Dysregulated bile acid signaling contributes to the neurological impairment in murine models of acute and chronic liver failure
| Autor: | Jingyu Yan, Beicheng Sun, Guoxiang Xie, Xiaoning Wang, Jun Panee, Ping Liu, Chun Yao, Herbert Yu, Cynthia Rajani, Runqiu Jiang, Weiping Jia, Xinzhu Liu, Wei Jia, Fengjie Huang, Aihua Zhao, Xiaojiao Zheng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Budesonide Male medicine.medical_specialty Cirrhosis Research paper medicine.drug_class Chronic liver disease General Biochemistry Genetics and Molecular Biology Cell Line Bile Acids and Salts End Stage Liver Disease 03 medical and health sciences chemistry.chemical_compound Mice Ammonia Internal medicine medicine Animals Humans Hepatic encephalopathy Bile acid business.industry Reabsorption Azoxymethane Transporter General Medicine Liver Failure Acute Middle Aged medicine.disease Bile acids 3. Good health Disease Models Animal 030104 developmental biology Endocrinology chemistry Hepatic Encephalopathy Apical sodium-dependent bile acid transporter Female business medicine.drug |
| Zdroj: | EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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