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Proc. Natl. Acad. Sci. USA, 2023 May 16;120(20):e2219644120 | https://doi.org/10.1073/pnas.2219644120 Upregulation of the ERRγ-VDAC1 axis underlies the molecular pathogenesis of pancreatitis

Dipanjan Chanda^a,1, Themis Thoudam^a,1, Ibotombi Singh Sinam^b, Chae Won Lim^b, Myeongjin Kim^a, Jiale Wang^c, Kyeong-Min Lee^d, Jing Ma^e, Romil Saxena^f, Jinhyuk Choi^g, Chang Joo Oh^a, Hoyul Lee^a, Yong Hyun Jeon^h, Sung Jin Choⁱ, Hoe-Yune Jung^j,k, Keun-Gyu Park^a,l, Hueng-Sik Choi^m, Jae Myoung Suh^g, Johan Auwerxⁿ, Baoan Ji^c, Suthat Liangpunsakul^e, Jae-Han Jeon^a,o,2, and In-Kyu Lee^a,l,2

^aResearch Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, South Korea;
^bBio-Medical Research Institute, Kyungpook National University Hospital, Daegu 41404, South Korea;
^cDepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32066;
^dDivision of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, South Korea;
^eDivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
^fDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202;
^gGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea;
^hLaboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea;
ⁱNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, South Korea;
^jR&D Center NovMetaPharma Co. Ltd., Pohang 37688, South Korea;
^kSchool of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 37673, South Korea;
^lDepartment of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu 41944, South Korea;
^mSchool of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, South Korea;
ⁿLaboratory of Integrative Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland;
^oDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, South Korea

¹D.C. and T.T. contributed equally to this work.
²To whom correspondence may be addressed. : Jae-Han Jeon, In-Kyu Lee

Abstract

Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ 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 ERRγ. Mechanistically, we showed that induction of ERRγ 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 ERRγ, modulates mitochondrial Ca²⁺ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca²⁺ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1^R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-09)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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