HEPATIC OVEREXPRESSION OF BOVINE SCAVENGER RECEPTOR-TYPE-I IN TRANSGENIC MICE PREVENTS DIET-INDUCED HYPERBETALIPOPROTEINEMIA

Hepatic scavenger receptors (SR) may play a protective role by clearin g modified lipoproteins before they target the artery wall. To gain in sight into this hypothesized function, transgenic mice expressing hepa tic bovine SR (TgSR) were created and studied when fed chow, and durin g diet-induced hyperlipidemia. SR overexpression resulted in extensive hepatic parenchymal cell uptake of fluorescently labeled acetylated h uman low density lipoprotein (DiI ac-hLDL) and a twofold increase in I -125-acetylated-LDL clearance. Food intake and cholesterol absorption was indistinguishable between control and TgSR mice. In chow-fed mice, lipoprotein cholesterol was similar in control and TgSR mice. However , on a 3-wk high fat/cholesterol (HFHC) diet, the rise in apoB contain ing lipoproteins was suppressed in TgSR+/- and TgSR+/+ mice. The rise in HDL was similar in control and TgSR+/- mice, but significantly elev ated in the TgSR+/+ mice. Overall, on chow, the ratio of apo-B contain ing lipoprotein cholesterol to HDL cholesterol was similar for all gro ups (control = 0.33; TgSR+/- = 0.32; TgSR+/+ = 0.38). However, after 3 wk on the HFHC diet, this ratio was markedly higher in control (2.34- /-0.21) than in either TgSR+/- (1.00+/-0.24) or TgSR+/+ (1.00+/-0.19) mice. In TgSR+/- mice, hepatic cholesteryl esters were reduced by 59%, 7 alpha-hydroxylase mRNA levels were elevated twofold, and a signific ant increase in fecal bile add flux was observed after the 3-wk HFHC d iet. These results suggest SR may play a protective role in liver by p reventing diet-induced increases in apoB containing lipoproteins.