Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Björkhem I, Pettersson S, Gustafsson J A
Department of Biosciences at Novum, Karolinska Institutet, Huddinge, Sweden.
J Clin Invest. 2001 Mar;107(5):565-73. doi: 10.1172/JCI9794.
The nuclear oxysterol-receptor paralogues LXRalpha and LXRbeta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRalpha has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRbeta 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 LXRbeta(-/-) 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 LXRbeta(-/-) mice compared with LXRbeta(+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRbeta(-/-) mice - in contrast to LXRalpha(-/-) 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 LXRbeta has no complete overlapping function compared with LXRalpha in the liver.
核氧甾醇受体旁系同源物肝X受体α（LXRα）和肝X受体β（LXRβ）具有高度的氨基酸同一性，并且以相似的亲和力结合内源性氧甾醇配体。虽然LXRα已被确定为胆固醇喂养小鼠中胆固醇分解代谢的重要调节因子，但LXRβ在体内的功能却知之甚少。我们构建了靶向破坏每种LXR受体的小鼠品系，并比较了它们对膳食胆固醇的反应。胆固醇喂养动物的血清和肝脏胆固醇水平以及脂蛋白谱显示，LXRβ基因敲除（LXRβ(-/-)）小鼠和野生型小鼠之间没有显著差异。与LXRβ基因野生型（LXRβ(+/+)）小鼠相比，当喂食标准饲料时，LXRβ(-/-)小鼠中3-羟基-3-甲基戊二酰辅酶A还原酶、法尼基二磷酸合酶和角鲨烯合酶的稳态mRNA水平升高。在标准饲料和2%胆固醇饲料喂养下，这些品系中胆固醇7α-羟化酶、氧甾醇7α-羟化酶、甾醇12α-羟化酶和甾醇27-羟化酶的mRNA水平相当。我们的结果表明，与LXRα(-/-)小鼠不同，LXRβ(-/-)小鼠尽管对参与脂质代谢的酶编码基因的表达有细微影响，但仍保持对膳食胆固醇的抗性。因此，我们的数据表明，在肝脏中，LXRβ与LXRα相比没有完全重叠的功能。
