High cholesterol and fatty liver disease are growing health concerns worldwide, often linked to unhealthy dietary habits and lifestyle choices. But what if we could precisely adjust how our bodies handle cholesterol at the molecular level? Scientists may have found a promising approach – by focusing on two crucial proteins in the liver.
Inside our liver, two key proteins – CAR (Constitutive Androstane Receptor) and PXR (Pregnane X Receptor) – function as switches that help process harmful substances, as well as the body's own fats and cholesterol.
When CAR is activated, it aids in the elimination of excess cholesterol by converting it into bile acids, which are then expelled from the body. On the other hand, activating PXR can increase cholesterol levels and lead to fat buildup in the liver. This means that medications activating PXR could potentially worsen metabolic disorders.
A team of researchers led by Radim Nencka from IOCB Prague and Petr Pávek from Charles University identified a novel molecule, MI-883, which activates CAR while inhibiting PXR. Essentially, MI-883 signals the liver to eliminate excess cholesterol without triggering the harmful effects of PXR. Scientists found that MI-883 lowers plasma cholesterol and increases bile acid excretion in mice on high-fat, high-cholesterol diets.
Most cholesterol-lowering drugs, such as statins, decrease cholesterol production. MI-883, however, employs a different approach by assisting the body in eliminating cholesterol more efficiently while minimizing side effects.
This discovery may lead to new treatments for conditions such as high cholesterol and fatty liver disease. By targeting multiple liver receptors simultaneously, scientists are advancing toward precision medicine, where treatments are designed to align with the body's natural systems.
Original article: Dusek, J.; Mejdrová, I.; Dohnalová, K.; Smutny, T.; Chalupsky, K.; Krutakova, M.; Skoda, J.; Rashidian, A.; Pavkova, I.; Škach, K.; Hricová, J.; Chocholouskova, M.; Smutna, L.; Kamaraj, R.; Hroch, M.; Leníček, M.; Mičuda, S.; Pijnenburg, D.; van Beuningen, R.; Holčapek, M.; Vítek, L.; Ingelman-Sundberg, M.; Burk, O.; Kronenberger, T.; Nencka, R.; Pavek, P. The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model. Nat. Commun. 2025, 16, 1418. https://doi.org/10.1038/s41467-025-56642-y
