LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM

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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.