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
- 来源:
- 关键词:Acetate-CoA LigaseAcetatesAcetyl Coenzyme AAlcohol consumptionAlcoholismAlcoholsAntibiotic TherapyAntibioticsBiochemicalBloodBlood CirculationCarbonCatabolismCatalogsCause of DeathChargeChronicCirrhosisConsumptionDataDevelopmentEnvironmentEthanolEthanol MetabolismEventExposure toFatty LiverFatty acid glycerol estersFeedsFructoseGoalsHepaticHistone AcetylationIncidenceInflammationInflammatoryIntakeLeaky GutLiquid substanceLiverLiver diseasesMalignant NeoplasmsMalignant neoplasm of liverMass Spectrum AnalysisMeasuresMediatingMetabolicMetabolismMetagenomicsMolecularMusOncogenicOutputPrevention strategyPrimary carcinoma of the liver cellsProductionProtocols documentationPublic HealthRiskRisk FactorsTechniquesTestingVenousbasecancer riskcarcinogenicityclinically relevantcolon microbiotacomparativediagnostic biomarkerdietarydietary guidelinesdrinkingfeedinggut microbiotain vivoinnovationinsightknock-downliver injurymetabolomicsmicrobialmicrobiotamicrobiota metabolitesmouse modelnovel strategiesoverexpressionsoft drinkstable isotopesuccesstooltumorigenic
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)
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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:
$ 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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