LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM

描述(由申请者提供)：压倒性证据将肥胖与包括非酒精性脂肪性肝病(NAFLD)在内的几种慢性病风险增加联系在一起。这种情况，NAFLD，既包括简单的肝脏脂肪变性，也包括更严重的非酒精性脂肪性肝炎(NASH；与脂肪变性损害相关的肝脏炎症和纤维化)。随着肥胖症在美国的流行，NAFLD的发生率急剧上升，成为最常见的肝病原因。尽管脂肪性肝炎可进展为肝硬变和肝功能衰竭，但NAFLD最常见的共同发病是肝脏胰岛素抵抗和循环中血糖、血脂和炎症介质浓度的全身性异常。需要对影响NAFLD发展和进展的因素有一个全面的了解。最近的工作表明，脂蛋白家族(脂蛋白1、2和3)通过其双功能分子活性来协调和连接肝脏线粒体和甘油脂的代谢。脂类是一种代谢酶，它使磷脂酸(PA)去磷酸化，在内质网膜上形成二酰甘油(DAG)(PAP活性)，但也在细胞核内通过与DNA结合的转录因子相互作用来调节编码线粒体酶的基因的表达。我们偶然产生了一个小鼠模型，它将使我们能够区分肝脏中脂类1的两个分子功能。本研究的目的是：[1]鉴定和区分Lipin 1在肝细胞中的核质效应，[2]确定Lipin 2是否也具有转录调节功能，并确定其靶标的基因组图谱，以及[3]在PAP活性降低的情况下，确定促进肝脏甘油三酯合成的代偿机制。这些研究的结果不仅对我们理解脂蛋白的生物学有意义，而且还将为中间代谢的基本分子调控提供新的见解。

DESCRIPTION (provided by applicant): Overwhelming evidence links obesity with increased risk for several chronic diseases including non- alcoholic fatty liver disease (NAFLD). The condition, NAFLD, encompasses both simple hepatic steatosis and the more severe non-alcoholic steatohepatitis (NASH; hepatic inflammation and fibrosis associated with steatotic lesions). With the epidemic of obesity in the U.S., the occurrence of NAFLD has risen exuberantly, becoming the most common cause of liver disease. Although steatohepatitis can progress to cirrhosis and liver failure, the most common co-morbidity of NAFLD is hepatic insulin resistance and systemic abnormalities in circulating glucose, lipid, and inflammatory mediator concentrations. A complete understanding of the factors that influence the development and progression of NAFLD is needed. Recent work has suggested that the lipin family of proteins (lipin 1, 2, and 3) coordinate and connect hepatic mitochondrial and glycerolipid metabolism through their bifunctional molecular activities. Lipins are metabolic enzymes that dephosphorylate phosphatidic acid (PA) to form diacylglycerol (DAG) (PAP activity) at the endoplasmic reticulum membrane, but also act in the nucleus to regulate the expression of genes encoding mitochondrial enzymes by interacting with DNA-bound transcription factors. We have serendipitously generated a mouse model that will allow us to distinguish the two molecular functions of lipin 1 in liver. The studies proposed herein are designed to: [1] characterize and distinguish the nucleocytoplasmic effects of lipin 1 in hepatocytes, [2] to determine whether lipin 2 also has transcriptional regulatory function and define the genomic profile of its targets, and [3] to define the compensatory mechanisms facilitating hepatic triglyceride synthesis in the context of diminished PAP activity. The results f these studies will not only have implications for our understanding of the biology of lipin proteins, but will also provide new insight into the basic molecular regulation of intermediary metabolism.