Potential antiatherogenic role of SR-B1 in extrahepatic tissues

Scavenger receptor B1 (SR-B1) is an HDL receptor that promotes selective uptake of HDL and removal from the plasma, and is therefore important in protecting against atherosclerosis. Although the main site of activity is in the liver, new data1 show that SR-B1 may also exert an antiatherogenic role in extrahepatic tissues.

In this study, researchers used three genetically modified mouse models differing in both tissue specificity and absolute levels of SR-B1 expression. The first model was a SR-B1 conditional knockout mouse model with a hypomorphic allele, i.e., an allele that reduces the activity of SR-B1 without eliminating it entirely (hypomSR-B1). The other two models were a mouse model with the hypomorphic allele in hepatocytes (hypomSR-B1-KOliver), and a mouse model deficient in SR-B1 (SR-B1-/-).

The researchers showed that the attenuated SR-B1 expression in the hypomSR-B1 mouse model resulted in a 2-fold increase in plasma total cholesterol levels. The hypomSR-B1-KOliver mouse model was also associated with high plasma total cholesterol levels, as well as an increase in the ratio of free to total cholesterol and a lipoprotein profile typical of SR-B1 deficient mice (SR-B1-/-).

When fed an atherogenic diet, atherosclerosis was increased 2.5-fold in hypomSR-B1 mice and controls. Atherosclerosis was also markedly enhanced in the hypomSR-B1-KOliver and SR-B1-/- mouse models. However, despite similar plasma lipid profiles and capacity of very low-density lipoproteins to induce cholesterol loading in the macrophages, atherosclerosis was less extensive in hypomSR-B1-KOliver mice than SR-B1-/- mice.

These findings indicate that peripheral SR-B1 expression may have a role in protecting against atherosclerosis via mechanisms independent of changes in plasma lipids. Both hepatic and extrahepatic SR-B1 expression appear to be involved in cholesterol haemostasis, and by implication, atherosclerosis susceptibility.

Reference

1. Huby T, Doucet C, Dachet C et al. Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-B1 in liver and peripheral tissues. J Clin Invest 2006;116: 2767- 76.

Commentary

The recent finding that mutation of the SR-B1 receptor leads to elevated levels of HDL cholesterol in a Dutch family (see AHA 2006 reports in News) First report of SR-B1 mutation in man influencing HDL cholesterol levels] identifies SR-B1 as a key player in cholesterol homeostasis in man. The development then of these genetically modified mouse models with tissue-specific alteration in the levels of SR-B1 expression constitutes a novel strategy for experimental evaluation of the role of this multi-ligand, ubiquitous receptor in cholesterol metabolism and in the pathophysiology of atherosclerosis.