A new piece of the PSC puzzle discovered

[Guest guest]

Dear All;

A paper in Nature Medicine (published Jul 27) shows that a gene

called Foxa2 is important in controlling bile acid levels, and

preventing liver injury cause by dietary cholic acid in mice:

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Nat Med. 2008 Jul 27. [Epub ahead of print]

Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis

and results in endoplasmic reticulum stress.

Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH

Department of Genetics and Institute for Diabetes, Obesity and

Metabolism, University of Pennsylvania School of Medicine, 415 Curie

Boulevard, Philadelphia, Pennsylvania 19104, USA.

Production of bile by the liver is crucial for the absorption of

lipophilic nutrients. Dysregulation of bile acid homeostasis can lead

to cholestatic liver disease and endoplasmic reticulum (ER) stress.

We show by global location analysis ('ChIP-on-chip') and cell type-

specific gene ablation that the winged helix transcription factor

Foxa2 is required for normal bile acid homeostasis. As suggested by

the location analysis, deletion of Foxa2 in hepatocytes in mice using

the Cre-lox system leads to decreased transcription of genes encoding

bile acid transporters on both the basolateral and canalicular

membranes, resulting in intrahepatic cholestasis. Foxa2-deficient

mice are strikingly sensitive to a diet containing cholic acid, which

results in toxic accumulation of hepatic bile salts, ER stress and

liver injury. In addition, we show that expression of FOXA2 is

markedly decreased in liver samples from individuals with different

cholestatic syndromes, suggesting that reduced FOXA2 abundance could

exacerbate the injury. PMID: 18660816.

________________

Most interestingly, in the Results section of the full paper they

show that in pediatric and adult PSC patients, the liver expression

of FOXA2 is markedly reduced in comparison to controls!!!

FOXA2 may be acting in a manner similar to the nuclear receptor PXR

(pregnane X receptor), controlling the expression of a number of

enzymes of bile acid metabolism/conjugation and transport in the

liver. PXR regulates lithocholic acid detoxification in the liver,

while FOXA2 appears to be key to cholic acid detoxification. Recall

that PXR has been implicated in susceptibility to ulcerative colitis,

and rate of progression of PSC. Perhaps FOXA2 should now be looked at

as a potential susceptibility gene in PSC?

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)