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Hormonal Regulation of Liver Metabolism

肝脏代谢的激素调节

基本信息

批准号：
9902412
负责人：
Rhonda D Kineman
金额：
$ 37.47万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902412
关键词：
Adipose tissue Adult Age Automobile Driving Biochemical Pathway Carbohydrates Cardiovascular Diseases Clinical Clinical Research Closure by clamp Coupled Data Diet Disease Progression Drug Targeting Economic Burden Exhibits Fatty Acids Fatty Liver Fatty acid glycerol esters Fibrosis Fructose Future Glucokinase Glucose Glycolysis Goals Growth Hormone Receptor Hepatic Hepatocyte Human Hyperglycemia IGF1 gene Impairment Inflammation Injury Insulin Insulin Resistance Insulin-Like Growth Factor I JAK2 gene Lipids Lipolysis Liver Mediating Medical Molecular Mus Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Production Publishing Receptor Signaling Regulation Reporting Resistance Signal Pathway Signal Transduction Somatotropin Testing Triglycerides Work clinically relevant cost effective therapy experimental study growth hormone deficiency hormonal signals hormone regulation insulin signaling knock-down lipid biosynthesis lipid metabolism liver injury liver metabolism mouse model mutant new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis prevent receptor reconstitution restoration transcription factor

项目摘要

Summary/Abstract Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of excess fat accumulation in the liver (steatosis) without or with inflammation/fibrosis (non-alcoholic steatohepatitis - NASH). NAFLD is commonly observed in obesity and type 2 diabetes, but is also observed in non-obese patients associated with cardiovascular disease. To date, there are no proven medical therapies to reverse NAFLD. In order to develop effective treatments, it is critical to understand the basic mechanisms controlling hepatic fat accumulation and associated liver damage. Since both clinical and experimental studies demonstrate hepatic growth hormone (GH)-signaling is reduced in NAFLD and increasing GH can reduce NAFLD both in humans and mice, our recent work has focused on determining how GH mediates these effects. We have used unique mouse models with adult-onset loss of the hepatocyte GH receptor (GHR) and demonstrated GH signaling controls steatosis by suppressing de novo lipogenesis (DNL), an action of GH not previously appreciated. Additional preliminary data, coupled with published reports, led us to formulate the HYPOTHESIS: GH directly controls hepatocyte DNL via GHR/Stat5b-mediated regulation of glycolysis, to protect the liver from injury. The following Specific Aims (SA) will test this hypothesis. SA1 - Determine if the GHR signals through Stat5 to directly suppress hepatic DNL and prevent NAFLD progression. Expt SA1A, will determine if enhancing Stat5b activity can suppress DNL and prevent NAFLD by expressing a constitutively active form of Stat5b (Stat5bCA) in mice lacking the hepatocyte GHR. Since Stat5b enhances hepatic IGF1 expression and raises circulating IGF1 levels, Stat5bCA will be expressed in mice with combined knockdown of hepatocyte GHR and IGF1, to determine what actions of Stat5b are IGF1-independent. Expt SA1B, will establish if GHR-mediated Stat5b activation is required to control DNL, by expressing a mutant GHR in the hepatocyte of adult mice lacking the endogenous GHR, where this mutant receptor cannot activate Stat5b, but can active other JAK2-dependent and independent pathways. In a subset of mice, hepatocyte IGF1 expression will be reconstituted, to prevent secondary changes due to IGF1 loss. SA2 – Determine if loss of hepatocyte GHR/Stat5b signaling acts independent of canonical insulin signaling to augment glycolysis-driven DNL. Expt SA2A, will determine if hepatocyte GHR loss and restoration of Stat5b activity regulates glycolytic flux and DNL when insulin and carbohydrate input to the liver is controlled, by assessing [1-13C] glucose enrichment of glycolytic, TCA intermediates and newly formed fatty acids, under hyperinsulinemic-hyperglycemic clamp conditions, in mice lacking the hepatocyte GHR, without or with Stat5bCA. Expt SA2B, will establish if the glycolysis-mediated transcription factor, Chrebp, is required to enhance DNL, steatosis and liver injury after hepatocyte GHR loss, by generating mice with adult-onset, hepatocyte knockdown of both Chrebpα and GHR. Completion of these studies will enhance our basic understanding of the mechanisms by which GH directly controls hepatocyte carbohydrate/lipid metabolism and protects the liver against injury, with the ultimate goal of unveiling novel “druggable” targets to treat NAFLD.

摘要/文摘