Growth hormone signaling and lipid metabolism in fatty liver disease

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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.