Abstract
Apolipoprotein B (apoB)-containing lipoproteins play a critical role in whole body lipid homeostasis and the 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 reesterification. Microsomal triacylglycerol hydrolase (TGH) has been demonstrated to play a role in the lipolysis/reesterification process. 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 in liver-specific expression of the enzyme associated with 3- to 4-fold increases in lipolytic activity that could be attenuated with a TGH-specific inhibitor. Augmented TGH activity led to increased secretion of newly synthesized apoB and plasma TG levels. These results suggest that increased hepatic expression of TGH leads to a more proatherogenic plasma lipid and apoB profile.
Highlights
Apolipoprotein B-containing lipoproteins play a critical role in whole body lipid homeostasis and the pathogenesis of atherosclerosis
The majority (60–70%) of VLDL-TG secreted from rat hepatocytes is derived from the lipolysis of stored TG to partial acylglycerols and fatty acids followed by reesterification of the lipolytic products by endoplasmic reticulum (ER)-localized acyltransferases [9,10,11,12,13,14]
The majority of VLDL-TG is believed to be derived from cytoplasmic TG stores through a process that involves lipolysis followed by reesterification of the released fatty acids and partial acylglycerols [9,10,11,12,13]
Summary
Apolipoprotein B (apoB)-containing lipoproteins play a critical role in whole body lipid homeostasis and the pathogenesis of atherosclerosis. The majority of TG associated with VLDL is derived from the hepatic cytoplasmic lipid stores by a process involving lipolysis followed by reesterification. The majority (60–70%) of VLDL-TG secreted from rat hepatocytes is derived from the lipolysis of stored TG to partial acylglycerols and fatty acids followed by reesterification of the lipolytic products by endoplasmic reticulum (ER)-localized acyltransferases [9,10,11,12,13,14]. Ectopic expression of hormone-sensitive lipase in HepG2 cells leads to the diversion of released fatty acids into the oxidative, and not the secretory, pathway, suggesting that the subcellular localization of the lipase(s) may be important in the channeling of substrates [19] Combined, these findings suggest that an ER-localized lipase participates in the provision of lipid for VLDL assembly. This article is available online at http://www.jlr.org
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