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Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization
Author(s) -
Uppal Hirdesh,
Zhai Yonggong,
Gangopadhyay Archana,
Khadem Shaheen,
Ren Songrong,
Moser James A.,
Xie Wen
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22175
Subject(s) - liver x receptor , ezetimibe , cholesterol , medicine , reverse cholesterol transport , endocrinology , gallbladder , ldl receptor , chemistry , lipoprotein , biology , nuclear receptor , biochemistry , transcription factor , gene
Gallstone disease is a hepatobiliary disorder due to biochemical imbalances in the gallbladder bile. In this report, we show that activation of nuclear receptor liver X receptor (LXR) sensitized mice to lithogenic diet–induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary concentrations of cholesterol and phospholipids and decreased biliary concentrations of bile salts in LXR‐activated mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. Interestingly, the lithogenic effect of LXR was completely abolished in the low‐density lipoprotein receptor ( Ldlr ) null background or when the mice were treated with Ezetimibe, a cholesterol‐lowering drug that blocks intestinal dietary cholesterol absorption. These results suggest that LDLR‐mediated hepatic cholesterol uptake and intestinal cholesterol absorption play an essential role in LXR‐promoted lithogenesis. Conclusion: The current study has revealed a novel lithogenic role of LXR as well as a functional interplay between LXR and LDLR in gallbladder cholesterol crystallization and possibly cholesterol gallstone disease (CGD). We propose that LXR is a lithogenic factor and that the LXR transgenic mice may offer a convenient CGD model to develop therapeutic interventions for this disease. (H EPATOLOGY 2008.)