Endogenous vitamin E metabolites mediate allosteric PPARγ activation with unprecedented co-regulatory interactions

Cell Chem Biol. 2021 Oct 21;28(10):1489-1500.e8. doi: 10.1016/j.chembiol.2021.04.019. Epub 2021 May 13.


Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.

Keywords: NASH; allosterism; garcinoic acid; metabolic syndrome; natural product; non-alcoholic steatohepatitis; nuclear receptor; peroxisome proliferator-activated receptor; tocopherol; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Benzopyrans / chemistry
  • Benzopyrans / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Hep G2 Cells
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • PPAR gamma / agonists
  • PPAR gamma / metabolism*
  • Pioglitazone / chemistry
  • Pioglitazone / metabolism
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction / drug effects
  • Transcriptome / drug effects
  • Vitamin E / chemistry
  • Vitamin E / metabolism*
  • Vitamin E / pharmacology


  • Benzopyrans
  • Ligands
  • PPAR gamma
  • Receptors, Cytoplasmic and Nuclear
  • garcinoic acid
  • Vitamin E
  • Pioglitazone