Deoxypodophyllotoxin in Anthriscus sylvestris alleviates fat accumulation in the liver via AMP-activated protein kinase, impeding SREBP-1c signal

• Published in: Chemico-biological interactions 2018-10, Vol.294, p.151-157
• Main Authors: Kim, Kwang-Youn, Park, Kwang-Il, Lee, Seul Gi, Baek, Su Youn, Lee, Eun Hye, Kim, Sang Chan, Kim, Sang-Hun, Park, Sul-Gi, Yu, Sun-Nyoung, Oh, Tae Woo, Kim, Joung-Hee, Kim, Keuk-Jun, Ahn, Soon-Cheol, Kim, Young Woo
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apiaceae - metabolism; Body Weight - drug effects; Cholesterol - metabolism; Deoxypodophyllotoxin; Diet, High-Fat; Drugs, Chinese Herbal; Hep G2 Cells; Hepatic steatosis; High fat diet; Humans; Hydrocarbons, Fluorinated - pharmacology; Lipid Metabolism - drug effects; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver X Receptors - agonists; Liver X Receptors - metabolism; Male; Mice; Mice, Inbred C57BL; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - pharmacology; Signal Transduction - drug effects; SREBP-1c; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Sulfonamides - pharmacology; Triglycerides - metabolism; Up-Regulation - drug effects
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2018.08.025

Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan in Anthriscus sylvestris known as cow parsley or wild chervil, and has been reported to have inhibitory effects against several pathological processes including cancer, inflammation and infection. Here, we report the effects of DPT in the fatty liver induced by high fat diet in vivo as well as its regulatory mechanism related with the transcription factor for lipogenic genes such as sterol regulatory element binding protein-1c (SREBP-1c) in vitro. C57BL/6 mice were fed high fat diet for 10 weeks and also orally administrated with DPT for additional 4 weeks. 5 and 10 mg/kg of DPT decreased lipid accumulation in the liver induced by high fat diet, as indicated by histological parameters such as Oil Red O staining and hematoxylin & eosin as well as the contents of hepatic triglyceride and cholesterol. In hepatocytes, DPT inhibited the liver X receptor α-mediated SREBP-1c induction and expression of the lipogenic genes, including fatty acid synthase, acetyl-CoA carboxylase and stearoyl-CoA desaturase-1. Moreover, DPT induced AMP-activated protein kinase (AMPK) activation, which has been known to inhibit the expression of SREBP-1c in hepatocyte. Also this compound restored the dysregulation of AMPK and SREBP-1c induced by high fat diet in mice. In conclusion, we demonstrated that DPT significantly inhibited fatty liver by adjusting lipid metabolism coordinated with AMPK activation and SREBP-1c inhibition. •Deoxypodophyllotoxin (DPT), a chemopreventive flavolignan, inhibited diet-induced fatty liver.•DPT inhibited the LXR-α-mediated sterol regulatory element binding protein (SREBP)-1c.•DPT blocked the expression of de novo lipogenic genes including FAS and ACC.•DPT activated AMPK related with SREBP-1c inhibition.•DPT might be a pharmaceutical candidate for hepatic steatosis.