Growth hormone signaling and lipid metabolism in fatty liver disease

脂肪肝疾病中的生长激素信号传导和脂质代谢

• 批准号: 8537917
• 负责人: ETHAN WEISS
• 金额: $ 32.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537917
• 关键词: A Mouse; Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Aging; Attenuated; Body Composition; CD36 gene; Catecholamines; Cells; Cirrhosis; Data; Development; Diet; Dietary Fats; Disease; Energy Metabolism; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genes; Genetic Crosses; Goals; Growth Hormone Receptor; Health; Hepatic; Hepatitis; Hepatocyte; Human; In Vitro; Indium; Insulin-Like Growth Factor I; JAK2 gene; Janus kinase 2; Knock-out; Lead; Lipids; Lipolysis; Liver; Liver diseases; Measures; Mediating; Metabolic Diseases; Methods; Molecular; Mus; Myocardium; Nonesterified Fatty Acids; Obesity; Organ; Phenotype; Physiological; Plasma; Publishing; Recruitment Activity; Regulation; Reporting; Resistance development; Role; STAT5A gene; Signal Transduction; Skeletal Muscle; Somatotrophin increased; Somatotropin; Starvation; Tissues; Up-Regulation; Work; adrenergic; cell type; fatty acid-transport protein; gain of function; growth hormone deficiency; in vivo; lipid biosynthesis; lipid metabolism; loss of function; mouse model; overexpression; research study; response; translocase; uptake

DESCRIPTION (provided by applicant): The effects of growth hormone (GH) on lipid metabolism are varied. Among these, GH mobilizes energy from fat cells in the form of plasma free fatty acids. Although the effects of GH on lipid metabolism and lipolysis have been known for many years, the exact role(s) of GH signaling in lipid flux in health and disease remains incompletely understood. Fatty liver is a common and increasingly prevalent problem, and the mechanisms of are many and varied. GH has been implicated in development of fatty liver, yet the precise mechanism(s) remain confusing with reports that administration of GH both causes and cures fatty liver. Furthermore, no published mouse models of GH excess or deficiency have described fatty liver. However, two recent reports have described fatty liver in mice with hepatocyte-specific abrogation of growth hormone signaling components. How these livers accumulate lipid remains unknown. GH signals through the Janus kinase 2 (JAK2). In recently published studies, mice with hepatocyte-specific deletion of JAK2 (JAK2L) were found to develop profound fatty liver. GH levels were markedly increased. The mice were lean; there was an increase in plasma free fatty acids (FFA) suggesting that the increased GH levels might contribute to the development of fatty liver through stimulating lipolysis. Indeed, a genetic cross to the GH-deficient "little" mice demonstrated that abrogation of GH secretion completely rescued the fatty liver phenotype. The overall goal of these studies is to determine how GH regulates lipolysis in adipocytes, fatty acid uptake in hepatocytes, and the overall effects on liver lipid metabolism. To do so, we ask these questions in the form of specific aims. 1) What is the effect of JAK2-dependent, GH signaling in adipocytes on lipolysis and the development of fatty liver? 2) What is the role of CD36 on hepatic fatty acid uptake and development of fatty liver? To answer these questions, we will first determine the effect of GH signaling in fat cells on mobilization of FFA and subsequent development of FL. We will explore exciting new preliminary data which suggest that GH may promote lipolysis in cell-types other than adipocytes. We will next determine how GH signaling in hepatocytes affects fatty acid uptake with the idea that increased uptake may mediate development of fatty liver disease. We will use gain of function/loss of function experiments to determine whether the overexpression of CD36, a known fatty acid transporter, leads to increased fatty acid uptake in hepatocytes and whether this leads to fatty liver. Finally, we will explore how GH signaling modulates expression of CD36. Overall, this work will lead to a greater understanding of how GH signaling serves to modulate lipid metabolism and how alterations in GH signaling can lead to the abnormal accumulation of lipid in the liver and other tissues.

性状（由申请方提供）：生长激素（GH）对脂质代谢的影响各不相同。其中，GH以血浆游离脂肪酸的形式从脂肪细胞中调动能量。虽然GH对脂质代谢和脂解的影响已经知道很多年了，但GH信号在健康和疾病中的脂质流动中的确切作用仍然不完全清楚。脂肪肝是一种常见且日益普遍的问题，其机制多种多样。GH与脂肪肝的发展有关，但确切的机制仍然令人困惑，有报道称GH的施用既能引起脂肪肝又能治愈脂肪肝。此外，没有发表的GH过量或缺乏的小鼠模型描述脂肪肝。然而，最近的两份报告描述了脂肪肝的小鼠肝细胞特异性废除生长激素信号成分。这些肝脏如何积累脂质仍不清楚。GH通过Janus激酶2（JAK 2）信号传导。在最近发表的研究中，发现肝细胞特异性JAK 2缺失（JAK 2L）的小鼠发生严重的脂肪肝。GH水平明显升高。老鼠都很瘦;血浆游离脂肪酸（FFA）升高，提示GH水平升高可能通过刺激脂解而促进脂肪肝的发展。事实上，与GH缺陷型“小”小鼠的遗传杂交表明，GH分泌的消除完全挽救了脂肪肝表型。这些研究的总体目标是确定GH如何调节脂肪细胞中的脂解、肝细胞中的脂肪酸摄取以及对肝脏脂质代谢的总体影响。为此，我们以具体目标的形式提出这些问题。1)脂肪细胞中JAK 2依赖性GH信号对脂解和脂肪肝发生的影响是什么？2)CD 36在肝脏脂肪酸摄取和脂肪肝发生发展中的作用是什么？为了回答这些问题，我们将首先确定GH信号在脂肪细胞动员FFA和随后的发展FL的效果。我们将探索令人兴奋的新的初步数据表明，GH可能会促进脂肪细胞以外的细胞类型的脂解。接下来我们将确定肝细胞中GH信号传导如何影响脂肪酸摄取，增加摄取可能介导脂肪肝疾病的发展。我们将使用功能获得/功能丧失实验来确定CD 36（一种已知的脂肪酸转运蛋白）的过表达是否会导致肝细胞中脂肪酸摄取增加，以及这是否会导致脂肪肝。最后，我们将探讨GH信号如何调节CD 36的表达。总体而言，这项工作将导致更好地了解生长激素信号如何调节脂质代谢，以及生长激素信号的改变如何导致肝脏和其他组织中脂质的异常积累。