Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease
阐明肝脏 mTORC2 作为碳水化合物代谢关键调节因子在非酒精性脂肪肝中的作用
基本信息
- 批准号:10387520
- 负责人:
- 金额:$ 3.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAblationAcetatesAcetyl Coenzyme AAcuteAddressAffectAmericanAuxinsBrown FatCarbohydratesCellsCirrhosisComplexConsumptionDeveloped CountriesDeveloping CountriesDietDoseEndocrineEnzymesFDA approvedFRAP1 geneFastingFatty LiverFatty acid glycerol estersFructoseGluconeogenesisGlucoseGlycogenGoalsHepaticHepatocyteHigh Fat DietHomeostasisHumanImpairmentLeadLife StyleLinkLipidsLiverMetabolicMetabolic DiseasesMetabolismModernizationMolecular BiologyMusNuclearNutrientObesityOrganPathogenesisPathologicPathologyPathway interactionsPersonsPhosphorylationPlantsPrevalencePrimary carcinoma of the liver cellsProcessProductionProteomicsRegulationRoleSignal TransductionSystemTestingTimeWorkbasecarbohydrate metabolismclinically relevantcostdietary supplementsfightingflexibilitylipid biosynthesislipid metabolismliver transplantationmetabolomicsneglectnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovel therapeuticsprotective effectresponsestandard of caresugar
项目摘要
Project Summary
Non-alcoholic fatty liver disease (NAFLD) currently effects around 30% of Americans and costs the U.S
approximately $103 billion annually. However, the standard of care remains lifestyle changes and liver
transplantation with currently no FDA approved therapies. NAFLD often correlates with obesity which is rising
in both developed and developing nations. Mammalian target of rapamycin complex 2 (mTORC2) is emerging
as a central hub for carbohydrate and lipid metabolism, with its activation having been linked to NAFLD in
mice. These recent studies have highlighted a role for mTORC2 modulation during high-fat diets in mice,
where hepatic mTORC2 ablation provides a protective effect against high-fat induced hepatic steatosis.
However, the dietary supplements that have been most attributed to the rise of NAFLD in humans are
carbohydrates, specifically fructose. While protective effects of mTORC2 ablation in the liver during high-fat
diet have been investigated, its impact on high-carbohydrate diets has been neglected. Here, I will examine the
ability for mTORC2 to protect against high-carbohydrate induced hepatic steatosis, as has previously been
seen in the context of high-fat diets. Mechanistically, I will investigate the role by which hepatic mTORC2
regulates carbohydrate derived acetyl-CoA synthesis and utilization, subsequently promoting the pathogenesis
of NAFLD. I will accomplish this by examining two distinct acetyl-CoA producing enzymes: ACLY and ACSS2.
Not only will I investigate mTORC2’s role in regulating both ACLY and ACSS2 through phosphorylation, but
also for the first time, investigate mTORC2 loss in an acute setting using an auxin degron system, which is a
plant based endogenous degradation tag. With the completion of this proposed work, I strongly believe that a
more detailed and mechanistic understanding of hepatic signaling, and metabolism will be obtained, providing
targets which could ultimately be used to treat NAFLD and other metabolic diseases.
项目总结
项目成果
期刊论文数量(0)
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John Anthony Haley其他文献
John Anthony Haley的其他文献
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{{ truncateString('John Anthony Haley', 18)}}的其他基金
Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease
阐明肝脏 mTORC2 作为碳水化合物代谢关键调节因子在非酒精性脂肪肝中的作用
- 批准号:
10548816 - 财政年份:2022
- 资助金额:
$ 3.4万 - 项目类别:
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