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. ? ? ?
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