Transgenic Mice Expressing Lipoprotein Lipase in Adipose Tissue

Abstract

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and adipocyte metabolism. Defects in LPL can lead to hypertriglyceridemia and the subsequent development of atherosclerosis. The mechanisms of regulation of this enzyme are complex and may occur at multiple levels of gene expression. Because the 3 -untranslated region (UTR) is involved in LPL translational regulation, transgenic mice were generated with adipose tissue expression of an LPL construct either with or without the proximal 3 -UTR and driven by the aP2 promoter. Both transgenic mouse colonies were viable and expressed the transgene, resulting in a 2-fold increase in LPL activity in white adipose tissue. Neither mouse colony exhibited any obvious phenotype in terms of body weight, plasma lipids, glucose, and non-esterified fatty acid levels. In the mice expressing hLPL with an intact 3 -UTR, hLPL mRNA expression approximately paralleled hLPL activity. However in the mice without the proximal 3 -UTR, hLPL mRNA was low in the setting of large amounts of hLPL protein and LPL activity. In previous studies, the 3 -UTR of LPL was critical for the inhibitory effects of constitutively expressed hormones, such as thyroid hormone and catecholamines. Therefore, these data suggest that the absence of the 3 -UTR results in a translationally unrepressed LPL, resulting in a moderate overexpression of adipose LPL activity.Lipoprotein lipase (LPL) 1 is a central enzyme in lipid metabolism. The enzyme is synthesized and secreted by adipocytes and muscle cells, and transported to the capillary endothelium, where hydrolysis of the triglyceride core of circulating VLDL and chylomicrons takes place. Although the changes in LPL activity with different physiologic states have been well described (1), the mechanism of LPL regulation is complex and occurs at levels of transcription (2-6), translation (7-11), and post-translational processing (12-15) in response to both cell type and regulatory factors. Previous studies have demonstrated translational regulation of LPL. In response to glucose (7), thyroid hormone (8), and catecholamines (9), there were significant changes in LPL protein synthesis, with no changes in adipocyte LPL mRNA levels. In addition, the decrease in LPL activity in both diabetic patients, and rats is due predominantly to decreased LPL translation (10, 16).LPL is an important marker of adipocyte differentiation, and LPL expression increases in parallel with cellular triglyceride accumulation in preadipocytes (17, 18). Although adipose tissue can synthesize non-esterified fatty acids (NEFA) de novo, NEFA for lipid storage are preferentially obtained from LPLmediated hydrolysis of plasma lipoproteins (19). Hence, LPL has been called "the gatekeeper of the adipocyte" (20), and has been implicated in the development of obesity.Based on LPL's putative role as an adipocyte "gatekeeper," one might expect that transgenic mice would become obese if LPL were overexpressed in adipose tissue, and lean if LPL were overexpressed in muscle. Several recent studies have ...

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

“…For example, LPL overexpression in aP2-LPL mice, which exhibit similarly elevated LPL activities in adipose tissue as aP2-Lmf1 mice, had no effect on plasma lipids, post-heparin LPL activity or other metabolic traits. 39 Likewise, Mck-LPL transgenic mice with muscle-specific LPL overexpression exhibited wild-type levels of plasma lipids, glucose and insulin. 3 However, in contrast to tissue-specific models, transgenic mice overexpressing LPL in all tissues showed elevated plasma LPL activity and altered lipid traits.…”