Lithocholic acid and PXR

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I don't know if this has been posted already, but I thought it was an interesting tie into what Dr. has been keeping us updated on as far as the pregnane X receptor (steroid xenobiotic receptor as it is known in humans). It is also interesting to me that UC has been linked to a decrease in diet fiber. Soluble fiber plays a role in sucking up water as well as other toxins in the feces, such as lithocholic acid (mentioned below in the abstract). Lithocholic acid (a toxic bile acid) with soluble fiber then get excreted in the feces rather than hitting the intestinal tract and subsequently being absorbed into the liver. Lithocholic acid has been linked to an increase incidence of colon cancer and as the abstract says, it will be interesting to see its role in UC and PSC's pathogenesis. Does anyone know about studies

linking increase intake of soluble fiber and a decrease in symptoms in liver diseases? 1: Clin Med. 2007 Apr;7(2):180-4. Links Coordinated defence and the liver. Elias E, Mills CO. Liver Unit, Queen Hospital, Birmingham. Elwyn.Elias@... The liver is strategically placed to protect the body against a vast array of potentially harmful compounds. The steps involved include phase I metabolism which makes molecules more reactive and phase II reactions which generally enhance solubility in bile or urine. Recent discoveries have shown how regulation of these reactions is also

closely allied to expression of membrane transporters which excrete the products of biotransformation into bile and prevent their reabsorption via the intestine. The coordinated activity of these various functions is orchestrated by orphan nuclear receptors which, in response to an encounter with a potential toxin, are able to induce expression of the genes involved in its biotransformation and excretion. Lithocholic acid (LCA) is routinely produced in our intestine by bacterial deconjugation of chenodeoxycholic acid a major bile acid in humans. In human liver the presence of LCA is sensed by the pregnane X receptor (PXR) which has the potential to switch on all the genes required for safe metabolism and elimination of LCA from the body. These include cytochrome P450 3A which hydroxylates LCA to more soluble forms and sulfotransferase (SULT2A1) which by sulphation of LCA makes it more readily solublein bile and enhances its faecal excretion. Similarly, PXR exposure to LCA

produces up-regulated expression of the membrane transporters MDR1 and MRP2 which excrete metabolites of LCA. Evidence is accumulating in support of the hypothesis that deficiencies in these defence mechanisms underlie susceptibility to primary sclerosing cholangitis and ulcerative colitis.

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