TY - JOUR
T1 - Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα
AU - Peet, Daniel J.
AU - Turley, Stephen D
AU - Ma, Wenzhen
AU - Janowski, Bethany A.
AU - Lobaccaro, Jean Marc A
AU - Hammer, Robert E
AU - Mangelsdorf, David J
N1 - Funding Information:
We thank Drs. Patricia Willy for antibodies, and Yasushi Kisanuki, Joyce Repa, Margrit Schwarz, and Mala Mahendroo for animal studies; Dr. E. J. Corey for 24(S), 25-epoxycholesterol; Drs. David Russell, Michael Brown, Joseph Goldstein, Helen Hobbs for Northern probes, technical resources, and critical review; Drs. John Dietschy, Jay Horton, Hitoshi Shimano, and James Richardson for critical comments. We thank Dr. David Spady for providing methodology for bile acid pool size analysis, and Dr. Iichiro Shimomura and Bobby Korn for mouse SCAP cDNA. We thank Jeffrey Graven, Brian Jefferson, Elizabeth Moore, Stephen Osterman, Scott Clark, and Heather Lawrence for expert technical assistance. D. J. M. is an Associate Investigator, and D. J. P. and J.-M. L. are Associates of the Howard Hughes Medical Institute (HHMI). This work was funded by HHMI and grants from the Robert A. Welch Foundation, US Public Health Service (HL09610), and Moss Heart Fund.
PY - 1998/5/29
Y1 - 1998/5/29
N2 - We demonstrate that mice lacking the oxysterol receptor, LXRα, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXRα (-/-) mice fail to induce transcription of the gene encoding cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXRα (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXRα as the major sensor of dietary cholesterol.
AB - We demonstrate that mice lacking the oxysterol receptor, LXRα, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXRα (-/-) mice fail to induce transcription of the gene encoding cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXRα (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXRα as the major sensor of dietary cholesterol.
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U2 - 10.1016/S0092-8674(00)81432-4
DO - 10.1016/S0092-8674(00)81432-4
M3 - Article
C2 - 9630215
AN - SCOPUS:0013199471
SN - 0092-8674
VL - 93
SP - 693
EP - 704
JO - Cell
JF - Cell
IS - 5
ER -