Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR beta-deficient mice

The nuclear oxysterol-receptor paralogues LXR alpha and LXR beta share a hi gh degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXR alpha has been established as an important r egulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXR beta in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared thei r responses to dietary cholesterol, Serum and hepatic cholesterol levels an d lipoprotein profiles of cholesterol-fed animals revealed no significant d ifferences between LXR beta (-/-) and wild-type mice. Steady-state mRNA lev els of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphat e synthase, and squalene synthase were increased in LXR beta (-/-) mice com pared with LXR beta (+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7 alpha -hydroxylase, oxysterol 7a-hydroxylase, sterol 12 alph a -hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indic ate that LXR beta (-/-) mice - in contrast to LXR alpha (-/-) mice - mainta in their resistance to dietary cholesterol, despite subtle effects on the e xpression of genes coding for enzymes involved in lipid metabolism. Thus, o ur data indicate that LXR beta has no complete overlapping function compare d with LXR alpha in the liver.