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.
项目总结:
--
非酒精性脂肪性肝病(NAFLD)是肝脏病理中最常见的疾病,也是最常见的疾病之一。
存在着深刻的健康差异。新的分子生物学途径(S)与非酒精性脂肪肝的发病机制密切相关。
随后的疾病进展到非酒精性脂肪性肝炎(NASH)仍然难以捉摸。我们之前已经证明过这一点。
癌胚抗原相关的胰岛素细胞黏附分子1(CEACAM1)在胰岛素清除过程中起着至关重要的作用。
在这项研究中,肝脏疾病和疾病将高胰岛素血症与NAFLD/NASH联系起来。他们的初步研究数据可以确定是什么原因导致细胞死亡。
DFF45--类;效应器蛋白(CIDEC;DFSP27),是一种脂滴和相关的蛋白质,可以调节细胞内的脂解反应。
脂肪组织,它通过肝脏CEACAM1调节肝脏的代谢功能,促进纤维化。最有趣的是,我们发现。
在常规饮食和随后的饮食中,FSP27/-小鼠表现出较低的肝脏CEACAM1水平。
胰岛素清除能力受损和高胰岛素血症可能反过来导致肝脏胰岛素抵抗。此外,
为了防止高胰岛素血症导致的肝脏脂肪变性,Fsp27-/-小鼠也表现出血浆内毒素水平升高。
自发性肝纤维化,可与Ceacam1基因敲除小鼠的主要表型相似。
功能的获得-我们可以开发出一种创新的脂肪特异性转基因小鼠模型,以表达人类-
FSP27.我们的初步研究数据显示,该小鼠模型在体内表现出正常的胰岛素水平和糖耐量异常。
对CEACAM1蛋白水平的反应与HF摄入量的增加同步进行,使肝脏CEACAM1蛋白水平显著提高~5倍。
脂肪分解-从白色脂肪组织(WAT)中提取的脂肪酸可以减少肝脏CEACAM1的表达,并迫使其表达。
CEACAM1基因的肝脏特异性基因过度表达或其腺病毒介导的基因传递基因可保护肝脏免受饮食诱导的心力衰竭的影响。
胰岛素抵抗和脂肪性肝炎、肝炎和肝纤维化的发生,我们假设FSP27的减少率在5%左右。
脂肪细胞可引起游离脂肪酸的释放和再分配,从而降低肝脏的CEACAM1水平。
随后,它会导致肝细胞损伤和肝纤维化。我们假设这些潜在的肝细胞损伤机制可能与肝纤维化有关。
表皮生长因子受体被多种脂肪酸和内毒素1激活,这是其主要的表达途径。
通过激活CEK/ERK-PPARg信号通路上调CEACAM1。AIM将不会调查CEACAM1是否在肝细胞中起作用。
调节脂肪细胞特异性Fsp27基因(旁分泌调节)缺失的小鼠的肝纤维化进程。
检查肝星状细胞中FSP27基因缺失对肝细胞自主性和纤维化的影响。
经过深思熟虑和精心设计,一种新颖的小鼠基因模型(包括基因敲除和转基因)将被用来进行新的交叉研究。
脂肪组织和肝脏之间的对话,在通过基因改变促进肝纤维化的进一步发展过程中发挥着至关重要的作用。
FSP27.本提案的一大优势是两位医生之间的跨学科合作,包括肝脏脂肪和疾病。
和(脂肪)代谢)和(脂肪)和(脂肪)生物学和脂类(代谢)。从最强劲的初步数据中可以清楚地看到。
这些科学家在一项新的提案上进行了卓有成效的合作,该提案将描绘出世界上最新的生物路径。
NAFLD/NASH的发病机制研究表明,这可能会导致针对这一显著的健康问题的新的药物治疗方法。
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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