91丝瓜视频

Dr. Zemin Yao

Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Canada

鈥淣ew insight into an intrahepatic role of human apoC-III in hyperlipidemia and hepatic stress induced by lipotoxicity鈥�

The plasma concentration of human apoC-III is positively associated with VLDL apoB-100 and triglyceride (TG); elevated apoC-III is invariably linked to hypertriglyceridemia in humans and transgenic mice. Although the hyperlipidemic role of apoC-III was ascribed for its action in inhibiting lipoprotein lipase-catalyzed TG hydrolysis and attenuating receptor-mediated endocytosis of TG-rich lipoproteins, several in vivo studies using stable isotopes have suggested a role of apoC-III in hepatic VLDL production in humans. Our transfection experiments with cultured hepatic cells showed that expression of human apoC-III enhanced assembly and secretion of apoB-100 in association with TAG-rich VLDL1 under lipid-rich conditions. Mutational analysis with two naturally occurring human apoC-III mutants, namely Ala23Thr and Lys58Glu, originally identified in respective hypotriglyceridemia and hyperalphalipoproteinemia subjects, has revealed loss-of-function phenotype in VLDL1 assembly/secretion. Structural-functional analysis has provided evidence for a two-domain model depicting apoC-III action 鈥� the C-terminal lipid-binding domain (a typical type A amphipathic a-helix) is responsible for the formation of lumenal lipid droplets (LLD) that are a precursor of VLDL1, whereas the N-terminal domain may play a role in promoting fusion of LLD with primordial VLDL. Kinetic studies have demonstrated that apoC-III, working in tandem with MTP, promotes formation of LLD. The human apoC-III stimulated VLDL1-apoB-100 production was readily observed (via adenovirus-mediated gene transfer) in apoC3-null mice fed with high fat diet or palm oil gavage. Further, cells stably expressing human apoC-III displayed resistance to ER stress (as determined by eIF2a phosphorylation) induced by palmitic acid. The data suggest that apoC-III may protect hepatic stress induced by lipotoxicity through purging lipids as TG-rich VLDL1.

Mandatory for Graduate Students