CHOLESTEROL AND BILE-ACID METABOLISM ARE IMPAIRED IN MICE LACKING THENUCLEAR OXYSTEROL RECEPTOR LXR-ALPHA

We demonstrate that mice lacking the oxysterol receptor, LXR alpha, lo se their ability to respond normally to dietary cholesterol and are un able to tolerate any amount of cholesterol in excess of that which the y synthesize de novo. When fed diets containing cholesterol, LXR alpha (-/-) mice fair to induce transcription of the gene encoding choleste rol 7 alpha-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of lar ge amounts of cholesterol in the liver that eventually leads to impair ed hepatic function. The regulation of several other crucial lipid met abolizing genes is also altered in LXR alpha (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forwa rd regulatory pathway for sterol metabolism and establish the role of LXR alpha as the major sensor of dietary cholesterol.