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/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Cholsoon Jang其他文献

Cholsoon Jang的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Development of palladium-catalyzed novel organic transformations of silylated allyl acetates
钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
    18K05101
  • 财政年份:
    2018
  • 资助金额:
    $ 34.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Biosynthesis of Methylketones and 2-Alkany l Acetates
甲基酮和 2-烷酰基乙酸酯的生物合成
  • 批准号:
    9118188
  • 财政年份:
    1992
  • 资助金额:
    $ 34.6万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了