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.
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.
|Tarling, Elizabeth J; Clifford, Bethan L; Cheng, Joan et al. (2017) RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest 127:3741-3754|
|Nakano, Haruko; Minami, Itsunari; Braas, Daniel et al. (2017) Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. Elife 6:|
|Org, Elin; Blum, Yuna; Kasela, Silva et al. (2017) Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort. Genome Biol 18:70|
|Pillai, Indulekha C L; Li, Shen; Romay, Milagros et al. (2017) Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell Stem Cell 20:218-232.e5|
|von Scheidt, Moritz; Zhao, Yuqi; Kurt, Zeyneb et al. (2017) Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis. Cell Metab 25:248-261|
|Nikkola, Elina; Ko, Arthur; Alvarez, Marcus et al. (2017) Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family. Atherosclerosis 264:58-66|
|Schugar, Rebecca C; Shih, Diana M; Warrier, Manya et al. (2017) The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. Cell Rep 19:2451-2461|
|Rau, Christoph D; Romay, Milagros C; Tuteryan, Mary et al. (2017) Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice. Cell Syst 4:121-128.e4|
|Wang, Huan; Airola, Michael V; Reue, Karen (2017) How lipid droplets ""TAG"" along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta 1862:1131-1145|
|Kessler, Thorsten; Wobst, Jana; Wolf, Bernhard et al. (2017) Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus. Circulation 136:476-489|
Showing the most recent 10 out of 493 publications