Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary
Background & Aims: Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study e...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001942 |
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| author | Lan Zhou Min Yan Qin Luo Wen Qiu Yu-Ru Guo Xiao-Qing Guo Hong-Bin Yu Jing-Ru Huo Yan-Lin Feng De-Ping Wang Teng Sun Kai-Fang Wang Jian-Yun Shi Xuan Shang Mei-Na Wu Lin Wang Ji-Min Cao |
| author_facet | Lan Zhou Min Yan Qin Luo Wen Qiu Yu-Ru Guo Xiao-Qing Guo Hong-Bin Yu Jing-Ru Huo Yan-Lin Feng De-Ping Wang Teng Sun Kai-Fang Wang Jian-Yun Shi Xuan Shang Mei-Na Wu Lin Wang Ji-Min Cao |
| author_sort | Lan Zhou |
| collection | DOAJ |
| description | Background & Aims: Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies. Methods: We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments. Results: Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution. Conclusions: Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study. |
| format | Article |
| id | doaj-art-243d6ab0b7bc4809a2bf5223e7c929c9 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-243d6ab0b7bc4809a2bf5223e7c929c92025-01-19T06:26:12ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01193101439Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummaryLan Zhou0Min Yan1Qin Luo2Wen Qiu3Yu-Ru Guo4Xiao-Qing Guo5Hong-Bin Yu6Jing-Ru Huo7Yan-Lin Feng8De-Ping Wang9Teng Sun10Kai-Fang Wang11Jian-Yun Shi12Xuan Shang13Mei-Na Wu14Lin Wang15Ji-Min Cao16Key Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaDepartment of Hepatology, Taiyuan Third People’s Hospital, Taiyuan, ChinaDepartment of General Surgery, Cancer Hospital of Shanxi Medical University, Shanxi Provincial Cancer Hospital, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Cardiology, The First Hospital and First College of Clinical Medicine, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaKey Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, ChinaDepartment of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China; Lin Wang, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.Key Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China; Department of Physiology, Shanxi Medical University, Taiyuan, China; Correspondence Address correspondence to: Ji-Min Cao, Key Laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Taiyuan, China.Background & Aims: Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies. Methods: We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments. Results: Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution. Conclusions: Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study.http://www.sciencedirect.com/science/article/pii/S2352345X24001942Bile AcidChronic Liver DiseaseCircadian Rhythm Sleep DisorderTakeda G Protein-Coupled Receptor 5 |
| spellingShingle | Lan Zhou Min Yan Qin Luo Wen Qiu Yu-Ru Guo Xiao-Qing Guo Hong-Bin Yu Jing-Ru Huo Yan-Lin Feng De-Ping Wang Teng Sun Kai-Fang Wang Jian-Yun Shi Xuan Shang Mei-Na Wu Lin Wang Ji-Min Cao Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary Cellular and Molecular Gastroenterology and Hepatology Bile Acid Chronic Liver Disease Circadian Rhythm Sleep Disorder Takeda G Protein-Coupled Receptor 5 |
| title | Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary |
| title_full | Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary |
| title_fullStr | Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary |
| title_full_unstemmed | Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary |
| title_short | Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver DiseasesSummary |
| title_sort | elevated bile acids induce circadian rhythm sleep disorders in chronic liver diseasessummary |
| topic | Bile Acid Chronic Liver Disease Circadian Rhythm Sleep Disorder Takeda G Protein-Coupled Receptor 5 |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001942 |
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