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Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase

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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.

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Acknowledgments

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A121185).

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Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Republic of Korea

    You-Jin Choi, Hyo-Ryung Suh, Yujin Yoon, Kyung-Jin Lee, Dong Gwang Kim, Sanghee Kim & Byung-Hoon Lee

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  1. You-Jin Choi
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  2. Hyo-Ryung Suh
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  3. Yujin Yoon
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  4. Kyung-Jin Lee
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  7. Byung-Hoon Lee
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Correspondence to Byung-Hoon Lee.

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Choi, YJ., Suh, HR., Yoon, Y. et al. Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase. Arch. Pharm. Res. 37, 1169–1176 (2014). https://doi.org/10.1007/s12272-014-0347-z

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