Lipid storage is critical for metabolic homeostasis, and influences components ofthe metabolic syndrome, including visceral obesity, insulin resistance, and dyslipidemia. The objectives are to further elucidate the function of lipin-1 in lipid synthesis, storage, and lipid signaling in adipose tissue and muscle, and to identify novel genes that influence adipose tissue mass and function. Our previous studies demonstrated that lipin-1 is a determinant of adipose tissue development, insulin sensitivity, and energy metabolism. Lipin-I is a phosphatidate phosphatase (PAP) enzyme that converts phosphatidate to diacylglyerol, and accounts for all PAP activity in adipose tissue and muscle. In addition, it is a transcriptional coactivator that influences expression of lipid metabolism genes in liver.
The specific aims are: (1) Determine how lipin-1 modulation of phosphatidate levels regulates adipogenesis and influences insulin sensitivity in skeletal muscle. In the absence of lipin-1, phosphatidate accumulates in tissues, which may activate signal transduction pathways and/or alter mitochondrial or ER membrane properties. We hypothesize that phosphatidate levels determined by lipin-1 influence expression of PPARgamma and adipocyte differentiation, and insulin sensitivity in muscle. We will investigate how dysregulation of lipin-1 and phosphatidate levels contribute to altered metabolism in adipose tissue, muscle, and liver. (2) Evaluate the role of lipin-1 in statin-induced myotoxicity. Human LPINI nonsense mutations cause childhood myopathy, and missense mutations have been associated with statin-induced myopathy. We will test the hypothesis that impaired lipin-1 activity and statin action interact to impair mitochondrial function. We will functionally characterize mutant lipin-1 proteins, evaluate effects of lipin-1 deficiency on statin-induced myotoxicity in the mouse, and evaluate a cohort of subjects with statin-induced myopathy for LPINI mutations. (3) Identify and characterize the molecular function of novel adiposity genes. We hypothesize that genetic variations that alter adiposity in vivo will reveal novel genes in adipose tissue function. We will investigate the function of 7 candidate genes identified by network modeling in the mouse for roles in adipocyte function using in vitro and in vivo methods.

Public Health Relevance

The regulation of fat storage is a key determinant of conditions associated with human disease, including obesity, diabetes, and heart disease. A better understanding ofthe genes and processes involved may contribute to the design of therapeutic intervention.

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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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University of California Los Angeles
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Rau, Christoph D; Wang, Jessica; Avetisyan, Rozeta et al. (2015) Mapping genetic contributions to cardiac pathology induced by Beta-adrenergic stimulation in mice. Circ Cardiovasc Genet 8:40-9
Iatan, Iulia; Choi, Hong Y; Ruel, Isabelle et al. (2014) The WWOX gene modulates high-density lipoprotein and lipid metabolism. Circ Cardiovasc Genet 7:491-504
Aguilar-Salinas, Carlos A; Tusie-Luna, Teresa; Pajukanta, Päivi (2014) Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia. Metabolism 63:887-94
Mao, Hui Z; Ehrhardt, Nicole; Bedoya, Candy et al. (2014) Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6? (Atf6?) signaling. J Biol Chem 289:24417-27
Hartiala, Jaana; Bennett, Brian J; Tang, W H Wilson et al. (2014) Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine. Arterioscler Thromb Vasc Biol 34:1307-13
He, Dan; Furlotte, Nicholas A; Hormozdiari, Farhad et al. (2014) Identifying genetic relatives without compromising privacy. Genome Res 24:664-72
Reue, Karen; Lee, Jessica M; Vergnes, Laurent (2014) Regulation of bile acid homeostasis by the intestinal Diet1-FGF15/19 axis. Curr Opin Lipidol 25:140-7
Mangul, Serghei; Wu, Nicholas C; Mancuso, Nicholas et al. (2014) Accurate viral population assembly from ultra-deep sequencing data. Bioinformatics 30:i329-37
Sha, Haibo; Sun, Shengyi; Francisco, Adam B et al. (2014) The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell Metab 20:458-70
Vergnes, Laurent; Reue, Karen (2014) Adaptive thermogenesis in white adipose tissue: is lactate the new brown(ing)? Diabetes 63:3175-6

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