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

Yang Zhang,Victor L Hsu,Christiane V Lohr,Malcolm B Lowry,Jan F Stevens,Thomas J Sharpton,Gerd Bobe,Claudia S Maier,Carmen P Wong,Adrian F Gombart,Donald B Jump,Cristobal L Miranda,Matthew M Robinson

doi:10.7554/elife.66398

Abstract

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a major global health threat characterized by excessive hepatic lipid droplet accumulation with a history of little or no alcohol consumption (Hashimoto et al, 2013)
Low-cost natural products like XN are of particular interest for treating obesity and NAFLD due to their availability, safety, and efficacy
Three studies propose that XN improves diet-induced hepatic steatosis by suppressing SREBP1c mRNA expression and SREBP activation

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a major global health threat characterized by excessive hepatic lipid droplet accumulation with a history of little or no alcohol consumption (Hashimoto et al, 2013). About one-quarter of the US population suffers from NAFLD (Estes et al, 2018), with rates in the rest of the world ranging from 14% in Africa to 32% in the Middle East. The continuing obesity and diabetes epidemic drives increasing rates of NAFLD (Estes et al, 2018). Sustained healthy lifestyle changes and weight loss are the only interventions proven effective in preventing the onset and progression of NAFLD (Stefan et al, 2019). There is a critical need for novel and effective interventions

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