Altenusin, a nonsteroidal microbial metabolite, attenuates nonalcoholic fatty liver disease by activating the farnesoid X receptor

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose, and lipids. FXR agonists have shown promise for the treatment of NAFLD. In this study, we report altenusin (2076A), a natural nonsteroidal fungal metabolite, as a novel selective agonist of FXR with an EC₅₀ value of 3.2 6 0.2 mM. Administration of 2076A protected mice from high-fat diet (HFD)–induced obesity by reducing the body weight and fat mass by 22.9% and 50.0%, respectively. Administration of 2076A also decreased the blood glucose level from 178.3 6 12.4 mg/dl to 116.2 6 4.1 mg/dl and the serum insulin level from 1.4 6 0.6 ng/dl to 0.4 6 0.1 ng/dl. Moreover, 2076A treatment nearly reversed HFD-induced hepatic lipid droplet accumulation and macrovesicular steatosis. These metabolic effects were abolished in FXR knockout mice. Mechanistically, the metabolic benefits of 2076A might have been accounted for by the increased insulin sensitivity and suppression of genes that are involved in hepatic gluconeogenesis and lipogenesis. In summary, we have uncovered a new class of nonsteroidal FXR agonist that shows promise in treating NAFLD and the associated metabolic syndrome.