Honokiol reverses alcoholic fatty liver by inhibiting the maturation of sterol regulatory element binding protein-1c and the expression of its downstream lipogenesis genes.
Ethanol induces hepatic steatosis via a complex mechanism that is not well understood. Among the variety of molecules that have been proposed to participate in this mechanism, the sterol regulatory element (SRE)-binding proteins (SREBPs) have been identified as attractive targets for therapeutic intervention. In the present study, we evaluated the effects of honokiol on alcoholic steatosis and investigated its possible effect on the inhibition of SREBP-1c maturation. In in vitro studies, H4IIEC3 rat hepatoma cells developed increased lipid droplets when exposed to ethanol, but co-treatment with honokiol reversed this effect. Honokiol inhibited the maturation of SREBP-1c and its translocation to the nucleus, the binding of nSREBP-1c to SRE or SRE-related sequences of its lipogenic target genes, and the expression of genes for fatty acid synthesis. In contrast, magnolol, a structural isomer of honokiol, had no effect on nSREBP-1c levels. Male Wistar rats fed with a standard Lieber-DeCarli ethanol diet for 4 weeks exhibited increased hepatic triglyceride and decreased hepatic glutathione levels, with concomitantly increased serum alanine aminotransferase and TNF-alpha levels. Daily administration of honokiol (10 mg/kg body weight) by gavage during the final 2 weeks of ethanol treatment completely reversed these effects on hepatotoxicity markers, including hepatic triglyceride, hepatic glutathione, and serum TNF-alpha, with efficacious abrogation of fat accumulation in the liver. Inhibition of SREBP-1c protein maturation and of the expression of Srebf1c and its target genes for hepatic lipogenesis were also observed in vivo. A chromatin immunoprecipitation assay demonstrated inhibition of specific binding of SREBP-1c to the Fas promoter by honokiol in vivo. These results demonstrate that honokiol has the potential to ameliorate alcoholic steatosis by blocking fatty acid synthesis regulated by SREBP-1c.
Yin
Hu-Quan
HQ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, Republic of Korea.
Kim
Youn-Chul
YC
Chung
Young-Suk
YS
Kim
Young-Chul
YC
Shin
Young-Kee
YK
Lee
Byung-Hoon
BH
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol; D005227:Fatty Acids / Q000096:biosynthesis; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019014:fas Receptor / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D000431:Ethanol; D005227:Fatty Acids; D005978:Glutathione; D017705:Lignans; D020011:Protective Agents; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C491898:Fas protein, rat; C497389:Srebf1 protein, rat; C005498:magnolol; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols