Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions |
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Authors: | Meenakshi Sundaram Shumei Zhong Maroun Bou Khalil Philip H. Links Yang Zhao Jahangir Iqbal M. Mahmood Hussain Robin J. Parks Yuwei Wang Zemin Yao |
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Affiliation: | 2. Mazankowski Alberta Heart Institute, Edmonton Canada, T6G 2B7;4. Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, NY 11203;11. Lipoprotein and Atherosclerosis Group, University of Ottawa Heart Institute, Ottawa, Canada, K1Y 4W7 |
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Abstract: | Apolipoprotein (apo) C-III plays a regulatory role in VLDL lipolysis and clearance. In this study, we determined a potential intracellular role of apoC-III in hepatic VLDL assembly and secretion. Stable expression of recombinant apoC-III in McA-RH7777 cells resulted in increased secretion efficiency of VLDL-associated triacylglycerol (TAG) and apoB-100 in a gene-dosage-dependent manner. The stimulatory effect of apoC-III on TAG secretion was manifested only when cells were cultured under lipid-rich (i.e., media supplemented with exogenous oleate) but not lipid-poor conditions. The stimulated TAG secretion was accompanied by increased secretion of apoB-100 and apoB-48 as VLDL1. Expression of apoC-III also increased mRNA and activity of microsomal triglyceride transfer protein (MTP). Pulse-chase experiments showed that apoC-III expression promoted VLDL1 secretion even under conditions where the MTP activity was inhibited immediately after the formation of lipid-poor apoB-100 particles, suggesting an involvement of apoC-III in the second-step VLDL assembly process. Consistent with this notion, the newly synthesized apoC-III was predominantly associated with TAG within the microsomal lumen that resembled lipid precursors of VLDL. Introducing an Ala23-to-Thr mutation into apoC-III, a naturally occurring mutation originally identified in two Mayan Indian subjects with hypotriglyceridemia, abolished the ability of apoC-III to stimulate VLDL secretion from transfected cells. Thus, expression of apoC-III in McA-RH7777 cells enhances hepatic TAG-rich VLDL assembly and secretion under lipid-rich conditions. |
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Keywords: | triacylglycerol hypotriglyceridemia hypertriglyceridemia microsomal triglyceride transfer protein hepatocyte |
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