Investigating Mechanisms of Acetyl-CoA Sensing and Its Implications in Non-Alcoholic Fatty Liver Disease
研究乙酰辅酶A传感机制及其在非酒精性脂肪肝中的意义
基本信息
- 批准号:10392510
- 负责人:
- 金额:$ 3.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetate-CoA LigaseAcetatesAcetyl Coenzyme AAddressAffectAmino AcidsBiologicalCarbohydratesCarbonCatabolismCell physiologyCellsCholesterolCitratesClinicalClinical TreatmentClinical TrialsCoenzyme ADataDefectDietary FatsDiseaseDisease ProgressionEnzymesFamilyFamily memberFatty AcidsFatty LiverFatty acid glycerol estersFructoseGene ExpressionGenesGeneticGenetic ModelsGenetic TranscriptionGoalsHealthHepaticHigh Fat DietHomeostasisHypoxiaIn VitroIndividualKnockout MiceLifeLipidsLiverLiver diseasesMammalian CellMediatingMessenger RNAMetabolicMetabolic DiseasesMetabolic stressMetabolismMitochondriaModelingMonitorNuclearNutrientOrganismPathogenesisPathologyPathway interactionsPhase III Clinical TrialsPhenotypePhysiologyPlayPositioning AttributePrevalenceProcessProductionProtein IsoformsProteinsPublic HealthRegulationReportingRoleSignal PathwayTestingTherapeuticTissuesUbiquinoneUp-RegulationWorkbasechronic liver diseasedetection of nutrientdietary excessfatty acid oxidationgenetic manipulationhypercholesterolemiaimprovedin vivoin vivo Modelinhibitorinsightlipid biosynthesismevalonatemitochondrial dysfunctionnon-alcoholic fatty liver diseasenovelprogramsresponsetooltranscription factortranscription factor S-IItreatment strategy
项目摘要
PROJECT SUMMARY
Nutrient sensing (i.e. the ability of cells and organisms to sense, report on, and respond to nutrient availability)
is a fundamental mechanism that is essential to life and health, but often dysregulated in the context of
diseases. While the discovery of sensing mechanisms for some nutrients, such as amino acids and ATP, have
yielded critical insight into their implications for disease, the mechanisms other essential metabolites may be
sensed remains unexplored. Acetyl-CoA is a metabolite at the intersection of several catabolic, anabolic, and
signaling pathways, and therefore, may be uniquely positioned to report on nutrient availability. Indeed, data
from our lab and others indicates that acetyl-CoA availability is sensed. Specifically, our lab has previously
shown that upon deletion or inhibition of ATP-citrate lyase (ACLY), cells and tissues upregulate Acetyl-CoA
synthetase short chain family member 2 (ACSS2) in order to maintain nuclear-cytosolic pools of acetyl-CoA.
However, we have a very limited understanding of the mechanisms by which cells sense acetyl-CoA and how
this sensing pathway can subsequently engage adaptive responses when acetyl-CoA production via ACLY is
compromised. Notably, a liver-specific inhibitor against ACLY is currently in phase 3 clinical trials for the
treatment of hypercholesterolemia. Despite this clinical therapeutic and the potential for the inhibitor to be
widely used in individuals with metabolic diseases, studies with genetic models of hepatic ACLY deficiency are
lacking, and in particular, no studies have investigated the implications of ACLY loss and subsequent
compensatory ACSS2 upregulation in metabolic liver disease, such as non-alcoholic fatty liver disease
(NAFLD). Based on my preliminary data, I hypothesize i) that the sensitivity of the mevalonate and cholesterol
pathway to ACLY loss mediates ACSS2 upregulation via activation of SREBP transcription factors and ii) that
suppression of lipogenic acetyl-CoA production and activation of this sensing mechanism has implications in
the pathogenesis of NAFLD by causing a defect in mitochondrial function and fatty acid oxidation. I will test this
hypothesis, first (aim 1) through quantification of cholesterol pathway metabolites and assessment of SREBP
transcriptional activity, using both an in vitro and in vivo model of ACLY deficiency. Further, I will characterize
(aim 2) the effect of suppressing lipogenic acetyl-CoA production an in vivo model of hepatic steatosis.
Specifically, I will investigate how a deficit in lipogenic acetyl-CoA production alters fatty acid oxidation and
mitochondrial function, and determine whether these changes are dependent on alterations in levels of the
mevalonate pathway product, ubiquinone. Overall, I expect the results of this study to address an essential
mechanism in acetyl-CoA sensing, as well as the functional consequences of targeting acetyl-CoA metabolism
in NAFLD, with the potential to impact treatment strategies of existing therapeutics.
项目总结
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 }}
Joyce Ying Liu其他文献
Joyce Ying Liu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('Joyce Ying Liu', 18)}}的其他基金
Investigating Mechanisms of Acetyl-CoA Sensing and Its Implications in Non-Alcoholic Fatty Liver Disease
研究乙酰辅酶A传感机制及其在非酒精性脂肪肝中的意义
- 批准号:
10251911 - 财政年份:2020
- 资助金额:
$ 3.42万 - 项目类别:














{{item.name}}会员




