Hormonal regulation of phospholipases and lipid metabolism

描述（由申请人提供）： 甲状腺功能减退症和肥胖症与高脂血症、非酒精性脂肪性肝病（NAFLD）和动脉粥样硬化有关。显性和亚临床甲状腺功能减退症是常见的临床疾病，可加重高脂血症和肝脏脂质蓄积。我们实验室一直在研究甲状腺激素（T3）调节控制肝脏代谢的基因的机制。T3可部分通过加速脂肪酸氧化和抑制脂肪生成来改善肝脂肪变性。我们鉴定了几种参与T3诱导脂质代谢基因的转录辅调节因子，包括过氧化物酶体增殖物激活受体γ辅激活因子（PGC- 1）和去乙酰化酶sirtuin 1（SIRT 1）。最近，我们发现T3抑制肝脏中的几种分泌型磷脂酶的表达，包括分泌型磷脂酶Ⅱ a（PLA 2g 2a）。PLA 2g 2a与包括动脉粥样硬化和关节炎在内的慢性炎性疾病有关。此外，PLA 2g 2a在甲状腺功能减退和饮食诱导的肥胖中升高。肝脏是细胞外PLA 2g 2a库的主要贡献者之一。虽然PLA 2g 2a在肝细胞中高度表达，但大多数先前的研究已经检查了PLA 2g 2a在巨噬细胞和免疫细胞中的调节。我们假设T3状态调节PLA 2g 2a的表达，并且T3介导的PLA 2g 2a的减少对高脂血症有益。在目标1中，我们提出定义T3抑制PLA 2g 2a基因表达的新机制。我们将集中在招募核辅阻遏物的配体TR的PLA 2g 2a基因。在目的2中，我们将研究PLA 2g 2a在高脂血症和脂肪变性伴甲状腺功能减退症中的作用。由于T3受体（TR）选择性激动剂的发展，人们对T3的药理学效用重新产生了兴趣，TR选择性激动剂主要作用于肝脏，降低血浆和肝脏脂质， 影响心血管系统。我们的研究将阐明T3的潜在有益作用， 减少与代谢综合征相关的病症，如高脂血症和NAFLD。肥胖、脂肪变性和相关疾病在老年退伍军人群体中发生频率非常高。

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.