Inhibition of SREBP-1c-mediated hepatic steatosis and oxidative stress by sauchinone, an AMPK-activating lignan in Saururus chinensis

• Published in: Free radical biology & medicine Vol. 48; no. 4; pp. 567 - 578
• Main Authors: Kim, Young Woo, Kim, Young Mi, Yang, Yoon Mee, Kim, Tae Hyun, Hwang, Se Jin, Lee, Jong Rok, Kim, Sang Chan, Kim, Sang Geon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2010
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Fatty Liver - metabolism; Free radicals; Gene Expression Regulation, Enzymologic; Hepatic steatosis; Hepatocytes - metabolism; High-fat diet; Humans; Hydrocarbons, Fluorinated - pharmacology; Lignans - chemistry; Liver - metabolism; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors - metabolism; Oxidative Stress; Plant Extracts - pharmacology; Rats; Sauchinone; Saururaceae - metabolism; SREBP-1c; Sterol Regulatory Element Binding Protein 1 - metabolism; Sulfonamides - pharmacology; ABCA1; FFA; Oxidative stress; NAFLD; Free radicals; HFD; LXRα; TBARS; MDA; Hepatic steatosis; SREBP-1c; GSK-3β; TG; SCD; T090; ND; High-fat diet; Sauchinone; ROS; AMPK; FAS; LXRE; HNE
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2009.12.006

Sauchinone, as an AMP-activated kinase (AMPK)-activating lignan in Saururus chinensis, has been shown to prevent iron-induced oxidative stress and liver injury. Sterol regulatory element binding protein-1c (SREBP-1c) plays a key role in hepatic steatosis, which promotes oxidative stress in obese subjects. Previously, we identified the role of AMPK in liver X receptor-α (LXRα)-mediated SREBP-1c-dependent lipogenesis. Because sauchinone as an antioxidant has the ability to activate AMPK, this study investigated its effects on SREBP-1c-dependent lipogenesis in hepatocytes and in high-fat diet (HFD)-induced hepatic steatosis and oxidative injury. Sauchinone prevented the ability of an LXRα agonist (T0901317) to activate SREBP-1c, repressing transcription of the fatty acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase-1, ATP-binding cassette transporter A1, and LXRα genes. Consistent with this, an HFD in mice caused fat accumulation in the liver with SREBP-1c induction, which was attenuated by sauchinone treatment. Also, sauchinone had the ability to inhibit oxidative stress as shown by decreases in thiobarbituric acid-reactive substance formation, nitrotyrosinylation, and 4-hydroxynonenal production. Moreover, it prevented not only the liver injury, but also the AMPK inhibition elicited by HFD feeding. These results demonstrate that sauchinone has the capability to inhibit LXRα-mediated SREBP-1c induction and SREBP-1c-dependent hepatic steatosis, thereby protecting hepatocytes from oxidative stress induced by fat accumulation.