"We hypothesized we should see changes in the amount of radioactivity in the cholesterol that was eliminated in the mice's feces, depending on whether they were given placebo or anti-miR-33," Baldn said. "That is in fact what we found. When the microRNA is silenced, the pathway is enhanced and more cholesterol is passed through."
Bile is produced by the liver to help the body digest dietary lipids. Bile is itself made up, in part, of cholesterol and cholesterol-derived bile acids, and it also serves a key function in controlling the body's balance of cholesterol.
When the body doesn't secrete and transport bile well, due to an obstruction like a gallstone, or, as examined in this study, because of a genetic variation or medication side effect, bile cannot flow from the liver to the small intestine. The resulting blockage causes cholestasis, a kind of liver damage.
In the final segment of the study, researchers took note of a genetic condition, called progressive familial intrahepatic cholestasis (PFIC), an inherited disease that causes cholestasis and can lead to liver failure. PFIC is caused by defects in the biliary transporters, such as ABCB11 and ATP8B1, the very genes that are regulated by miR-33. Interestingly, the same group of symptoms can occur in a less severe form, called benign recurrent intrahepatic cholestasis (BRIC) in some people with less severe genetic mutations.
"Intriguingly, a very small number of patients who take statins develop a syndrome identical to BRIC, a milder version of the same illness experienced by people who have the genetic disease PFIC," Baldn said. "In this case, though, statins caused the condition pharmacologically.
"We further hypothesized that conditions that induce miR-33 could, under certain circumstances, also induce a BRIC-like syndrome, by reducing the expression of ABCB11 and/or ATP8B1."
To test this theory, researchers fed mice a special high fat
|Contact: Carrie Bebermeyer|
Saint Louis University