| First Author | Chanda D | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 20 | Pages | e2219644120 |
| PubMed ID | 37155882 | Mgi Jnum | J:342409 |
| Mgi Id | MGI:7548294 | Doi | 10.1073/pnas.2219644120 |
| Citation | Chanda D, et al. (2023) Upregulation of the ERRgamma-VDAC1 axis underlies the molecular pathogenesis of pancreatitis. Proc Natl Acad Sci U S A 120(20):e2219644120 |
| abstractText | Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor gamma (ERRgamma), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRgamma in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRgamma gene expression via activation of STAT3. Acinar-specific ERRgamma haploinsufficiency or pharmacological inhibition of ERRgamma significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRgamma. Mechanistically, we showed that induction of ERRgamma in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRgamma, modulates mitochondrial Ca(2+) and ROS levels. Inhibition of the ERRgamma-VDAC1 axis could alleviate mitochondrial Ca(2+) accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRgamma-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1(R122H)-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRgamma inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRgamma in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis. |
