Abstract
Mutated mouse lipoprotein lipase (LPL) containing a leucine (L) to histidine (H) substitution at position 452 was transferred into mouse liver by hydrodynamics-based gene delivery (HD). Mutated-LPL (MLPL) gene transfer significantly increased the concentrations of plasma MLPL and triglyceride (TG) but significantly decreased the activity of plasma LPL. Moreover, the gene transfer caused adiposis hepatica and significantly increased TG content in mouse liver. To understand the effects of MLPL gene transfer on energy metabolism, we investigated the expression of key functional genes related to energy metabolism in the liver, epididymal fat, and leg muscles. The mRNA contents of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), fatty acid-binding protein (FABP), and uncoupling protein (UCP) were found to be significantly reduced. Furthermore, we investigated the mechanism by which MLPL gene transfer affected fat deposition in the liver, fat tissue, and muscle. The gene expression and protein levels of forkhead Box O3 (FOXO3), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) were found to be remarkably decreased in the liver, fat and muscle. These results suggest that the Leu452His mutation caused LPL dysfunction and gene transfer of MLPL in vivo produced resistance to the AMPK/PGC-1α signaling pathway in mice.
Highlights
Lipoprotein lipase (LPL), a 55 kDa glycoprotein, is a ratelimiting enzyme for the hydrolysis of triglyceride (TG)-rich lipoprotein
To construct the pTarget/MLPL expression vector, total RNA was extracted from the epididymal fat of Institute of Cancer Research (ICR) mice, and cDNA was obtained by room temperature (RT)-PCR
The observed specific bands for MLPL mRNA were 1425 bp in size. This result suggests that MLPL mRNA was adequately produced in the liver after hydrodynamics-based gene delivery (HD) gene transfer in vivo
Summary
Lipoprotein lipase (LPL), a 55 kDa glycoprotein, is a ratelimiting enzyme for the hydrolysis of triglyceride (TG)-rich lipoprotein. Active LPL is bound to the surface of endothelial cells and can be released into the blood by heparin. LPL hydrolyzes chylomicrons and very lowdensity lipoproteins to release free fatty acids (FFAs), produce remnant lipoproteins, and induce high-density lipoprotein formation [1]. Genetic defects in LPL are responsible for the reduction in TG-rich lipoprotein clearance, and mutations in the LPL gene play important roles in the development of hypertriglyceridemia in the general population [5,6,7]. Approximately 143 different mutations have been found in the human LPL gene, 90% of which occur in the coding regions and affect LPL functions through catalytic activity, dimerization, secretion, and heparin bonding [8]
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