PT  - JOURNAL ARTICLE
AU  - Zhihui Zheng
AU  - Zanmei Zhao
AU  - Shuqiang Li
AU  - Xinhua Lu
AU  - Mengxi Jiang
AU  - Jie Lin
AU  - Yunqi An
AU  - Yang Xie
AU  - Meishu Xu
AU  - Wenbin Shen
AU  - Grace Guo
AU  - YIxian Huang
AU  - Song Li
AU  - Xuexia Zhang
AU  - Wen Xie
TI  - Altenusin, a non-steroidal microbial metabolite, attenuates non-alcoholic fatty liver disease by activating the farnesoid X receptor
AID  - 10.1124/mol.117.108829
DP  - 2017 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.108829
4099  - http://molpharm.aspetjournals.org/content/early/2017/07/24/mol.117.108829.short
4100  - http://molpharm.aspetjournals.org/content/early/2017/07/24/mol.117.108829.full
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.