Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights
Abstract
primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.
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Authors: Lianyuan Tao, Peng He, Jiachen Ge, Qifei Guan, Erpei Wang, Ipsita Mohanty, Cristina Bez, Won-Suk Song, Ling Lan, Jingjing Qi, Yueqi Zhang, Peng Zhang, Yuxiao Liu, Avinash Mukkala, Yechen Feng, Mandy Zhu, Qiong Zhou, Tingting Ai, Kosuke Watari, Laura Antonucci, Li Gu, Li Huang, Tao Qin, Deyu Li, D. Xiu, Cholsoon Jang, Judith A. Varner, Pieter C. Dorrestein, Beicheng Sun, Michael Karin
Institutions: First Affiliated Hospital Zhejiang University, University of California, Los Angeles, University of California San Diego, Peking University, Sichuan University, West China Hospital of Sichuan University, Peking University Third Hospital, Anhui Medical University, First Affiliated Hospital of Anhui Medical University, Wenzhou Medical University, Pennsylvania State University, Henan Provincial People's Hospital, Ruian People's Hospital, Discovery Institute, Scripps Research Institute, Gene Therapy Laboratory, Therapeutics Clinical Research, International Centre for Genetic Engineering and Biotechnology, Society of Surgical Oncology