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Regulation and consequences of hepatic lipid droplet catabolism

肝脏脂滴分解代谢的调节和后果

基本信息

批准号：
9366252
负责人：
Douglas G Mashek
金额：
$ 37.68万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9366252
关键词：
Ablation Address Adipose tissue Affect American Autophagocytosis Autophagosome Binding Cardiovascular Diseases Catabolism Cell Nucleus Cell membrane Cell model Cell physiology Cells Characteristics Chemicals Circadian Rhythms Comorbidity Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Deacetylase Development Diet Disease Energy Metabolism Etiology FOXO1A gene Fatty Acids Fatty acid glycerol esters Genetic Transcription Glean Glucagon Goals Health Hepatic Hormones Human In Situ Insulin Laboratories Life Style Link Lipase Lipids Lipolysis Liver Liver diseases Lysosomes Mediating Metabolic Diseases Metabolism Modeling Non-Insulin-Dependent Diabetes Mellitus Oleates Organelles PPAR alpha Pathway interactions Pharmacologic Substance Physiological Prevalence Primary carcinoma of the liver cells Process Property Proteins Publishing Regulation Risk Role SIRT1 gene Signal Transduction Steatohepatitis TRP channel Testing Therapeutic Triglycerides Work arm base hepatic lipase in vitro Model in vivo innovation lipid metabolism mouse model non-alcoholic fatty liver novel overexpression oxidation perilipin prevent response small molecule targeted treatment therapeutic target trafficking

项目摘要

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is tightly linked to numerous metabolic diseases. Lipid droplet (LDs) are the major storage organelles of intracellular triacylglycerol (TAG) and, therefore, are the defining characteristic of NAFLD. In contrast to historical views of LDs as simply inert forms of energy storage, recent studies have identified LDs as important organelles that influences cellular function and signaling in addition to the regulation of TAG content and turnover. Given the prevalence of NAFLD and its massive burden worldwide, understanding the mechanisms governing LD metabolism is paramount if we aim to progress to effective dietary, lifestyle or pharmaceutical therapies targeting NAFLD and its comorbidities. This application will build upon recent findings from our laboratory regarding the role of adipose triglyceride lipase (ATGL) in liver energy metabolism. Our published and preliminary data show that ATGL is a major hepatic lipase that promotes oxidation of hydrolyzed fatty acids (FAs) and links cAMP/PKA signaling to sirtuin 1 (SIRT1)-mediated induction of PGC-1a and its transcriptional binding partners (e.g. PPAR-a and FoxO1). Once activated in response to ATGL, SIRT1 promotes autophagy/lipophagy, which in turn is responsible for bulk degradation of hepatic LDs and the subsequent efflux of FAs. Based on this data, the objective of this proposal is to elucidate the physiological and mechanistic regulation of lipophagy and trafficking of lysosome-derived FAs. We hypothesize that ATGL, via intracellular trafficking of oleate, activates SIRT1 to control specific arms of lipophagy leading to LD catabolism and lysosomal-mediated FA efflux. To test our hypothesis, we will conduct the following specific aims: 1) to characterize the physiological regulation of and interplay between ATGL and lipophagy/FA efflux; 2) to define the mechanism linking ATGL to SIRT1 signaling and lipophagy induction; and 3) to elucidate the regulation and consequences of lysosomal-mediated FA efflux on hepatic energy metabolism. Aim 1 will employ cell, perfused liver and mouse models to characterize how physiological factors regulate lipophagy. Aim 2 will use both cell and mouse models to dissect out the signaling network linking ATGL to the regulation of autophagy/lipophagy and FA efflux. Aim 3 will focus on lysosome fusion to the plasma membrane as a therapeutic target to increase lipophagy. These studies are innovative in that they will answer novel questions about the regulation of LD catabolism and signaling. This work is significant because it advances our understanding of the defining characteristic of NAFLD (i.e. LDs), which will have a positive and sustained impact towards the goal of preventing or treating NAFLD and related comorbidities.

项目总结