Experimental Drug Reverses Fatty Liver Disease, Cuts Cholesterol

Researchers at Yale School of Medicine have announced that an experimental drug reversed a condition in nonhuman primates that is a precursor to heart disease and type 2 diabetes (T2D), while also driving down levels of low-density lipoprotein (LDL) cholesterol.

The drug, called controlled-release mitochondrial protonophore (CRMP), works by activating mitochondria in the liver to mediate metabolic syndrome and other related abnormalities. CRMP successfully caused the liver to use excess energy, causing protons to flow from the mitochondria, but without the same chemical effect on the body that would normally occur when the mitochondria are activated.

In the Yale study, CRMP therapy reversed non-alcoholic fatty liver disease (NAFLD), a condition that has been on the rise among Americans as obesity rates have increased. When this condition progresses, it can result in liver cell damage, or nonalchoholic steatohepatitis (NASH). Right now there are no approved therapies for NAFLD, according to the National Institutes of Health. However, there have been studies involving existing therapies to treat NAFLD.

Last year, results from the E-LIFT trial appeared in Diabetes Care, and showed that empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, reduces liver fat. The study’s author, Mohammad Shafi Kuchay, MBBS, MD, said at the time that the E-LIFT results and other data suggest that patients diagnosed with T2D who also have NAFLD should be treated first with empagliflozin (Jardiance, from Eli Lilly and Boehringer-Ingelheim).

In this study, the researchers used positional isotopomer nuclear magnetic resonance tracer analysis to show that treatment with 5 mg/kg of CRMP increased the rate of hepatic mitochondrial fat oxidation by 40%. After 6 weeks, the obese rhesus macaques treated with CRMP saw lower liver triglycerides that happened independent of changes in body weight, body temperature, changes in food intake, or any adverse reactions. The treatment was also associated with a 20% to 30% drop in fasting plasma triglycerides and LDL cholesterol in the nonhuman primates who had insulin resistance, the researchers reported.

“Lifestyle changes such as diet and exercise are still the primary course of treatment for metabolic syndrome, NAFLD, and type 2 diabetes, but in most cases this approach is not effective in the long run so there is a great need for novel therapies,” senior author Gerald I. Shulman, professor of cellular and molecular physiology at Yale School of Medicine, said in a statement.

Funding for the study came from the National Institutes of Health and Gilead Sciences.

Reference

Goedeke L, Peng L, Montalvo-Romeral V, et al. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Science Transl Med. 2019;11(512):eaay0284. doi:10.1126/scitranslmed.aay0284.