Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ

eLife

Gerd Bobe¹  Victor L Hsu²  Christiane V Lohr³  Claudia S Maier⁴  Thomas J Sharpton⁵  Malcolm B Lowry⁶  Jan F Stevens⁷  Cristobal L Miranda⁷  Adrian F Gombart⁸  Matthew M Robinson⁹  Carmen P Wong^1,10  Yang Zhang^1,10  Donald B Jump^1,10 

[1] Department of Animal Sciences, Linus Pauling Institute, Oregon State University, Corvallis, United States;Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States;Department of Biomedical Science, Carlson College of Veterinary Medicine, Corvallis, United States;Department of Chemistry, Linus Pauling Institute, Oregon State University, Corvallis, United States;Department of Microbiology, Department of Statistics, Oregon State University, Corvallis, United States;Department of Microbiology, Oregon State University, Corvallis, United States;Department of Pharmaceutical Sciences, Linus Pauling Institute, Oregon State University, Corvallis, United States;Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, United States;School of Biological and Population Health Sciences, Kinesiology Program, Oregon State University, Corvallis, United States;School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State University, Corvallis, United States;

关键词: ppar gamma;    xanthohumol;    obesity;    hepatosteatosis;    metabolic syndrome;    antagonist;    Mouse;   

DOI  :  10.7554/eLife.66398

来源: eLife Sciences Publications, Ltd

【 摘 要 】

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8–10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

【 授权许可】

CC BY