Re: Mouse model of sclerosing cholangitis

[Guest guest]

Hi Nina;

Cholic acid and chenodeoxycholic are made in the liver from cholesterol

through many steps. Cholic acid and chenodeoxycholic and the 2 main

bile acids produced in the human liver. In the gut, these can get

metabolized to more toxic bile acids, deoxycholic acid and lithocholic

acid, respectively. Both of these are recirculated to the liver. I

think it may be these more toxic, secondary bile acids, produced by

bacteria in the gut that are are more problematic. For example,

deoxycholate (derived from cholic acid) is implicated in causing colon

cancer. Lithocholic acid can cause sclerosing cholangitis when given to

laboratory animals.

The main mechanism for detoxifying lithocholate is the pregnane X

receptor, PXR, which is activated by rifampin. PXR increases the

expression of a number of enzymes of bile acid metabolism and transport

which help to get rid of lithocholate. Until recently the receptor

responsible for coordinating the detoxification of cholic

acid/deoxycholate has not been identified. However, the recent paper in

Nature Medicine:

Bochkis IM, Rubins NE, White P, Furth EE, Friedman JR, Kaestner KH 2008

Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and

results in endoplasmic reticulum stress. Nat. Med. 14: 791-889.

suggests that the FOXA2 gene may be responsible. The mice deficient in

FOXA2 are very sensitive to a cholic acid rich diet. As has been

mentioned on the message board a few times already this month, the

article by Bochkis includes the intriguing finding that adults with PSC

have unusually low levels of expression of FOXA2.

It's already known that deficiency in PXR can predispose to IBD, and an

accelerated course of PSC. Perhaps deficiency in FOXA2 may also cause

susceptibility to PSC? More needs to be learned about how FOXA2 is

regulated, and whether the low levels of expression of FOXA2 in PSC

patients are just a consequence of cirrhosis, or a specific marker of

the disease? Is the low level of expression due to a mutation in the

FOXA2 gene, or a consequence of inflammation? Lots of questions!

It has been shown that high-dose ursodiol will reduce the amount of

cholic acid and chenodeoxycholic acid in the bile. Reducing intake of

cholesterol would also tend to lower the level of these bile acids, as

would taking a cholesterol synthesis inhibitor, such as a statin. But

you'd have to talk with your doctor about the pro's and con's of these

strategies.

I hope this answers your question.

Best regards,

Dave R.

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

>

> That is very interesting - does anyone know enough about nutrition to

> know which foods contain (or lead the body to create) cholic acid?

> Thanks,

>

> Nina in Philly

[Guest guest]

, thank you so much for this information - I know you've put this

out here before, and I'm so sorry I'm so slow on the uptake! This

sure does make it sound like a vegan diet would be ideal for PSCers,

doesn't it? I guess I have to start taking my husband's cholesterol

numbers as seriously as I take his liver panel numbers... One thing

is still confusing to me, though. If cholic acid is something the

liver makes out of cholesterol, how do you feed a mouse a cholic acid

rich diet? Do they mean a high cholesterol diet that the mouses then

turn into a high cholic acid diet? Thanks so much,

Nina in Philly

> Cholic acid and chenodeoxycholic are made in the liver from

cholesterol

> through many steps.

The mice deficient in

> FOXA2 are very sensitive to a cholic acid rich diet.

[Guest guest]

Hi Nina;

I think they just add the cholic acid to the mouse's chow!

Best regards,

Dave R.

> If cholic acid is something the liver makes out of cholesterol, how

do you feed a mouse a cholic acid rich diet? Do they mean a high

cholesterol diet that the mouses then turn into a high cholic acid

diet?

[Guest guest]

Dave, Does this suggest that it might be important to monitor

cholesterol? I'm wondering if it would make sense for my son to

limit the eggs that he eats?

Sandy