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: 8719090
• 负责人: ETHAN WEISS
• 金额: $ 33.6万
• 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/8719090
• 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; Peroxisome Proliferator-Activated Receptors; 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.

描述(申请人提供)：生长激素(GH)对脂肪代谢的影响是多种多样的。其中，生长激素以血浆游离脂肪酸的形式动员脂肪细胞的能量。尽管生长激素对脂代谢和脂解的影响已经被知道很多年了，但是生长激素信号在健康和疾病中在脂流中的确切作用(S)仍然不完全清楚。脂肪肝是一种常见且日益流行的疾病，其发病机制多种多样。生长激素与脂肪肝的发生发展有关，但确切的机制(S)仍令人困惑，有报道称应用生长激素既可引起脂肪肝，也可治疗脂肪肝。此外，还没有发表的生长激素过多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肝细胞特异性取消生长激素信号成分的小鼠脂肪肝。目前尚不清楚这些肝脏是如何积聚脂肪的。GH通过Janus kinase2(JAK2)传递信号。在最近发表的研究中，肝细胞特异性JAK2缺失(JAK2L)的小鼠被发现患上严重的脂肪肝。GH水平明显升高。小鼠较瘦；血浆游离脂肪酸(FFA)增加，提示GH水平升高可能通过刺激脂肪分解而促进脂肪肝的发展。事实上，与生长激素缺乏的“小”鼠的基因杂交表明，取消生长激素分泌完全挽救了脂肪肝的表型。这些研究的总体目标是确定生长激素如何调节脂肪细胞的脂肪分解、肝细胞的脂肪酸摄取以及对肝脏脂肪代谢的整体影响。为了做到这一点，我们以具体目标的形式提出这些问题。1)脂肪细胞中依赖JAK2的GH信号在脂肪分解和脂肪肝发生中的作用是什么？2)CD36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，我们将首先确定脂肪细胞中的GH信号在FFA动员和随后的FL发生中的作用。我们将探索令人兴奋的新的初步数据，这些数据表明GH可能促进脂肪细胞以外的细胞类型的脂肪分解。接下来，我们将确定肝细胞中的生长激素信号如何影响脂肪酸的摄取，因为摄取增加可能会介导脂肪肝的发展。我们将通过功能获得/功能丧失实验来确定已知的脂肪酸转运蛋白CD36的过度表达是否导致肝细胞对脂肪酸摄取的增加，以及这是否导致脂肪肝。最后，我们将探讨GH信号如何调节CD36的表达。总体而言，这项工作将有助于更好地理解GH信号如何调节脂质代谢，以及GH信号的变化如何导致肝脏和其他组织中脂质的异常积聚。