Hormonal regulation of phospholipases and lipid metabolism

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DESCRIPTION (provided by applicant): Hypothyroidism and obesity are associated with hyperlipidemia, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Overt and subclinical hypothyroidism are commonly observed clinical disorders that exacerbate hyperlipidemia and hepatic lipid accumulation. Our laboratory has been investigating the mechanisms by which thyroid hormone (T3) regulates genes controlling hepatic metabolism. T3 can ameliorate hepatic steatosis in part by accelerating fatty acid oxidation and inhibiting lipogenesis. We identified several transcriptional coregulators that participate in T3 induction of lipid metabolizing genes including the peroxisome proliferator activated receptor gamma coactivator (PGC- 1�) and the deacetylase sirtuin 1 (SIRT1). Recently, we discovered that T3 inhibits the expression of several secretory phospholipases in the liver including secretory phospholipase group IIa (PLA2g2a). PLA2g2a has been linked with chronic inflammatory diseases including atherosclerosis and arthritis. Furthermore, PLA2g2a is elevated with hypothyroidism and diet induced obesity. The liver is one of the major contributors to the pool of extracellular PLA2g2a. Although PLA2g2a is highly expressed in hepatocytes, most previous studies have examined the regulation of PLA2g2a in macrophages and immune cells. We hypothesize that the T3 status modulates PLA2g2a expression and that the T3 mediated reduction in PLA2g2a is beneficial for hyperlipidemia. In aim 1, we propose to define novel mechanisms by which T3 inhibits expression of PLA2g2a gene. We will focus on the recruitment of nuclear corepressors to the liganded TR on the PLA2g2a gene. In aim 2, we will examine the role of PLA2g2a in hyperlipidemia and steatosis with hypothyroidism. Interest in the pharmacologic utility of T3 has been revitalized by the development of T3 receptor � (TR�) selective agonists which act primarily in the liver to reduce plasma and hepatic lipids with little impact the cardiovascular system. Our studies will illuminate potential beneficial actions of T3 in the reduction of conditions associated with the metabolic syndrome such as hyperlipidemia and NAFLD. Obesity, steatosis and associated morbidities occur with very high frequency in the aging Veteran population.