Inhibition of SREBP-1c-mediated hepatic steatosis and oxidative stress by sauchinone, an AMPK-activating lignan in Saururus chinensis.
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-alpha (LXRalpha)-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 LXRalpha 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 LXRalpha 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 LXRalpha-mediated SREBP-1c induction and SREBP-1c-dependent hepatic steatosis, thereby protecting hepatocytes from oxidative stress induced by fat accumulation.
Kim
Young Woo
YW
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Kim
Young Mi
YM
Yang
Yoon Mee
YM
Kim
Tae Hyun
TH
Hwang
Se Jin
SJ
Lee
Jong Rok
JR
Kim
Sang Chan
SC
Kim
Sang Geon
SG
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D005234:Fatty Liver / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D017705:Lignans / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D018384:Oxidative Stress; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D032134:Saururaceae / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D055372:AMP-Activated Protein Kinases; D006845:Hydrocarbons, Fluorinated; D017705:Lignans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010936:Plant Extracts; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides