RT Journal Article
SR Electronic
T1 Altenusin, a non-steroidal microbial metabolite, attenuates non-alcoholic fatty liver disease by activating the farnesoid X receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.117.108829
DO 10.1124/mol.117.108829
A1 Zhihui Zheng
A1 Zanmei Zhao
A1 Shuqiang Li
A1 Xinhua Lu
A1 Mengxi Jiang
A1 Jie Lin
A1 Yunqi An
A1 Yang Xie
A1 Meishu Xu
A1 Wenbin Shen
A1 Grace Guo
A1 YIxian Huang
A1 Song Li
A1 Xuexia Zhang
A1 Wen Xie
YR 2017
UL http://molpharm.aspetjournals.org/content/early/2017/07/24/mol.117.108829.abstract
AB Non-alcoholic 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. Here we report Altenusin (2076A), a natural non-steroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3.2 ± 0.2 μM. 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 ± 12.4 mg/dL to 116.2 ± 4.1 mg/dL, the serum insulin level from 1.4 ± 0.6 ng/dL to 0.4 ± 0.1 ng/dL. Moreover, 2076A treatment nearly reversed HFD-induced hepatic lipid droplet accumulation and macrovescicular 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 non-steroidal FXR agonist that shows promise in treating NAFLD and the associated metabolic syndrome.