title: Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase.
abstract: Non-alcoholic fatty liver disease is associated with inhibited AMP-activated kinase (AMPK) and activation of sterol regulatory element binding protein 1 (SREBP-1). AMPK phosphorylation inhibits SREBP-1, a major transcription factor of de novo lipogenesis, by inhibiting the liver X receptor (LXR) or by direct phosphorylation. Resveratrol, a polyphenol, has regulatory effects on hepatic lipid metabolism as a potent AMPK activator. In this study, we evaluated the anti-steatogenic effects of resveratrol and its derivatives and identified the molecular mechanism in vitro and in vivo. Resveratrol and its derivatives decreased lipid accumulation by free fatty acids (FFA mixture; 0.5 mM, oleic acid:palmitic acid = 2: 1) in H4IIEC3 cells. Synthesized derivatives of resveratrol had lower cytotoxicity than the parental molecule with similar potency. SY-102 suppressed SREBP-1 maturation by T0901317, an LXR agonist, and decreased SRE luciferase activity and the mRNA levels of lipogenic genes. Inhibition of AMPK by pre-treatment with compound C completely blocked the effects of SY-102. To evaluate their efficacy in vivo, mice were fed a high-fat diet for 5 days, and resveratrol or SY-102 was administered orally for the last 2 days. Oral administration of the SY-102 increased AMPK phosphorylation, followed by reduced hepatic triglyceride accumulation to a similar extent as resveratrol. These data demonstrate that SY-102, a synthesized derivative of resveratrol, might provide a promising therapeutic effect against fatty liver disease.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Hyo-Ryung
authors.initials: HR
authors.lastname: Suh
authors.forename: Yujin
authors.initials: Y
authors.lastname: Yoon
authors.forename: Kyung-Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Dong Gwang
authors.initials: DG
authors.lastname: Kim
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008082:Lipotropic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008745:Methylation; D008813:Mice, Inbred ICR; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D000077185:Resveratrol; D013047:Specific Pathogen-Free Organisms; D013267:Stilbenes / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D005230:Fatty Acids, Nonesterified; D008082:Lipotropic Agents; C000597556:SY-102; D013267:Stilbenes; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol