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Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion
Dean Gilham1, Samuel Ho, Mehdi Rasouli
1Department of Cell Biology, CIHR Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Insights
Inhibiting triacylglycerol hydrolase significantly reduced the secretion of very low-density lipoprotein (VLDL) particles, including apolipoprotein B-100 (apoB-100). This suggests triacylglycerol hydrolase is a potential drug target for lowering blood lipids.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Disease Research
Background:
- Elevated circulating triacylglycerol (TG)-rich very low-density lipoprotein (VLDL) and apolipoprotein B-100 (apoB-100) are independent risk factors for coronary artery disease.
- Triacylglycerol hydrolase (TGH) mobilizes cytoplasmic TG stores, but its role in VLDL assembly is unclear.
Purpose of the Study:
- To investigate the role of TGH in providing core lipids for VLDL assembly.
- To determine the effect of inhibiting TGH activity on lipid and apoB synthesis and secretion.
Main Methods:
- Primary rat hepatocytes and hepatoma cells transfected with TGH cDNA were used.
- Lipase activity was inhibited to analyze lipid and apoB synthesis and secretion.
- Secreted lipoproteins and apolipoproteins were analyzed.
Main Results:
- Inhibition of lipolysis dramatically decreased TG secretion.
- Secretion of cholesteryl ester and phosphatidylcholine was also substantially reduced.
- ApoB-100 secretion was more sensitive to lipase inhibition than apoB-48 secretion.
Conclusions:
- Intracellular TG hydrolysis significantly decreases apoB-100 secretion.
- TGH may be a viable pharmacological target for reducing plasma lipid levels.
- Preferential lipidation of apoB-100 was observed in TGH-transfected cells.
Abstract:
The presence of elevated circulating triacylglycerol (TG)-rich very low density lipoprotein (VLDL) and apolipoprotein B-100 (apoB-100) levels represents an independent risk factor for coronary artery disease. Triacylglycerol hydrolase catalyzes the mobilization of cytoplasmic TG stores. To test the hypothesis that the enzyme plays a role in the provision of core lipids for the assembly of VLDL, we inhibited the lipase activity in primary rat hepatocytes and analyzed lipid and apoB synthesis and secretion. Inhibition of lipolysis resulted in a dramatic decrease in secretion of TGs. In addition, secretion of cholesteryl ester and phosphatidylcholine was substantially decreased. Analysis of secreted apolipoproteins indicated that apoB-100 secretion was much more sensitive to lipase inhibition than was apoB-48 secretion, perhaps because of the ability of apoB-48 to be secreted as a relatively lipid-poor particle. The results agreed with those obtained with hepatoma cells transfected with triacylglycerol hydrolase cDNA, in which preferential lipidation of apoB-100 was observed. Together, our findings provide evidence that inhibition of intracellular TG hydrolysis significantly decreases apoB-100 secretion and suggest that triacylglycerol hydrolase may be a suitable pharmacological target in efforts to lower plasma lipid levels.