Despite the well-established role of liver X receptors (LXRs) in regulating cholesterol homeostasis, their contribution to lipid homeostasis remains unclear. Here we show that LXR null mice are defective in hepatic lipid metabolism and are resistant to obesity when challenged with a diet containing both high fat and cholesterol. This phenotype is dependent on the presence of dietary cholesterol and is accompanied by the aberrant production of thyroid hormone in liver. Interestingly, the inability of LXR-/- mice to induce SREBP-1c-dependent lipogenesis does not explain the LXR-/- phenotype, since SREBP-1c null mice are not obesity resistant. Instead, the LXR-/- response is due to abnormal energy dissipation resulting from uncoupled oxidative phosphorylation and ectopic expression of uncoupling proteins in muscle and white adipose. These studies suggest that, by selectively sensing the cholesterol component of a lipid-rich diet, LXRs govern the balance between storage and oxidation of dietary fat.
Bibliographical noteFunding Information:
We thank Drs. Michael Brown and Joseph Goldstein for SREBP-1c −/− mice; Antonio Moschetta, Steve Kliewer, Joyce Repa, Oleg Guryev, Ronald Estabrook, Cai Li, Stephen Turley, and Helen Hobbs for comments and suggestions; Norma Anderson, Amy Liverman, Angie Bookout, and Stacie Cary for help on experiments; and members of the Mango lab for helpful suggestions. D.J.M is an investigator, and K.C.G. is an associate of the Howard Hughes Medical Institute. This work was funded by the Howard Hughes Medical Institute, the Robert A. Welch Foundation, and National Institutes of Health grants (U19DK62434 and P20RR20691). D.J.M. serves as a consultant for Exelixis, Inc.