Lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) have long been appreciated as important biochemical players in triglyceride (TG) and cholesterol metabolism. More recently, these lipases emerged as some ofthe strongest genetic determinants of plasma TG and HDL cholesterol levels in the general population. Dysregulation of LPL results in pathological changes associated with the Metabolic Syndrome, including dyslipidemia, insulin resistance, cardiomyopathy and beta-cell dysfunction. Although much ofthe physiological regulation of LPL activity occurs at the post-translational level, the underlying molecular mechanisms have been poorly understood. In the current PPG cycle we identified a novel factor, Lipase Maturation Factor 1 (Lmf1), which facilitates the folding, assembly and secretion of lipases. While Lmf1 is clearly required for lipase expression, the metabolic consequences of combined lipase deficiency in the adult organism, and the molecular function of Lmf1 remain unexplored.
Three aims will be pursued to address these issues.
In Aim 1, we will generate and characterize conditional and tissue-specific knock-out mouse models to investigate the role of Lmf1 in systemic and adipose metabolism. To extend these studies to humans in Aim 2, we will identify variants associated with fasting or postprandial plasma TG levels by resequencing LMFI in various populations. Furthermore, naturally occurring variants affecting Lmf1 expression in inbred mouse strains will be exploited to address the role of this protein in lipid metabolism and related traits.
In Aim 3, we will investigate the molecular aspects of Lmf1 function by identifying the proteome of Lmf1-interacting factors using genetic and biochemical approaches.
Emerging evidence suggests a principal role for lipases in the determination of plasma TG and HDLcholesterol levels in the general population. The current proposal focuses on a novel factor, Lmf 1, and a novel molecular mechanism in the regulation of lipases. Thus, Lmf1 may play an important role in lipid metabolism relevant to the Metabolic Syndrome and cardiovascular disease.
|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|
Showing the most recent 10 out of 367 publications