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: 8334596
• 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/8334596
• 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.

描述（由申请人提供）：生长激素（GH）对脂质代谢的影响是多种多样的。其中，GH以血浆游离脂肪酸的形式从脂肪细胞中调动能量。尽管 GH 对脂质代谢和脂肪分解的影响已为人所知很多年，但 GH 信号传导在健康和疾病中脂质流动中的确切作用仍不完全清楚。脂肪肝是一个常见且日益普遍的问题，其发病机制多种多样。 GH 与脂肪肝的发展有关，但有关 GH 既能引起又能治愈脂肪肝的报道仍然令人困惑，其确切机制仍然令人困惑。此外，尚无已发表的 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肝细胞特异性消除生长激素信号成分的小鼠脂肪肝。这些肝脏如何积累脂质仍不清楚。 GH 通过 Janus 激酶 2 (JAK2) 发出信号。在最近发表的研究中，发现肝细胞特异性缺失 JAK2 (JAK2L) 的小鼠会患上严重的脂肪肝。 GH 水平显着升高。老鼠很瘦；血浆游离脂肪酸 (FFA) 增加，表明 GH 水平增加可能通过刺激脂肪分解促进脂肪肝的发展。事实上，与缺乏 GH 的“小”小鼠的基因杂交表明，废除 GH 分泌可以完全挽救脂肪肝表型。这些研究的总体目标是确定 GH 如何调节脂肪细胞中的脂肪分解、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 JAK2 依赖性 GH 信号传导对脂肪分解和脂肪肝的发展有什么影响？ 2）CD36对肝脏脂肪酸摄取和脂肪肝的发展有何作用？为了回答这些问题，我们首先确定脂肪细胞中 GH 信号传导对 FFA 动员和随后 FL 发展的影响。我们将探索令人兴奋的新初步数据，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 GH 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疾病的发展。我们将使用功能获得/功能丧失实验来确定 CD36（一种已知的脂肪酸转运蛋白）的过度表达是否会导致肝细胞中脂肪酸的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 CD36 的表达。总体而言，这项工作将有助于更好地了解 GH 信号传导如何调节脂质代谢，以及 GH 信号传导的改变如何导致肝脏和其他组织中脂质的异常积累。