty Liver Fatty acid glycerol esters Feeds Fructose Goals Hepatic Histone Acetylation Incidence Inflammatory Intake Leaky Gut Liquid substance Liver Malignant Neoplasms Malignant neoplasm of liver Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Metagenomics Molecular Mus Oncogenic Output Prevention strategy Primary carcinoma of the liver cells Production Protocols documentation Public Health Risk Risk Factors Techniques Testing Venous cancer risk cancer type carcinogenicity clinically relevant colon microbiota comparative diagnostic biomarker dietary dietary guidelines drinking fatty liver disease feeding gut microbiota in vivo innovation insight knock-down liver inflammation liver injury metabolomics microbial microbiota microbiota metabolites mortality mouse model novel strategies overexpression soft drink stable isotope success tool tumorigenic

项目摘要

Project Summary/Abstract Hepatocellular carcinoma (HCC) has been alarmingly increased, in part due to rapid increases in fatty liver disease. Owing to the lack of early diagnostic markers, HCC's 5-year survival is only 10%. Alcoholism is a well-known HCC risk factor, but the mechanism of how alcohol induces HCC is still unclear. Another HCC risk factor is consumption of dietary fructose, especially in liquid form (soft drinks), which has increased 100-fold over the past two centuries. Based on our preliminary data, we hypothesize that fructose alters hepatic alcohol metabolism via induction of acetyl-CoA synthetase 2 (ACSS2), which enhances the hepatic usage of alcohol carbons to generate carcinogenic metabolites and thereby creates a pro-tumorigenic environment. When alcohol reaches the liver, it is converted to acetate and mostly released into circulation. However, when ACSS2 is activated, flux is shifted from acetate release to acetate catabolism, resulting in excessive production of acetyl-CoA, a high-energy- charged, reactive metabolite. This alteration can initiate and support HCC in many ways, including carcinogenic metabolite production. Indeed, ACSS overexpression and increased acetate usage are commonly observed in cancers including HCC. We recently found that mice exposed to fructose showed strongly induced hepatic ACSS2 activity and acetate usage. Thus, fructose drinking will shift the metabolic fate of alcohol from release as acetate to usage of acetate within the liver. Fructose drinking also induces gut leakiness and alters microbiota metabolism. The resulting toxic microbiota metabolites cause chronic hepatic inflammation, which is a pro-tumorigenic microenvironment. We will test these hypotheses by systematically defining the impact of fructose-elicited ACSS2 induction and microbiota changes on liver alcohol metabolic flux. In Aim 1, we will determine whether and how fructose and alcohol synergistically increase HCC risk. Using in vivo stable isotope tracing of 13C- ethanol and hepatic-portal comparative metabolomics in mice, we will quantitatively define progressive changes of hepatic alcohol metabolism during HCC initiation and progression. This will build a comprehensive catalog of HCC-associated, alcohol-derived metabolites. We will then choose the top candidate metabolites and test whether these metabolites can trigger HCC. In Aim 2, we will test our hypothesis that fructose-induced hepatic ACSS2 activity and/or colonic microbiota changes enhance carcinogenic metabolite production in the liver, thereby triggering HCC. To this end, we will use our newly generated liver-specific ACSS2 knockdown mice and antibiotics treatment. These studies will provide molecular evidence for a clinically relevant question about how the two best-known dietary risk factors, alcohol and fructose, synergistically initiate and advance HCC. Our study's success will have direct impacts on public dietary guidelines and provide mechanistic insights into alcohol-induced HCC.

项目概要/摘要肝细胞癌 (HCC) 的发病率已惊人地增加，部分原因是发病率的快速增加在脂肪肝疾病中。由于缺乏早期诊断标志物，HCC的5年生存率仅为10%。酗酒是众所周知的 HCC 危险因素，但酒精诱发 HCC 的机制仍不清楚不清楚。另一个 HCC 危险因素是膳食果糖的摄入，尤其是液体形式的果糖（软质果糖）饮料），在过去两个世纪里增加了 100 倍。根据我们的初步数据，我们假设果糖通过诱导乙酰辅酶 A 合成酶 2 改变肝脏酒精代谢 (ACSS2)，增强肝脏对醇碳的利用，产生致癌代谢物从而创造一个促肿瘤发生的环境。酒精到达肝脏后会转化为醋酸盐，大部分释放到循环中。然而，当 ACSS2 被激活时，通量从醋酸盐释放到醋酸盐分解代谢，导致乙酰辅酶A过量产生，乙酰辅酶A是一种高能量的带电的反应性代谢物。这种改变可以通过多种方式引发和支持 HCC，包括致癌代谢物的产生。事实上，ACSS 过度表达和醋酸盐用量增加是常见于包括 HCC 在内的癌症。我们最近发现，暴露于果糖的小鼠显示出强烈诱导的肝 ACSS2 活性和醋酸盐的使用。因此，果糖饮用方式将发生变化酒精的代谢命运从以乙酸盐的形式释放到肝脏内乙酸盐的使用。果糖饮酒还会导致肠道渗漏并改变微生物群代谢。由此产生的有毒微生物群代谢物引起慢性肝脏炎症，这是一种促肿瘤发生的微环境。我们将通过系统地定义果糖引起的 ACSS2 诱导的影响来检验这些假设微生物群变化对肝脏酒精代谢通量的影响。在目标 1 中，我们将确定是否以及如何果糖和酒精协同增加肝癌风险。使用 13C- 体内稳定同位素示踪乙醇和小鼠肝门比较代谢组学，我们将定量定义进展 HCC 发生和进展过程中肝脏酒精代谢的变化。这将构建一个与 HCC 相关的酒精衍生代谢物的综合目录。然后我们选择最上面的候选代谢物并测试这些代谢物是否可以引发 HCC。在目标 2 中，我们将测试我们的果糖诱导的肝脏 ACSS2 活性和/或结肠微生物群变化增强的假设肝脏中产生致癌代谢物，从而引发肝癌。为此，我们将使用我们的新产生的肝脏特异性 ACSS2 敲除小鼠和抗生素治疗。这些研究将为临床相关问题提供分子证据，即两种最著名的饮食风险如何酒精和果糖等因素协同引发和促进 HCC。我们研究的成功将会对公共饮食指南产生直接影响，并为酒精诱发的肝癌提供机制见解。