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:
    10454804
  • 负责人:
  • 金额:
    $ 35.33万
  • 依托单位:
  • 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

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.
项目摘要/摘要 肝细胞癌(肝细胞癌)的增加令人震惊,部分原因是增长迅速 在脂肪肝方面。由于缺乏早期诊断标记物,肝细胞癌的5年生存率仅为10%。 酒精中毒是众所周知的肝细胞癌的危险因素,但酒精如何诱发肝细胞癌的机制仍不清楚。 不清楚。另一个肝细胞癌的危险因素是饮食中果糖的摄入,特别是液体形式(软的 饮料),在过去的两个世纪里增长了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),它增加了肝脏对酒精碳的利用,以产生致癌代谢物 从而创造了一个有利于肿瘤形成的环境。当酒精到达肝脏时,它被转化为 醋酸盐,大部分释放到循环中。然而,当ACSS2被激活时,磁通从 醋酸盐释放到醋酸盐分解代谢,导致过量产生乙酰辅酶A,一种高能... 带电的反应性代谢物。这一改变可以在许多方面发起和支持肝细胞癌,包括 致癌代谢物的产生。事实上,ACSS的过度表达和醋酸盐使用量的增加 通常在包括肝癌在内的癌症中观察到。我们最近发现,接触果糖的小鼠 表现出强烈的诱导肝脏ACSS2活性和醋酸盐使用。因此,果糖饮用量将发生变化。 酒精在肝脏中从以醋酸盐的形式释放到使用的代谢命运。果糖 饮酒还会导致肠道渗漏,改变微生物区系代谢。由此产生的有毒微生物群 代谢产物会引起慢性肝脏炎症,这是一个促肿瘤的微环境。我们会 通过系统定义果糖诱导的ACSS2诱导和ACSS2的影响来测试这些假设 微生物区系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 果糖和酒精协同作用增加了患肝癌的风险。~(13)C-的体内稳定同位素示踪 乙醇和小鼠肝-门脉比较代谢组学,我们将定量定义进展 肝细胞癌发生发展过程中肝组织酒精代谢的变化这将构建一个 肝细胞癌相关酒精衍生代谢物的综合目录。然后我们将选择最好的 候选代谢物并测试这些代谢物是否会引发肝细胞癌。在目标2中,我们将测试我们的 果糖诱导的肝脏ACSS2活性和/或结肠微生物区系变化增强的假说 肝脏产生致癌代谢物,从而引发肝细胞癌。为此,我们将使用我们的 新产生的肝脏特异性ACSS2基因敲除小鼠和抗生素治疗。这些研究将 为一个与临床相关的问题提供分子证据,该问题涉及两种最知名的饮食风险 酒精和果糖等因素协同作用启动和推进了肝细胞癌。我们研究的成功将会有 对公众饮食指南的直接影响,并提供对酒精诱导的肝细胞癌的机械性见解。

项目成果

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Cholsoon Jang其他文献

Cholsoon Jang的其他文献

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{{ truncateString('Cholsoon Jang', 18)}}的其他基金

Elucidating alcohol-induced metabolic remodeling of critical organs
阐明酒精诱导的关键器官代谢重塑
  • 批准号:
    10667050
  • 财政年份:
    2023
  • 资助金额:
    $ 35.33万
  • 项目类别:
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:
    10833393
  • 财政年份:
    2021
  • 资助金额:
    $ 35.33万
  • 项目类别:
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:
    10627856
  • 财政年份:
    2021
  • 资助金额:
    $ 35.33万
  • 项目类别:
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:
    10184696
  • 财政年份:
    2021
  • 资助金额:
    $ 35.33万
  • 项目类别:

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  • 批准号:
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