The prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including non-alcoholic fatty liver disease (NAFLD). Indeed, obesity is tightly linked to the development of hepatic steatosis, inflammation, and dysfunction. It is believed that, in obese subjects, the supply of fatty acids far exceeds the hepatic capacity for fatty acid oxidation or secretion in lipoproteins. Therefore, a more complete understanding of the pathways that control hepatic lipid homeostasis has important physiological and clinical implications. The capacity for fatty acid catabolism is known to be controlled at the level of gene transcription by a family of nuclear receptor transcription factors, the peroxisome proliferator-activated receptors (PPARs), and their coactivator protein (PGC-1?). PGC-1?? is a highly-inducible coactivator that transcriptionally regulates multiple energy metabolic pathways including mitochondrial oxidative phosphorylation and fatty acid oxidation. Recently, we generated mice deficient for PGC-1?? (PGC- 1?? -/- mice). Although PGC-1?? -/- mice appeared outwardly normal, hepatocytes from PGC-1?? -/- mice exhibited diminished rates of fatty acid oxidation and fasting-induced steatosis. Gene expression profiling identified the gene encoding lipin 1 as markedly fasting-induced in the liver of wild-type, but not PGC-1?? -/- mice. Lipin 1 gene mutations lead to lipodystrophy and fatty liver in fld mice and hepatocytes from fld mice exhibit perinatal steatosis and diminished rates of palmitate oxidation. Our preliminary data indicate that lipin 1 augments the activity of the PPAR?? /PGC-1?? system and increases the expression of genes involved in mitochondrial fatty acid oxidation. Based on our preliminary data, we hypothesize that lipin 1 plays an important role in controlling lipid homeostasis via transcriptional regulation of genes involved in hepatic mitochondrial fatty acid metabolism. Furthermore, we postulate that lipin 1 mediates many of these effects via interactions with PGC-1?? and its partner transcription factors. This proposal is designed to [1] characterize the functional interaction between lipin 1 and PGC-1??, [2] elucidate the transcriptional effects of lipin 1 on hepatic fatty acid metabolism using complimentary gain-of-function and loss-of-function approaches, and [3] to evaluate the effects of constitutive lipin 1 activation on the development of NAFLD in mouse models. The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including non-alcoholic fatty liver disease (NAFLD). We believe that understanding how a protein called lipin 1 impacts fatty acid metabolism may be important for the development of new therapies to treat patients with NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078187-03
Application #
7743098
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2008-01-01
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
3
Fiscal Year
2010
Total Cost
$300,960
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Liss, Kim H H; Lutkewitte, Andrew J; Pietka, Terri et al. (2018) Metabolic importance of adipose tissue monoacylglycerol acyltransferase 1 in mice and humans. J Lipid Res 59:1630-1639
Lutkewitte, Andrew J; Schweitzer, George G; Kennon-McGill, Stefanie et al. (2018) Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. Food Chem Toxicol 115:273-283
Vozenilek, Aimee E; Navratil, Aaron R; Green, Jonette M et al. (2018) Macrophage-Associated Lipin-1 Enzymatic Activity Contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis. Arterioscler Thromb Vasc Biol 38:324-334
Liss, Kim H H; McCommis, Kyle S; Chambers, Kari T et al. (2018) The impact of diet-induced hepatic steatosis in a murine model of hepatic ischemia/reperfusion injury. Liver Transpl 24:908-921
Hall, Angela M; Finck, Brian N (2017) ChREBP refines the hepatic response to fructose to protect the liver from injury. J Clin Invest 127:2533-2535
McCommis, Kyle S; Hodges, Wesley T; Brunt, Elizabeth M et al. (2017) Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65:1543-1556
Liss, Kim H H; Finck, Brian N (2017) PPARs and nonalcoholic fatty liver disease. Biochimie 136:65-74
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

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