Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization.
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.


CONCLUSIONS
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.
Uppal
Hirdesh
H
Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Zhai
Yonggong
Y
Gangopadhyay
Archana
A
Khadem
Shaheen
S
Ren
Songrong
S
Moser
James A
JA
Xie
Wen
W
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use; D001647:Bile Acids and Salts / Q000378:metabolism; D002764:Cholecystitis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003460:Crystallization; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects; D000069438:Ezetimibe; D005260:Female; D005704:Gallbladder / Q000378:metabolism*; D042882:Gallstones / Q000378:metabolism* / Q000517:prevention & control; D020869:Gene Expression Profiling; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D002784:Cholesterol; D000069438:Ezetimibe