Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice

The nuclear oxysterol-receptor paralogues LXR alpha and LXR beta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXR alpha has been established as an important regulator 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 their responses to dietary cholesterol, Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXR beta (-/-) and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXR beta (-/-) mice compared with LXR beta (+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7 alpha -hydroxylase, oxysterol 7a-hydroxylase, sterol 12 alpha -hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXR beta (-/-) mice - in contrast to LXR alpha (-/-) mice - maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXR beta has no complete overlapping function compared with LXR alpha in the liver.