Baylor liver study

[Guest guest]

Dave, I was just reading the newspaper and came across a blurb about

Baylor doing a research study on bile acids. " the livers of mice that

are fed bile acids regenerate more quickly than livers in other mice. "

Certain anti-cholesterol meds that lower the level of bile appear to

prevent the liver from regenerating. " The bile seems to activate

Farnesoid X receptors or FXR which in turn promote liver growth.

Other receptors may be involved as well. It is possible that drugs

could be developed that could promote the growth of liver cells and

help restore function "

I wonder how this might work in conjunction with URSO which as I

understand thins the bile so that it can flow smoothly through the

ducts. My logic says that the more bile that flows weell through the

ducts, the better the chance that the liver cells are able to regenerate.

I'm no scientist and I'd appreciate getting your sense of whether or

not this kind of research might be beneficial to psc'rs. Also in what

stage of development are the researchers in and how do they see their

efforts playing out.

Thanks

Joan -mom of , 19--psc 2004-normal liver enzymes and doing great!

[Guest guest]

Dear Joan;

The paper was just published in Science. Let me know if you would

like to see the full paper. Here's the abstract:

____________________

Science. 2006 Apr 14;312(5771):233-6.

Nuclear receptor-dependent bile acid signaling is required for

normal liver regeneration.

Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B,

Huang X, DD.

Department of Molecular and Cellular Biology, Baylor College of

Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Liver mass depends on one or more unidentified humoral signals that

drive regeneration when liver functional capacity is diminished.

Bile acids are important liver products, and their levels are

tightly regulated. Here, we identify a role for nuclear receptor-

dependent bile acid signaling in normal liver regeneration. Elevated

bile acid levels accelerate regeneration, and decreased levels

inhibit liver regrowth, as does the absence of the primary nuclear

bile acid receptor FXR. We propose that FXR activation by increased

bile acid flux is a signal of decreased functional capacity of the

liver. FXR, and possibly other nuclear receptors, may promote

homeostasis not only by regulating expression of appropriate

metabolic target genes but also by driving homeotrophic liver growth.

PMID: 16614213

_______________________

Ursodiol (UDCA) seems to be in part acting as an activator/ligand of

the FXR:

________________________

J Biol Chem. 2004 Mar 5;279(10):8856-61.

The farnesoid X receptor controls gene expression in a ligand- and

promoter-selective fashion.

Lew JL, Zhao A, Yu J, Huang L, De Pedro N, Pelaez F, SD, Cui

J.

Department of Atherosclerosis and Endocrinology, Merck Research

Laboratories, Rahway, New Jersey 07065, USA.

Farnesoid X receptor (FXR) is a nuclear receptor for bile acids.

Ligand activated-FXR regulates transcription of genes to allow

feedback control of bile acid synthesis and secretion. There are

five major bile acids in humans. We have previously demonstrated

that lithocholate acts as an FXR antagonist, and here we show that

the other four bile acids, chenodeoxycholate (CDCA), deoxycholate

(DCA), cholate (CA), and ursodeoxycholate (UDCA), act as selective

FXR agonists in a gene-specific fashion. In an in vitro coactivator

association assay, CDCA fully activated FXR, whereas CA partially

activated FXR and DCA and UDCA had negligible activities. Similar

results were also obtained from a glutathione S-transferase pull-

down assay in which only CDCA and the synthetic FXR agonist GW4064

significantly increased the interaction of SRC-1 with FXR. In FXR

transactivation assays with a bile salt export pump (BSEP) promoter-

driven luciferase construct, bile acids showed distinct abilities to

activate the BSEP promoter: CDCA, DCA, CA, and UDCA increased

luciferase activity by 25-, 20-, 18-, and 8-fold, respectively.

Consistently, CDCA increased BSEP mRNA by 750-fold in HepG2 cells,

whereas DCA, CA, and UDCA induced BSEP mRNA by 250-, 75-, and 15-

fold, respectively. Despite the partial induction of BSEP mRNA, CA,

DCA, and UDCA effectively repressed expression of cholesterol 7alpha-

hydroxylase, another FXR target. We further showed that all four

bile acids significantly increased FXR protein, suggesting the

existence of an auto-regulatory loop in FXR signaling pathways. In

conclusion, these results suggest that the binding of each bile acid

results in a different FXR conformations, which in turn

differentially regulates expression of individual FXR targets.

PMID: 14684751

________________________

Therefore, if it's possible to extrapolate from mice to humans (?),

taking ursodiol might not only promote bile transporters such as the

bile salt export pump, but also might aid in liver regeneration?

Glad to hear that is doing great!

Best regards,

Dave

(father of (20); PSC 07/03; UC 08/03)