TitleTetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ.
Publication TypeJournal Article
Year of Publication2021
AuthorsZhang Y, Bobe G, Miranda CL, Lowry MB, Hsu VL, Löhr CV, Wong CP, Jump DB, Robinson MM, Sharpton TJ, Maier CS, Stevens JF, Gombart AF
Date Published2021 Jun 15

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 IC 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.

Alternate JournalElife
PubMed ID34128467
PubMed Central IDPMC8205491
Grant List5R01AT009168 / NH / NIH HHS / United States
S10 RR027878 / RR / NCRR NIH HHS / United States
Buhler-Wang Research Fund / / OSU Foundation /
R01 AT009168 / AT / NCCIH NIH HHS / United States
1S10RR027878 / NH / NIH HHS / United States
Marion T. Tsefalas Graduate Fellowship / / Linus Pauling Institute /
ZRT Laboratory Fund / / Linus Pauling Institute /