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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of California Los Angeles
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Zhu, W; Buffa, J A; Wang, Z et al. (2018) Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk. J Thromb Haemost 16:1857-1872
Lee, Jessica M; Ong, Jessica R; Vergnes, Laurent et al. (2018) Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants. J Lipid Res 59:429-438
Miao, Zong; Alvarez, Marcus; Pajukanta, Päivi et al. (2018) ASElux: an ultra-fast and accurate allelic reads counter. Bioinformatics 34:1313-1320
Kurt, Zeyneb; Barrere-Cain, Rio; LaGuardia, Jonnby et al. (2018) Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ 9:46
Orozco, Luz D; Farrell, Colin; Hale, Christopher et al. (2018) Epigenome-wide association in adipose tissue from the METSIM cohort. Hum Mol Genet 27:1830-1846
Chella Krishnan, Karthickeyan; Kurt, Zeyneb; Barrere-Cain, Rio et al. (2018) Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell Syst 6:103-115.e7
Freund, Malika Kumar; Burch, Kathryn S; Shi, Huwenbo et al. (2018) Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits. Am J Hum Genet 103:535-552
Pan, David Z; Garske, Kristina M; Alvarez, Marcus et al. (2018) Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS. Nat Commun 9:1512
Small, Kerrin S; Todor?evi?, Marijana; Civelek, Mete et al. (2018) Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition. Nat Genet 50:572-580
Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas et al. (2018) ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol 19:36

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