Wölle S, Via D P, Chan L, Cornicelli J A, Bisgaier C L
Department of Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
J Clin Invest. 1995 Jul;96(1):260-72. doi: 10.1172/JCI118030.
Hepatic scavenger receptors (SR) may play a protective role by clearing modified lipoproteins before they target the artery wall. To gain insight into this hypothesized function, transgenic mice expressing hepatic bovine SR (TgSR) were created and studied when fed chow, and during diet-induced hyperlipidemia. SR overexpression resulted in extensive hepatic parenchymal cell uptake of fluorescently labeled acetylated human low density lipoprotein (DiI ac-hLDL) and a twofold increase in 125I-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 containing lipoproteins was suppressed in TgSR+/- and TgSR+/+ mice. The rise in HDL was similar in control and TgSR+/- mice, but significantly elevated in the TgSR+/+ mice. Overall, on chow, the ratio of apo-B containing lipoprotein cholesterol to HDL cholesterol was similar for all groups (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 significant increase in fecal bile acid flux was observed after the 3-wk HFHC diet. These results suggest SR may play a protective role in liver by preventing diet-induced increases in apoB containing lipoproteins.
肝脏清道夫受体（SR）可能通过在修饰的脂蛋白靶向动脉壁之前将其清除而发挥保护作用。为了深入了解这一假设功能，构建了表达肝脏牛SR（TgSR）的转基因小鼠，并在喂食普通饲料时以及饮食诱导的高脂血症期间对其进行研究。SR的过表达导致肝脏实质细胞对荧光标记的乙酰化人低密度脂蛋白（DiI ac-hLDL）的大量摄取，以及125I-乙酰化-LDL清除率增加两倍。对照小鼠和TgSR小鼠的食物摄入量和胆固醇吸收没有差异。在喂食普通饲料的小鼠中，对照小鼠和TgSR小鼠的脂蛋白胆固醇相似。然而，在高脂/高胆固醇（HFHC）饮食3周后，TgSR+/-和TgSR+/+小鼠中含载脂蛋白B的脂蛋白的升高受到抑制。对照小鼠和TgSR+/-小鼠中高密度脂蛋白（HDL）的升高相似，但在TgSR+/+小鼠中显著升高。总体而言，在喂食普通饲料时，所有组中含载脂蛋白B的脂蛋白胆固醇与HDL胆固醇的比值相似（对照=0.33；TgSR+/-=0.32；TgSR+/+=0.38）。然而，在HFHC饮食3周后，该比值在对照小鼠（2.34±0.21）中明显高于TgSR+/-（1.00±0.24）或TgSR+/+（1.00±0.19）小鼠。在TgSR+/-小鼠中，肝脏胆固醇酯减少了59%，7α-羟化酶mRNA水平升高了两倍，并且在HFHC饮食3周后观察到粪便胆汁酸通量显著增加。这些结果表明，SR可能通过防止饮食诱导的含载脂蛋白B的脂蛋白增加而在肝脏中发挥保护作用。
