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

• 批准号: 10454804
• 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
• 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/10454804
• 关键词: Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Alcohol consumption; Alcoholism; Alcohols; Antibiotic Therapy; Antibiotics; Biochemical; Blood; Blood Circulation; Carbon; Catabolism; Catalogs; Cause of Death; Charge; Chronic; 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; base; cancer risk; 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; mouse model; novel strategies; overexpression; soft drink; stable isotope; success; tool; tumorigenic

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.

项目摘要/摘要 肝细胞癌（HCC）令人震惊地增加，部分原因是迅速增加 在脂肪肝病中。由于缺乏早期诊断标记，HCC的5年生存仅为10％。 酒精中毒是众所周知的HCC危险因素，但酒精诱导HCC的机制仍然 不清楚。 HCC的另一个危险因素是食用饮食果糖，尤其是在液体形式的情况下（柔软 饮料），在过去两个世纪中增加了100倍。根据我们的初步数据，我们 假设果糖通过诱导乙酰-COA合成酶2改变了肝醇代谢2 （ACSS2），这增强了酒精碳的肝脏使用以产生致癌代谢物 从而创造了一个亲穆罗尼的环境。当酒精到达肝脏时，它被转换为 醋酸盐，主要释放到循环中。但是，当激活ACSS2时，通量会从 乙酸盐释放到乙酸盐分解代谢，导致过度产生乙酰基-COA，这是一种高能量 充电，反应性代谢产物。这种更改可以在许多方面启动和支持HCC，包括 致癌代谢产物产生。实际上，ACS的过表达和乙酸盐使用量增加是 通常在包括HCC在内的癌症中观察到。我们最近发现暴露于果糖的小鼠 表现出强烈诱导的肝ACSS2活性和乙酸盐的使用。因此，果糖饮用会改变 酒精的代谢命运从乙酸盐释放到肝内乙酸的使用。果糖 饮酒还会引起肠道泄漏并改变微生物群的代谢。产生的有毒菌群 代谢物引起慢性肝发炎，这是一种亲氧化的微环境。我们将 通过系统地定义果糖引起的ACSS2诱导和 肝酒代谢通量的微生物群变化。在AIM 1中，我们将确定是否以及如何 果糖和酒精协同增加HCC风险。使用13C-的体内稳定同位素跟踪 乙醇和肝道路比较代谢组中的小鼠，我们将定义进行性渐进性 HCC启动和进展过程中肝酒精代谢的变化。这将建立一个 与HCC相关的酒精衍生代谢产物的综合目录。然后，我们将选择顶部 候选代谢物并测试这些代谢物是否可以触发HCC。在AIM 2中，我们将测试我们的 果糖诱导的肝ACSS2活性和/或结肠菌群变化的假设增强了 肝脏中的致癌代谢产物产生，从而触发HCC。为此，我们将使用我们的 新生成的肝特异性ACSS2敲低小鼠和抗生素治疗。这些研究会 提供分子证据，说明两个最著名的饮食风险如何 酒精和果糖的因素协同启动并提高HCC。我们的研究的成功将有 直接影响公共饮食指南，并为酒精引起的HCC提供机械洞察力。