Regulation of SREBP-1 Processing Lipogenesis by LPCAT
Regulation of SREBP-1 Processing Lipogenesis by LPCAT
批准号:
9189573
负责人:
Bo Wang
金额:
$6.0万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2019-08-31
关键词:
ADD-1 proteinAcyltransferaseAffectAgonistAnabolismBiologicalBiological AssayCarbohydratesCellsCytosolDataDevelopmentDiabetes MellitusDiabetic mouseDietDiseaseDyslipidemiasEnzymesFastingFatty AcidsFatty LiverGene ExpressionGene TargetingGenesGenetic TranscriptionGoalsGolgi ApparatusHealthcareHeart DiseasesHepaticHepatocyteHistologyHormonalHumanIn VitroInsulinKnock-outKnockout MiceLecithinLifeLigandsLipidsLiverLiver FailureLiver X ReceptorLiver diseasesLysophosphatidylcholinesMalignant NeoplasmsMeasuresMediatingMembraneMembrane FluidityMessenger RNAMetabolicMetabolic DiseasesMolecularMusNuclearNuclear ReceptorsNutritionalObese MiceObesityOrganellesPathway interactionsPhosphatidylethanolaminePhospholipidsPhysiologicalPhysiological ProcessesPolyunsaturated Fatty AcidsPost-Translational Protein ProcessingPrevalenceProcessPublishingRegulationResearchResearch Project GrantsRoleSRE-1 binding proteinSRE-2 binding proteinSignal TransductionSpecificitySterolsTestingTherapeuticTranscriptional ActivationTransport ProcessTriglyceridesUnsaturated Fatty AcidsVery low density lipoproteinVesicleWestern WorldWorkbaseeffective therapyfatty acid biosynthesisfeedinghuman diseasehuman subjectin vivoinsightknock-downknockout animallipid biosynthesislipid metabolismliver transplantationmRNA Expressionnon-alcoholic fatty livernonalcoholic steatohepatitisnovelnovel therapeuticspolyunsaturated phosphatidylcholineprotein expressionresponsetraffickingtranscription factor
中文摘要
项目摘要
固醇调节元件结合蛋白-1(SREBP-1)是造脂酶的关键激活剂
参与了脂肪酸的合成。SREBP-1的转录和蛋白水解性切割受
生理和病理条件下的营养和激素因素。胰岛素大幅增加
SREBP-1mRNA的转录主要通过增加LXRs的活性,并促进翻译后
蛋白质的加工。在肥胖/肥胖糖尿病小鼠肝脏中,核SREBP-1c被高度诱导并参与
导致肝脏脂肪酸生物合成和脂肪变性升高。除了类固醇外,还发现了其他类脂。
调节SREBP-1的加工,包括不饱和脂肪酸(FAs)和磷脂。其作用机制
磷脂对SREBP-1c表达的影响机制尚不清楚。我们实验室最近的工作是
发现了一条动态调节细胞膜磷脂(磷脂酰胆碱和磷脂)的LXR-Lpcat3途径
磷脂酰乙醇胺)的组成对细胞脂代谢的变化作出反应。LXR的激活
优先通过诱导多不饱和脂肪酸与磷脂结合
重塑酶Lpcat3。Lpcat3在肝脏中的丢失选择性地减少了肝膜上的花生四烯酸PC,
并导致膜流动性降低。在我们最初的工作之后,我们发现Lpcat3调节
LXR介导的脂肪酸生物合成相关基因的表达。我们的初步数据表明
Lpcat3主要通过调控SREBP的蛋白水解性裂解来调节致脂基因的表达。
1.在本提案中,我们的目标是1)定义Lpcat3通过以下方式调节SREBP-1加工的机制
Lpcat3肝脏特异性敲除原代肝细胞和小鼠。2)确定Lpcat3和磷脂
重塑参与生理或病理条件下肝脏SREBP-1c表达的调节
条件。我们将评估Lpcat3是否介导胰岛素诱导的肝细胞和WT中SREBP-1的表达
和LKO小鼠肝脏在禁食/再喂养过程中。我们将检测Lpcat3抑制对SREBP-1的影响
在ob/ob小鼠中的处理。最后,我们将确定Lpcat3与磷脂重塑的关系。
人类非酒精性脂肪肝病(NAFLD)。鉴于新发疾病的调控失调与
脂肪生成和人类主要疾病,了解SREBP-1表达的调节有望
为脂肪肝和血脂异常发展的分子控制提供了新的见解,并可能
为这些疾病提供潜在的治疗机会。
英文摘要
Project Summary
Sterol regulatory element-binding protein-1 (SREBP-1) is a pivotal activator of lipogenic enzymes
involved in fatty acid synthesis. Transcription and proteolytic cleavage of SREBP-1 is tightly regulated by
nutritional and hormonal factors under physiological and pathological conditions. Insulin dramatically increases
the transcription of SREBP-1 mRNA primarily by increasing the activity of LXRs, and promotes post-translational
processing of the protein. In ob/ob diabetic mouse livers, nuclear SREBP-1c is highly induced and contributes
to the elevated hepatic fatty acid biosynthesis and steatosis. Besides sterols, other lipids have also been shown
to regulate SREBP-1 processing, including unsaturated fatty acids (FAs) and phospholipids. The mechanisms
by which phospholipids affect SREBP-1c expression remain to be resolved. Recent work from our lab has
identified an LXR-Lpcat3 pathway that dynamically modulates membrane phospholipid (phosphatidylcholine and
Phosphatidylethanolamine) composition in response to changes in cellular lipid metabolism. Activation of LXRs
preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the
remodeling enzyme Lpcat3. Loss of Lpcat3 in liver selectively reduces arachidonoyl PC in liver membranes,
and results in decreased membrane fluidity. Following on our initial work, we discovered that Lpcat3 regulates
the LXR-mediated expression of genes involved in fatty acid biosynthesis. Our preliminary data suggest that
Lpcat3 regulates the expression of lipogenic genes mainly through manipulating proteolytic cleavage of SREBP-
1. In this proposal, we aim to 1) Define the mechanisms by which Lpcat3 regulates SREBP-1 processing using
Lpcat3 liver specific knockout primary hepatocytes and mice. 2) Determine whether Lpcat3 and phospholipid
remodeling are involved in the regulation of SREBP-1c expression in liver under physiological or pathological
conditions. We will assess if Lpcat3 mediates insulin-induced SREBP-1 expression in hepatocytes and in WT
and LKO mouse livers during fasting/refeeding. We will examine the effect of Lpcat3 inhibition on SREBP-1
processing in ob/ob mice. Finally we will determine the involvement of Lpcat3 and phospholipid remodeling in
human nonalcoholic fatty liver diseases (NAFLD). Given the close association between dysregulation of de novo
lipogenesis and major human diseases, understanding the regulation of SREBP-1 expression is expect to
provide novel insights into the molecular control of the development of fatty liver and dyslipidemia, and may
suggest potential therapeutic opportunities for these diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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依托单位:
海外基金