1. Academic Validation
  2. Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure

Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure

  • EBioMedicine. 2018 Nov:37:294-306. doi: 10.1016/j.ebiom.2018.10.030.
Guoxiang Xie 1 Xiaoning Wang 2 Runqiu Jiang 3 Aihua Zhao 4 Jingyu Yan 5 Xiaojiao Zheng 4 Fengjie Huang 4 Xinzhu Liu 5 Jun Panee 6 Cynthia Rajani 7 Chun Yao 8 Herbert Yu 7 Weiping Jia 4 Beicheng Sun 9 Ping Liu 10 Wei Jia 11
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
  • 2 E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 3 University of Hawaii Cancer Center, Honolulu, HI 96813, USA; Liver Transplantation Center of the First Affiliated Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • 4 Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
  • 5 E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 6 Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
  • 7 University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
  • 8 Guangxi University of Chinese Medicine, Nanning, Guangxi 530001, China.
  • 9 Liver Transplantation Center of the First Affiliated Hospital, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
  • 10 E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: liuliver@vip.sina.com.
  • 11 Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA. Electronic address: wjia@cc.hawaii.edu.
Abstract

Background: Hepatic encephalopathy (HE), a severe neuropsychiatric complication, is associated with increased blood levels of ammonia and bile acids (BAs). We sought to determine (1) whether abnormally increased blood BAs in liver cirrhotic patients with HE is caused by elevation of apical sodium-dependent BA transporter (ASBT)-mediated BA reabsorption; and (2) whether increased BA reabsorption would exacerbate ammonia-induced brain injuries.

Methods: We quantitatively measured blood BA and ammonia levels in liver cirrhosis patients with or without HE and healthy controls. We characterized ASBT expression, BA profiles, and ammonia concentrations in a chronic liver disease (CLD) mouse model induced by streptozotocin-high fat diet (STZ-HFD) and an azoxymethane (AOM) - induced acute liver failure (ALF) mouse model. These two mouse models were treated with SC-435 (ASBT inhibitor) and budesonide (ASBT activator), respectively.

Findings: Blood concentrations of ammonia and conjugated BAs were substantially increased in cirrhotic patients with HE (n = 75) compared to cirrhotic patients without HE (n = 126). Pharmacological inhibition of the enterohepatic BA circulation using a luminal- restricted ASBT inhibitor, SC-435, in mice with AOM-induced ALF and STZ-HFD -induced CLD effectively reduced BA and ammonia concentrations in the blood and brain, and alleviated liver and brain damages. Budesonide treatment induced liver and brain damages in normal mice, and exacerbated these damages in AOM-treated mice.

Interpretation: ASBT mediated BA reabsorption increases intestinal luminal pH and facilitates conversion of intestinal ammonium to ammonia, leading to abnormally high levels of neurotoxic ammonia and cytotoxic BAs in the blood and brain. Inhibition of intestinal ASBT with SC-435 can effectively remove neurotoxic BAs and ammonia from the bloodstream and thus, mitigate liver and brain injuries resulting from liver failure.

Keywords

Ammonia; Apical sodium-dependent bile acid transporter; Bile acids; Hepatic encephalopathy.

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