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:
    10184696
  • 负责人:
  • 金额:
    $ 34.6万
  • 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.
项目总结/摘要 肝细胞癌(HCC)的发病率惊人地增加,部分原因是快速增长 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%。 酒精中毒是一个众所周知的肝癌危险因素,但酒精如何诱导肝癌的机制仍然是 不清楚另一个HCC风险因素是食用果糖,特别是液体形式的果糖(软果糖)。 在过去的两个世纪里,这一数字增加了100倍。根据初步数据,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 (ACSS 2),它增强了肝脏对酒精碳的利用,产生致癌代谢物 从而产生促肿瘤发生的环境。当酒精到达肝脏时,它被转化为 醋酸盐并大部分释放到循环中。然而,当ACSS 2被激活时,通量从 乙酸释放到乙酸催化剂,导致过量生产乙酰辅酶A,一种高能量- 带电的活性代谢物这种改变可以在许多方面启动和支持HCC,包括 致癌代谢物的产生。事实上,ACSS过度表达和乙酸盐使用增加是 常见于包括HCC在内的癌症中。我们最近发现暴露在果糖中的老鼠 显示强烈诱导的肝脏ACSS 2活性和乙酸盐使用。因此,果糖饮料将改变 酒精在肝脏内从乙酸盐释放到乙酸盐使用的代谢命运。果糖 饮酒还会导致肠道渗漏并改变微生物群的新陈代谢。由此产生的有毒微生物群 代谢物引起慢性肝脏炎症,这是一种促肿瘤微环境。我们将 通过系统地定义果糖诱导的ACSS 2诱导的影响来测试这些假设, 微生物群的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HCC风险。使用体内稳定同位素示踪13 C- 乙醇和肝门比较代谢组学在小鼠中,我们将定量定义进行性 肝细胞癌发生和发展过程中肝脏酒精代谢的变化。这将建立一个 肝癌相关、酒精衍生代谢物的全面目录。然后我们会选出 候选代谢物,并测试这些代谢物是否可以触发HCC。在目标2中,我们将测试 假设果糖诱导肝ACSS 2活性和/或结肠微生物群变化增强 在肝脏中产生致癌代谢物,从而引发HCC。为此,我们将利用我们的 新产生的肝特异性ACSS 2敲除小鼠和抗生素治疗。这些研究将 为一个临床相关问题提供了分子证据,即两种最著名的饮食风险 因子,酒精和果糖,协同启动和推进HCC。我们研究的成功 对公众饮食指南的直接影响,并为酒精诱导的HCC提供机制性见解。

项目成果

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Cholsoon Jang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:
    $ 34.6万
  • 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:
    10454804
  • 财政年份:
    2021
  • 资助金额:
    $ 34.6万
  • 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:
    $ 34.6万
  • 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:
    $ 34.6万
  • 项目类别:

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  • 批准号:
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