Transgenic Expression and Genetic Variation of Lmf1 Affect LPL Activity in Mice and Humans

Abstract

Objective Lipoprotein lipase (LPL) is a principal enzyme in lipoprotein metabolism, tissue lipid utilization and energy metabolism. LPL is synthesized by parenchymal cells in adipose, heart and muscle tissues followed by secretion to extracellular sites, where lipolyic function is exerted. The catalytic activity of LPL is attained during post-translational maturation, which involves glycosylation, folding and subunit assembly within the endoplasmic reticulum (ER). A lipase-chaperone, lipase maturation factor 1 (Lmf1), has recently emerged as a critical factor in this process. Previous studies demonstrated that loss-of-function mutations of Lmf1 result in diminished lipase activity and severe hypertriglyceridemia in mice and human subjects. The objective of this study is to investigate whether, beyond its role as a required factor in lipase maturation, variation in Lmf1 expression is sufficient to modulate LPL activity in vivo. Methods and Results To assess the effects of Lmf1 overexpression in adipose and muscle tissues, we generated aP2-Lmf1 and Mck-Lmf1 transgenic mice. Characterization of relevant tissues revealed increased LPL activity in both mouse strains. In the omental and subcutaneous adipose depots, Lmf1 overexpression was associated with increased LPL specific activity without changes in LPL mass. In contrast, increased LPL activity was due to elevated LPL protein level in heart and gonadal adipose tissue. To extend these studies to humans, we detected association between LMF1 gene variants and post-heparin LPL activity in a dyslipidemic cohort. Conclusions Our results suggest that variation in Lmf1 expression is a post-translational determinant of LPL activity.

Peroxisome proliferator‐activated receptor γ activation favours selective subcutaneous lipid deposition by coordinately regulating lipoprotein lipase modulators, fatty acid transporters and lipogenic enzymes

“…, Hosseini et al . ), we wished to extend our previous findings by assessing the depot specificity of action of chronic PPAR γ activation at the levels of LPL mass/specific activity, and recently characterized, major modulators of LPL action. In SF of fasted animals, the induction of LPL activity by PPAR γ activation was of higher magnitude than that of its mass, which is suggestive of a positive post‐translational regulation of LPL.…”

“…, Hosseini et al . ). Whereas lipase maturation factor 1 (LMF1) and glycosylphosphatidylinositol‐anchored HDL‐binding protein 1 (GPIHBP1) increase LPL activity by, respectively, coordinating the proper folding of LPL into its active form and its transport from the adipocyte to the capillary endothelium where TG is hydrolysed, angiopoietin‐like protein 4 (ANGPTL4) catalyses a conformational switch from active LPL dimers to catalytically inactive monomers (Sukonina et al .…”

“…As it has been hypothesized that the regulation of these new modulators of LPL activity could be major factors in energy trafficking and lipid storage (Fisher , Hosseini et al . ), one objective of the present study was to assess whether PPAR γ activation exerts a depot‐specific action on their expression as is the case for LPL. The catalytic activity of LPL is also sensitive to product inhibition and depends upon the capacity of tissues to take up and stably store TG‐derived lipids (Olivecrona & Olivecrona ).…”

Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism in High Fat Diet-induced Obesity

“…A similar observation was made by Levak-Frank et al (32), who found that increasing muscle LPL expression increased HDL turnover. It will be interesting to explore the mechanism in the future in the Adipoq-LPL model because there have been different reports of the effect of increasing LPL on HDL in other models, with some models of LPL overexpression having no change in HDL (31,33,34) and one model reporting an increase in HDL (35).…”

Lipase Maturation Factor 1 (Lmf1) Is Induced by Endoplasmic Reticulum Stress Through Activating Transcription Factor 6α (Atf6α) Signaling

“…Canonical signaling through Ire1␣ affects lipogenesis and very low-density lipoprotein (VLDL) secretion (42)(43)(44), whereas non-canonical UPR signaling involving the cAMP response element-binding protein, hepatocyte-specific regulates lipolysis through the transcriptional regulation of apolipoproteins that activate or inhibit lipoprotein lipase activity (45). As Lmf1 overexpression results in elevated tissue lipoprotein lipase activity (46), UPR-induced Lmf1 expression may represent a novel mechanism through which ER stress modulates lipolysis and tissue lipid uptake. However, our study demonstrates that ER stress-induced Lmf1 regulation also occurs in a lipase-independent cellular context.…”