Icaritin, a metabolite of Icarrin, Alleviates non-alcoholic fatty liver disease via inhibition of lipogenesis and ER stress

Non-alcoholic fatty liver disease (NAFLD) is one of the most serious global public health concerns. However, there are currently no effective drugs for treatment of this disease. Icariin (ICA), a small-molecule natural product extracted from Epimedium brevicornu Maxim, offers various pharmacological activities. In the present work, we wondered whether ICA can attenuate NAFLD in db/db mice treated with ICA for 8 weeks and how ICA exerts an influence on NAFLD. In db/db mice, ICA treatment had a robust effect on inhibition of lipogenesis associated with NAFLD amelioration by decreasing liver lipid deposition, together with ameliorating insulin sensitivity, glucose tolerance, and fasting serum glucose. Of note, ICA-treated rats showed a much higher con-centration of icaritin (ICT) in plasma, a major metabolite of ICA, about 2000 times higher than that of ICA by liquid chromatography mass spectrometry (LC-MS). Interestingly, ICT, rather than ICA, can dramatically decrease hepatic lipogenesis-related markers in oleate acid/palmitate acid (OA/PA)-induced steatosis in primary hepatocytes (PH) and HepG2 cells, and hepatic lipid accumulation in db/db mice, demonstrating the inhibitory effect of ICT on lipogenesis. Mechanistically, we found that anti-lipogenic activities of ICT were related to reducing endoplasmic reticulum (ER) stress as evidenced by Western blot, qPCR, and other assays in thapsigargin (THP) induced-ER stress models. To our knowledge, this is the first report showing the unexpected and key role for ICT on the prevention of NAFLD in db/db mice through an ER stress mechanism.

Automated summary

Icariin (ICA) can attenuate non-alcoholic fatty liver disease (NAFLD) by reducing liver lipid deposition and improving insulin sensitivity, glucose tolerance, etc. The main metabolite of ICA, icaritin (ICT), inhibits hepatic lipid accumulation and lipogenesis by reducing endoplasmic reticulum (ER) stress.