MicroRNA MiR-33 Manipulation can Improve Liver Toxicity caused by Statins
Angel Baldán, PhD., investigator at Saint Louis University, discovered that the microRNA miR-33 plays a key role in the regulation of bile metabolism. The research, which was funded by the National Institutes of Health and the American Heart Association and it is published in EMBO Molecular Medicine.
“As we learn more about the way cholesterol is moved and metabolised through the body, we have more tools at our disposal to try to limit potential side effects of cholesterol managing drugs like statins.” (Baldán – assistant professor of biochemistry and molecular biology at Saint Louis University)
Earlier research showed that miR-33 plays a key role in regulating cholesterol. Baldán’s team found that decreasing the levels of the microRNA aided the rise of HDL (“good cholesterol”) in an animal model. These results were mirrored in four other laboratories in 2010. Baldán examined the two bile transporters, ABCB11 and ATP8B1 to find that miR-33 directly regulates them. Baldán’s research team went on to discover that silencing miR-33 caused increases in bile secretion from the liver meaning more bile was recovered in the gallbladder. Researchers then treated two groups of mice with an anti-miR-33 drug and tracked radioactively labelled cholesterol as it moved.
“We hypothesised we should see changes in the amount of radioactivity in the cholesterol that was eliminated in the mice’s faeces, depending on whether they were given placebo or anti-miR-33. That is in fact what we found. When the microRNA is silenced, the pathway is enhanced and more cholesterol is passed through.” (Baldán)
Bile is partly made up of cholesterol and cholesterol-derived bile acids and it also helps regulate cholesterol in the body. If bile cannot flow from the liver to the small intestine due to a gall stone, medication side effects or genetic variation, cholestasis can occur (a type of liver damage).
Baldán’s researchers had a look at the genetic condition – progressive familial intrahepatic cholestasis (PFIC) which can lead to liver damage. It is caused by defects in the biliary transporters, such as the aforementioned ABCB11 and ATP8B1.
“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. In this case, though, statins caused the condition pharmacologically. We further hypothesised that conditions that involve miR-33 could, under certain circumstances, also induce a BRIC-like syndrome, by reducing the expression of ABCB11 and/or ATP8B1.” (Baldán)
To test this, the researchers gave the mice a special high fat, high cholesterol diet, in the presence or absence of statins. The results from this test are as follows;
- Mice that did not receive statins tolerated the diet with no problems
- Mice that did receive the statins developed liver damage
“To conclusively prove that this was due to the induction of miR-33, we treated the animals with anti-miR-33, and, when we did, their livers recovered. In effect, miR-33 encourages some of the undesired, hepatotoxic effects of statins and by silencing this signal we were able to avoid these toxic side effects. This discovery may ultimately lead to treatment options both for those with BRIC, and more broadly, those who suffer from statin side effects.” (Baldán)