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:  characterize and distinguish the nucleocytoplasmic effects of lipin 1 in hepatocytes,  to determine whether lipin 2 also has transcriptional regulatory function and define the genomic profile of its targets, and  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.
The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases of the liver including non-alcoholic fatty liver disease (NAFLD). We believe that understanding how the family of lipin proteins control hepatic fatty acid metabolism may be important for the development of new therapies to treat patients with NAFLD.
|Liss, Kim H H; Finck, Brian N (2016) PPARs and nonalcoholic fatty liver disease. Biochimie :|
|McCommis, Kyle S; Hodges, Wesley T; Brunt, Elizabeth M et al. (2016) Targeting the Mitochondrial Pyruvate Carrier Attenuates Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis. Hepatology :|
|Wang, Jiayou; Kim, Chunki; Jogasuria, Alvin et al. (2016) Myeloid Cell-Specific Lipin-1 Deficiency Stimulates Endocrine Adiponectin-FGF15 Axis and Ameliorates Ethanol-Induced Liver Injury in Mice. Sci Rep 6:34117|
|DeBosch, Brian J; Heitmeier, Monique R; Mayer, Allyson L et al. (2016) Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal 9:ra21|
|Schweitzer, George G; Chen, Zhouji; Gan, Connie et al. (2015) Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice. J Lipid Res 56:848-58|
|Finck, Brian N; Hall, Angela M (2015) Does Diacylglycerol Accumulation in Fatty Liver Disease Cause Hepatic Insulin Resistance? Biomed Res Int 2015:104132|
|McCommis, Kyle S; Chen, Zhouji; Fu, Xiaorong et al. (2015) Loss of Mitochondrial Pyruvate Carrier 2 in the Liver Leads to Defects in Gluconeogenesis and Compensation via Pyruvate-Alanine Cycling. Cell Metab 22:682-94|
|McCommis, Kyle S; Finck, Brian N (2015) Mitochondrial pyruvate transport: a historical perspective and future research directions. Biochem J 466:443-54|
|Mazar, Joseph; Zhao, Wei; Khalil, Ahmad M et al. (2014) The functional characterization of long noncoding RNA SPRY4-IT1 in human melanoma cells. Oncotarget 5:8959-69|
|Debosch, Brian J; Chen, Zhouji; Saben, Jessica L et al. (2014) Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. J Biol Chem 289:10989-98|
Showing the most recent 10 out of 43 publications