LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM

描述（由申请人提供）：压倒性的证据将肥胖与几种慢性疾病（包括非酒精性脂肪性肝病（NAFLD））的风险增加联系起来。NAFLD包括单纯性肝脂肪变性和更严重的非酒精性脂肪性肝炎（NASH;与脂肪性病变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，成为肝脏疾病的最常见原因。虽然脂肪性肝炎可进展为肝硬化和肝功能衰竭，但NAFLD最常见的并发症是肝脏胰岛素抵抗和循环葡萄糖、脂质和炎症介质浓度的全身异常。需要全面了解影响NAFLD发展和进展的因素。最近的工作表明，脂蛋白家族的蛋白质（脂蛋白1，2和3）协调和连接肝线粒体和甘油脂质代谢，通过其双功能的分子活动。脂蛋白是代谢酶，其使磷脂酸（PA）去磷酸化以在内质网膜形成二酰基甘油（DAG）（PAP活性），但也在核中起作用以通过与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。我们偶然地产生了一个小鼠模型，这将使我们能够区分肝脏中lipin 1的两种分子功能。本文提出的研究旨在：[1]表征和区分脂蛋白1在肝细胞中的核质效应，[2]确定脂蛋白2是否也具有转录调节功能并定义其靶点的基因组谱，[3]定义在PAP活性降低的背景下促进肝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节提供新的见解。

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.