Shikonin Binds and Represses PPARγ Activity by Releasing Coactivators and Modulating Histone Methylation Codes

Shikonin, a natural ingredient produced by Lithospermum erythrorhizon, has anti-inflammatory, anti-cancer, and anti-obesity effects. It also inhibits adipocyte differentiation; however, the underlying molecular and epigenetic mechanisms remain unclear. We performed RNA-sequencing of shikonin-treated 3T3-L1 cells. Gene ontology and gene set enrichment analysis showed that shikonin is significantly associated with genes related to adipogenesis, histone modification, and PPAR gamma. Shikonin treatment downregulated the mRNA expression of PPAR gamma-responsive genes and rosiglitazone-induced transcriptional activity of PPAR gamma. Microscale thermophoresis assays showed a K-D value 1.4 +/- 0.13 mu M for binding between shikonin and PPAR gamma. Glutathione S-transferase pull-down assays exhibited that shikonin blocked the rosiglitazone-dependent association of PPAR gamma with its coactivator CBP. In addition, shikonin decreased the enrichment of the active histone code H3K4me3 and increased the repressive code H3K27me3 of PPAR gamma target promoters. Shikonin is a PPAR gamma antagonist that suppresses adipogenesis by regulating the enrichment of histone codes during adipogenesis. Therefore, it may be used to treat obesity-related disorders via epigenetic changes.

Automated summary

Shikonin, a natural ingredient produced by Lithospermum erythrorhizon, has anti-inflammatory, anti-cancer, and anti-obesity effects. It modulates adipocyte differentiation by regulating adipogenesis-related genes and histone modification. This finding highlights the potential of shikonin in treating obesity-related disorders.