Abstract 512: Link Between the Lipolysis-Stimulated Lipoprotein Receptor and Lipogenesis in the Liver

Abstract

The lipolysis stimulated lipoprotein receptor (LSR) plays an important role in hepatic uptake of triglyceride (TG)-rich lipoproteins during the postprandial (PPL) phase. We recently reported the regulation of LSR by leptin, accompanied by changes in hepatic lipid metabolism. In this study, we sought to determine if a direct link exists between LSR and lipogenesis in the liver, focusing on ATP citrate lyase (ACL) and fatty acid synthase (FAS), two key enzymes for de novo fatty acid synthesis. Garcinia cambogia extract (GCE) contains hydroxycitric acid, an ACL potent inhibitor found to lower plasma TG and body weight in rodent and human studies. In female 10 wk-old C57BL/6Rj mice treated 30 days with corn oil emulsion containing 20 mg GCE (n=8), we observed reduced fasting (21%, p<0.03) and PPL (22%, p<0.02) plasma TG accompanied by a >1.5 fold (p<0.02) increase in liver membrane LSR protein as compared to controls (emulsion alone, n=8). While hepatic LDL-R protein was moderately increased (NS), TG and total cholesterol content, as well as ACL and FAS protein in the liver were significantly higher as compared to controls. Significant correlations were observed between LSR protein and LDL-receptor (LDL-R) protein as well as liver cholesterol content. Furthermore, stepwise regression revealed a potential association (p < 0.03) between ACL and LSR. ACL and FAS protein have previously been shown to be modified by dietary fat content. Female 10-wk old LSR +/- (n=11) mice and LSR +/+ littermates (n=7) were placed on a high fat (60% kcal) diet for 6 wks; LSR +/- exhibited higher weight gain, fat mass and PPL plasma TG vs LSR +/+ as previously reported. A >2-fold (p<0.04) reduction in ACL, but not FAS protein in LSR +/- was observed as compared to controls. Interestingly, strong correlations were found between LSR and FAS (r = 0.8, p<0.01) and LDL-R (r=0.74, p<0.01), but only in LSR +/- mice. We therefore propose that there exists a close link between the regulation of the uptake of lipoproteins via the LSR and LDL-R pathways and de novo lipogenesis in the liver. Further studies will provide insight in the mechanisms involved in maintaining lipid homeostasis, leading towards potential treatments for hyperlipidemia associated with obesity, 2 high risk factors for atherosclerosis.