Protein protects liver against excess bile

August 2nd, 2008 - 2:38 pm ICT by IANS  

Washington, Aug 2 (IANS) Researchers have discovered a protein that controls genes maintaining proper level of bile in the liver. The protein, called FOXA2, is likely to become the focus for new therapies to treat diseases involvng regulation of bile salts.

Bile, made in the liver, is stored in the gall bladder and transported through ducts to the small intestine where it helps to digest fats from food.

Bile salts, chemicals in bile that help digest fats and also keep cholesterol dissolved in the bile, are reabsorbed from the intestine and returned to the liver where they are broken up.

The liver maintains a balance of bile salts by degrading old bile salts and synthesising new ones. Problems arise when too many bile salts accumulate in the liver.

Diseases of bile regulation, like primary sclerosing cholangitis (PSC), are characterised by problems with bile transport from the liver to the gut. Researchers found that in both children with biliary atresia and adults with PSC, expression of FOXA2 in the liver is severely reduced.

FOXA2 regulates expression of transporter proteins responsible for moving bile out of the liver, as well as several enzymes that function in bile acid detoxification. The study suggests that strategies to maintain FOXA2 expression might be a novel therapeutic goal.

In PSC, blockage of bile transport leads to inflammation of the bile duct and, over time, liver damage. The causes of PSC and related syndromes are not known, but may be autoimmune-related.

PSC is associated with an increased risk of liver cirrhosis and liver cancer. Biliary atresia is a birth defect in which the bile ducts do not have normal openings, preventing bile from leaving the liver. The condition causes jaundice and cirrhosis of the liver.

Senior author Klaus Kaestner, professor of genetics, named the family of FOX genes and previous work in his lab showed that FOXA2 was important for glucose metabolism in the liver.

“Our interest in using genomics to study metabolic diseases led us to screen DNA from liver cells that expressed FOXA2 with an assay called ChIP on Chip,” explained co-author Irina Bochkis, of the Institute for Diabetes, Obesity, and Metabolism at Pennsylvania School of Medicine.

Chip-on-Chip assay stands for Chromatin ImmunoPrecipitation on a gene chip.

The study was published online this week in Nature Medicine.

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