Abstract 21251: Lipase Maturation Factor 1 Plays a Lipase-Independent Role in Energy Metabolism and Adiposity

Abstract

Vascular lipases including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL) are important determinants of plasma lipid homeostasis and coronary artery disease risk. The ER-resident lipase-chaperone Lipase Maturation Factor 1 (LMF1) plays a key role in the biogenesis of active vascular lipases and plasma lipid metabolism. While mice and humans harboring loss-of-function mutations in LMF1 exhibit deficiencies in all three vascular lipases and hypertriglyceridemia, detailed metabolic characterization of LMF1 deficiency has been hampered by the neonatal lethality of LMF1-/- mice. The goal of the present study was to investigate the metabolic consequences of combined lipase deficiency in the adult mouse. To overcome the lethality associated with whole-body LMF1 deficiency, we pursued a transgene rescue strategy involving cross-breeding of Mck-LMF1 transgenic and LMF1-/- mice. Mice expressing LMF1 exclusively in muscle tissue (Mck-LMF1-/-) exhibited normal survival and plasma lipid levels indicating that restoration of LPL activity in muscle only is sufficient to normalize plasma lipid metabolism in LMF1-/- mice. However, Mck-LMF1-/- mice also demonstrated decreased body weight (BW) and adiposity, reduced hepatic steatosis and improved insulin sensitivity; phenotypes that have not been observed in single-lipase deficient mouse models. Mechanistic studies revealed that decreased energy expenditure was responsible for diminished BW in Mck-LMF1-/- mice. To investigate the role of adipose tissue in this phenotype, we generated adipose-specific LMF1 knock-out (Ad-LMF1-KO) mice. While Ad-LMF1-KO mice exhibited hypertriglyceridemia, BW and adiposity remained unaffected indicating that adipose tissue was not the driver of lean phenotype in LMF1 deficiency. Furthermore, normolipemic heterozygous LMF1+/- mice exhibited lower BW and adiposity relative to wild-type littermates. Finally, we observed direct correlation between hepatic LMF1 expression and adiposity across ~100 inbred mouse strains in the Hybrid Mouse Diversity Panel. In conclusion, our results implicate hepatic LMF1 expression in energy metabolism and suggest that LMF1 plays a novel, lipase-independent role in metabolic regulation.