Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice

Enhui Wei, Mustafa Alam, Fengcheng Sun, Luis B. Agellon, Dennis E. Vance, and Richard Lehner

Pediatrics and Cell Biology, University of Alberta, Edmonton, Alberta T6G 2S2

Corresponding Author: richard.lehner{at}ualberta.ca

ApoB-containing lipoproteins play a critical role in whole-body lipid homeostasis and pathogenesis of atherosclerosis. The assembly of hepatic apoB-containing lipoproteins, VLDL, is governed by the availability of lipids, including triacylglycerol (TG). The majority of TG associated with VLDL is derived from the hepatic cytoplasmic lipid stores by a process involving lipolysis followed by re-esterification. Microsomal triacylglycerol hydrolase (TGH) has been demonstrated to play a role in the lipolysis/re-esterification process. In order to evaluate the potential regulatory role of TGH in hepatic VLDL assembly we developed inducible transgenic mice expressing a human TGH minigene under the control of the mouse metallothionein promoter. Induction of human TGH by zinc resulted liver-specific expression of the enzyme associated with 3- to 4-fold increase in lipolytic activity that could be attenuated with a TGH-specific inhibitor. Augmented TGH activity led to increased secretion of newly synthesized apolipoprotein B and plasma TG levels. The results suggest that increased hepatic expression of TGH leads to a more proatherogenic plasma lipid and apolipoprotein B profile.

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