Activation of LXRs prevents bile acid toxicity and cholestasis in female mice

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Activation

of LXRs prevents bile acid toxicity and cholestasis in female mice

Hirdesh

Uppal , Simrat

P.S. Saini ,

Moschetta ,

Ying Mu , Jie

Zhou , Haibiao Gong1, Yonggong Zha,

Songrong Ren, K. Michalopoulos , J. Mangelsdorf , Wen

Xie

Abstract

Liver

X receptors (LXRs) have been identified as sterol

sensors that regulate cholesterol and lipid homeostasis and macrophage

functions. In this study, we found that LXRs also affect sensitivity to bile acid toxicity and cholestasis. Activation of LXR in transgenic mice confers a female-specific resistance to lithocholic acid (LCA)-induced hepatotoxicity

and bile duct ligation (BDL)-induced cholestasis. This resistance was

also seen in wild-type female mice treated with the synthetic LXR ligand

TO1317. In contrast, LXR double knockout (DKO) mice

deficient in both the and isoforms exhibited heightened cholestatic sensitivity. LCA and

BDL resistance in transgenic mice was associated with increased expression of

bile acid-detoxifying sulfotransferase 2A (Sult2a) and selected bile acid

transporters, whereas basal expression of these gene products was reduced in

the LXR DKO mice. Promoter analysis showed that the

mouse Sult2a9 gene is a

transcriptional target of LXRs. Activation of LXRs also suppresses expression of oxysterol

7-hydroxylase

(Cyp7b1), which may lead to

increased levels of LXR-activating oxysterols. Conclusion:

We propose that LXRs have evolved to have the dual

functions of maintaining cholesterol and bile acid homeostasis by increasing

cholesterol catabolism and, at the same time, preventing toxicity from bile

acid accumulation. (HEPATOLOGY

2007;45:422-432.)

((FYI – I am a “wild-type female mouse”

whose with me????))