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TXN, a Xanthohumol Derivative, Attenuates High-Fat Diet Induced Hepatic Steatosis by Antagonizing PPARγ

View ORCID ProfileYang Zhang, View ORCID ProfileGerd Bobe, Cristobal L. Miranda, Malcolm B. Lowry, Victor L. Hsu, Christiane V. Löhr, Carmen P. Wong, View ORCID ProfileDonald B. Jump, Matthew M. Robinson, View ORCID ProfileThomas J. Sharpton, View ORCID ProfileClaudia S. Maier, View ORCID ProfileJan F. Stevens, View ORCID ProfileAdrian F. Gombart
doi: https://doi.org/10.1101/2021.01.11.426043
Yang Zhang
1School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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  • For correspondence: adrian.gombart@oregonstate.edu
Gerd Bobe
2Department of Animal Sciences, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Cristobal L. Miranda
3Department of Pharmaceutical Sciences, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Malcolm B. Lowry
4Department of Microbiology, Oregon State University, Corvallis, OR 97331, USA
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Victor L. Hsu
5Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
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Christiane V. Löhr
6Department of Biomedical Science, Carlson College of Veterinary Medicine, Corvallis, OR 97331, USA
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Carmen P. Wong
1School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Donald B. Jump
1School of Biological and Population Health Sciences, Nutrition Program, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Matthew M. Robinson
7School of Biological and Population Health Sciences, Kinesiology Program, Oregon State University, Corvallis, OR 97331, USA
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Thomas J. Sharpton
8Department of Microbiology, Department of Statistics, Oregon State University, Corvallis, OR 97331, USA
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Claudia S. Maier
9Department of Chemistry, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Jan F. Stevens
3Department of Pharmaceutical Sciences, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
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Adrian F. Gombart
10Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
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  • For correspondence: adrian.gombart@oregonstate.edu
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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 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 PPARγ competitive binding assay showed XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8-10 times stronger than oleate. Molecular docking simulations demonstrated XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Title length was reduced. Minor changes to Methods and Materials. Figure legends indicate source data required for journal review.

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Posted January 25, 2021.
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TXN, a Xanthohumol Derivative, Attenuates High-Fat Diet Induced Hepatic Steatosis by Antagonizing PPARγ
Yang Zhang, Gerd Bobe, Cristobal L. Miranda, Malcolm B. Lowry, Victor L. Hsu, Christiane V. Löhr, Carmen P. Wong, Donald B. Jump, Matthew M. Robinson, Thomas J. Sharpton, Claudia S. Maier, Jan F. Stevens, Adrian F. Gombart
bioRxiv 2021.01.11.426043; doi: https://doi.org/10.1101/2021.01.11.426043
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TXN, a Xanthohumol Derivative, Attenuates High-Fat Diet Induced Hepatic Steatosis by Antagonizing PPARγ
Yang Zhang, Gerd Bobe, Cristobal L. Miranda, Malcolm B. Lowry, Victor L. Hsu, Christiane V. Löhr, Carmen P. Wong, Donald B. Jump, Matthew M. Robinson, Thomas J. Sharpton, Claudia S. Maier, Jan F. Stevens, Adrian F. Gombart
bioRxiv 2021.01.11.426043; doi: https://doi.org/10.1101/2021.01.11.426043

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