Regulation of Hepatic Lipid Accumulation and Insulin Resistance
肝脏脂质蓄积和胰岛素抵抗的调节
基本信息
- 批准号:9841676
- 负责人:
- 金额:$ 19.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) and the progressive non-alcoholic steatohepatitis (NASH) are often associated with obesity, insulin resistance and coronary artery diseases. Most studies on hepatic steatosis have focused on enzymes involved in de novo lipogenesis. However, emerging data also point to critical contributions of proteins regulating intrahepatic lipolysis, including the key triglyceride hydrolae ATGL (adipose triglyceride lipase) along with its coactivator CGI-58 (Comparative Gene Identification-58). Our previous studies have identified G0S2 (G0/G1 Switch Gene 2) as an endogenous inhibitor of ATGL, and have provided compelling evidence that differential expression of G0S2 plays a crucial role in regulating adipose lipolysis, adipose-liver FA flux and hepatic lipid content. Interestingly, we have obtained preliminary evidence that G0S2 also functions independently of ATGL in the glycerol phosphate pathway for TG synthesis. The objective of this application is to further explore the roles of G0S2 in hepatic lipid and energy metabolism, and the development of obesity-associated hepatic steatosis and insulin resistance. The hypothesis of the proposed studies is that by acting downstream of the liver X receptor-α (LXRα), G0S2 is a dual-function protein that possesses activities of both a lipolytic inhibitor and a lysophosphatidic acid acyltransferase (LPAAT). While both functions contribute to hepatic steatosis during fasting and in response to high-fat and high-carbohydrate feeding, G0S2's role as a LPAAT promotes synthesis of phosphatidic acid (PA) and diacylglycerol (DG) in the liver and is responsible for its detrimental effect in mice with diet-induced obesity (DIO).
The rationale for the proposed research is that identifying the role of G0S2 in mediating hepatic lipid accumulation will provide significant insight into the etiology of NAFLD and related disorders, thereby advancing the possibilities for development of nutritional or pharmaceutical therapies. The hypothesis will be tested using three specific aims: 1) to characterize the LXRα-G0S2 axis and its role in hepatic lipid metabolism; 2) to determine the physiologic relevance of G0S2 as a LPAAT in promoting hepatic TG accumulation; and 3) to determine the ATGL-independent role of G0S2 in diet-induced insulin resistance. We will perform both gain- and loss-of- function studies by combining the usage of cell biological and physiological approaches established in our laboratory with unique animal models deficient in G0S2, LXRα or ATGL that are available. These studies are innovative because they focus on the roles of a unique dual-function regulator of TG synthesis and hydrolysis in the development of hepatic steatosis and insulin resistance. Understanding how hepatic TG metabolism is regulated is significant because it not only impacts the treatment of NAFLD, but also will advance the field of energy metabolism as it relates to obesity.
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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Jun Liu其他文献
Jun Liu的其他文献
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{{ truncateString('Jun Liu', 18)}}的其他基金
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III 型志贺氏菌分泌注射剂的组装和激活的表征
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- 资助金额:
$ 19.25万 - 项目类别:
Characterization of assembly and activation of the Shigella type III secretion injectisome
III 型志贺氏菌分泌注射剂的组装和激活的表征
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10673048 - 财政年份:2022
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Functional and Structural Analysis of the Dot/Icm Type IVB Secretion Machine
Dot/Icm型IVB分泌机的功能和结构分析
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10463690 - 财政年份:2020
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Functional and Structural Analysis of the Dot/Icm Type IVB Secretion Machine
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