Linking fat metabolism to hepatic fibrosis
将脂肪代谢与肝纤维化联系起来
基本信息
- 批准号:10377377
- 负责人:
- 金额:$ 51.57万
- 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:2020-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAdipose tissueAffectAgonistAmericanAnimal ModelApoptosisBenignBiologyCell Adhesion MoleculesCell DeathCellsCentral obesityCharacteristicsChickensChronicCirrhosisClinical ResearchDataDevelopmentDiagnosisDietDiseaseEndothelin-1Epidermal Growth Factor ReceptorExhibitsFatty AcidsFatty LiverFibrosisFunctional disorderGenesGlycerolGoalsHealthHepaticHepatic Stellate CellHepatocyteHigh Fat DietHistologicHumanHyperinsulinismHypertriglyceridemiaImpairmentInflammatoryInsulinInsulin ResistanceIntakeKnock-outKnockout MiceLeadLinkLipaseLipidsLipolysisLiverLiver DysfunctionLiver FibrosisLiver diseasesMEKsMediatingMetabolicModalityMolecularMusMutationNon-Insulin-Dependent Diabetes MellitusObesityPathogenesisPathologyPathway interactionsPatientsPatternPhenotypePhosphorylationPioglitazonePlasmaPlayProcessProteinsRegulationRepressionRisk FactorsRoleScientistSignal TransductionSteatohepatitisTestingTherapeuticTransgenic MiceTransgenic OrganismsUnited StatesWaterWeight Gainadenoviral-mediatedbasecarcinoembryonic antigen-related cell adhesion moleculesdesigndrug developmentexperimental studyfatty liver diseasegain of functionglucose tolerancehealth disparityhepatocyte injuryinnovationinsulin receptor tyrosine kinaseinsulin sensitivityinsulin toleranceinterdisciplinary collaborationknock-downlipid biosynthesislipid metabolismliver inflammationmetabolic phenotypemouse modelmutantnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnull mutationoverexpressionparacrinereceptorreconstitutionresponsestellate celltherapeutic targetuptake
项目摘要
Project Summary
Non-alcoholic fatty liver disease (NAFLD), the most common of liver pathologies, is one of the most
profound health disparities. The molecular pathway(s) associated with the pathogenesis of NAFLD and its
subsequent progression to nonalcoholic steatohepatitis (NASH) remains elusive. We have previously shown that
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays a critical role in insulin clearance
in the liver and links hyperinsulinemia to NAFLD/NASH. Preliminary data identify that Cell death-Inducing
DFF45-like Effector (Cidec;; also termed Fsp27), a lipid droplet associated protein that regulates lipolysis in the
adipose tissue, regulates liver metabolic function and fibrosis via hepatic CEACAM1. Most interestingly, we found
that FSP27–/– mice exhibited lower hepatic CEACAM1 levels on regular and HF diets, and subsequently,
impaired insulin clearance and hyperinsulinemia that could in turn, mediate hepatic insulin resistance. In addition
to hyperinsulinemia-driven hepatic steatosis, Fsp27–/– mice also exhibited elevated plasma Endothelin 1 and
spontaneous hepatic bridging-fibrosis, comparable to the phenotype of Ceacam1 knockout mice. To study the
gain-of-function we have developed an innovative adipose-specific transgenic mouse model expressing human-
FSP27. Our preliminary data show that this mouse model exhibits normal insulin and glucose tolerance in
response to HF intake in parallel to a remarkable ~5-fold induction of hepatic CEACAM1 protein levels. Since
lipolysis-derived fatty acids from white adipose tissue (WAT) reduces hepatic CEACAM1 expression and forced
liver-specific overexpression of CEACAM1 or its adenoviral-mediated delivery protects against HF diet-induced
insulin resistance and steatohepatitis, and fibrosis in WAT and liver, we hypothesize that reduction of FSP27 in
adipocytes causes FFA release and redistribution to the liver to reduce hepatic CEACAM1 levels and
subsequently, cause hepatocyte injury and hepatic fibrosis. We postulate the underlying mechanisms to involve
activation of epidermal growth factor receptor by fatty acids and Endothelin 1, the expression of which is
upregulated by the MEK/ERK-PPARg pathway. Aim 1 will investigate whether CEACAM1 in hepatocytes
regulates hepatic fibrosis in mice with adipocyte-specific deletion of Fsp27 (paracrine regulation). Aim 2 will
examine the cell-autonomous fibrogenic effect of FSP27 deletion in hepatic stellate cells. This approach is well-
thought and well-designed where novel mouse models (both knockout and transgenic) will be used to study the cross-
talk between adipose tissue and liver which plays a critical role in the development of hepatic fibrosis via altering
FSP27. A strength of this proposal is an interdisciplinary collaboration between Drs. S. Najjar (fatty liver disease
and lipid metabolism) and V. Puri (adipose biology and lipid metabolism). As is clear from the strong preliminary data,
these scientists have productively collaborated on a proposal that will delineate the novel pathways in the
pathogenesis of NAFLD/NASH that might lead to novel treatments against this remarkable health problem.
项目摘要
非酒精性脂肪性肝病(NAFLD)是最常见的肝脏病理,也是最常见的肝脏疾病之一。
与NAFLD发病机制相关的分子途径及其
随后进展为非酒精性脂肪性肝炎(NASH)仍然是难以捉摸的。我们以前已经表明,
癌胚抗原相关细胞粘附分子1(CEACAM 1)在胰岛素清除中起关键作用
并将高胰岛素血症与NAFLD/NASH联系起来。 初步数据表明,细胞死亡诱导
DFF 45-Fsp 27样效应子(Cidec; Fsp 27),一种调节脂肪分解的脂滴相关蛋白,
脂肪组织,通过肝脏CEACAM 1调节肝脏代谢功能和纤维化。最有趣的是,
FSP 27-/-小鼠在常规和HF饮食中表现出较低的肝脏CEACAM 1水平,随后,
胰岛素清除率受损和高胰岛素血症,进而可能介导肝脏胰岛素抵抗。
Fsp 27-/-小鼠也表现出血浆内皮素1和内皮素2水平升高,
自发性肝桥接纤维化,与Ceacam 1敲除小鼠的表型相当。
我们已经开发了一种创新的脂肪特异性转基因小鼠模型,
我们的初步数据显示,该小鼠模型在FSP 27中表现出正常的胰岛素和葡萄糖耐受性。
HF摄入的反应平行于肝脏CEACAM 1蛋白水平的显著~5倍诱导。
来自白色脂肪组织(WAT)的脂解衍生的脂肪酸减少肝脏CEACAM 1表达,并迫使
CEACAM 1的肝特异性过表达或其腺病毒介导的递送可保护HF饮食诱导的
胰岛素抵抗和脂肪性肝炎,以及WAT和肝脏纤维化,我们假设
脂肪细胞引起FFA释放并重新分布到肝脏,以降低肝脏CEACAM 1水平,
随后,导致肝细胞损伤和肝纤维化。我们推测其潜在机制涉及
表皮生长因子受体被脂肪酸和内皮素1激活,其表达是
通过MEK/ERK-PPARg β途径上调。 目的1:研究CEACAM 1在肝细胞中的表达
在脂肪细胞特异性缺失Fsp 27的小鼠中调节肝纤维化(旁分泌调节)。
检测FSP 27缺失在肝星状细胞中的细胞自主性纤维化作用。
新的小鼠模型(基因敲除和转基因)将被用于研究交叉免疫,
脂肪组织和肝脏之间的对话,通过改变肝纤维化的发展起着关键作用,
FSP 27.该建议的一个优势是S. Najjar博士(脂肪肝疾病)
和脂质代谢)和V. Puri(脂肪生物学和脂质代谢)。从强有力的初步数据中可以清楚地看出,
这些科学家已经富有成效地合作了一项提案,该提案将描绘出
NAFLD/NASH的发病机制,可能导致针对这一显着的健康问题的新治疗。
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)
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Sonia M. Najjar其他文献
Molecular cloning of pp120/ECTO-ATPase, an endogenous substrate of the insulin receptor kinase.
pp120/ECTO-ATPase(胰岛素受体激酶的内源性底物)的分子克隆。
- DOI:
- 发表时间:
1993 - 期刊:
- 影响因子:0
- 作者:
Sonia M. Najjar;Neubert Philippe;Simeon I. Taylor;Domenico Accili - 通讯作者:
Domenico Accili
Modifications of RNA processing modulate the expression of hemoglobin genes.
RNA 加工的修饰可调节血红蛋白基因的表达。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:11.1
- 作者:
Panagoula Kollia;Eitan Fibach;Sonia M. Najjar;Alan N. Schechter;C. T. Noguchi - 通讯作者:
C. T. Noguchi
Hepatic insulin receptor: new views on the mechanisms of liver disease
肝胰岛素受体:肝病机制的新观点
- DOI:
10.1016/j.metabol.2023.155607 - 发表时间:
2023-08-01 - 期刊:
- 影响因子:11.900
- 作者:
Wang-Hsin Lee;Sonia M. Najjar;C. Ronald Kahn;Terry D. Hinds - 通讯作者:
Terry D. Hinds
Sonia M. Najjar的其他文献
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{{ truncateString('Sonia M. Najjar', 18)}}的其他基金
Novel Molecular Determinants of Insulin Clearance
胰岛素清除率的新分子决定因素
- 批准号:
10609503 - 财政年份:2022
- 资助金额:
$ 51.57万 - 项目类别:
Novel Molecular Determinants of Insulin Clearance
胰岛素清除率的新分子决定因素
- 批准号:
10446927 - 财政年份:2022
- 资助金额:
$ 51.57万 - 项目类别:
CEACAM1: A link between metabolic and cardiovascular diseases
CEACAM1:代谢与心血管疾病之间的联系
- 批准号:
8237746 - 财政年份:2012
- 资助金额:
$ 51.57万 - 项目类别:
CEACAM1: A link between metabolic and cardiovascular diseases
CEACAM1:代谢与心血管疾病之间的联系
- 批准号:
8403751 - 财政年份:2012
- 资助金额:
$ 51.57万 - 项目类别:
CEACAM1: A link between metabolic and cardiovascular diseases
CEACAM1:代谢与心血管疾病之间的联系
- 批准号:
8597957 - 财政年份:2012
- 资助金额:
$ 51.57万 - 项目类别:
Insulin resistance in the pathogenesis of NASH
NASH 发病机制中的胰岛素抵抗
- 批准号:
7943014 - 财政年份:2009
- 资助金额:
$ 51.57万 - 项目类别:
Insulin resistance in the pathogenesis of NASH
NASH 发病机制中的胰岛素抵抗
- 批准号:
7755556 - 财政年份:2009
- 资助金额:
$ 51.57万 - 项目类别:
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