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Ren C, Cha L, Huang SY, Bai GH, Li JH, Xiong X, Feng YX, Feng DP, Gao L, Li JY. Dysregulation of bile acid signal transduction causes neurological dysfunction in cirrhosis rats. World J Hepatol 2025; 17:101340. [PMID: 40177200 PMCID: PMC11959655 DOI: 10.4254/wjh.v17.i3.101340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/19/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND The pathogenesis of hepatic encephalopathy (HE) remains unclear, and the classical theory of ammonia toxicity lacks sufficient justification. AIM To investigate the potential of bile acids as intervention targets for HE. METHODS This study employed 42 wild-type male SD rats weighing 200 ± 20 g. Using a random number table method, two rats were randomly selected to undergo common bile duct ligation (BDL). The remaining 40 rats were randomly assigned to four groups serving as controls: The vehicle + control diet (VC) group, the thioacetamide (TAA) group, the TAA + total bile acids (TAAT) group, and the TAA + cholestyramine (TAAC) group. Except for the VC group, all rats were intraperitoneally injected with 100 mg/kg TAA solution once daily for ten consecutive days to establish a HE model. Simultaneously, the TAAT and TAAC groups were administered a diet containing 0.3% bile acids (derived from BDL rats) and 2% cholestyramine, respectively, by gavage for ten days. For the BDL rat model group, the common BDL procedure was performed following the aforementioned protocol. After four weeks, laparotomy revealed swollen bile ducts at the ligation site, and bile was collected. Following successful modeling, behavioral tests, including the elevated plus maze and open field test, were conducted to assess the HE status of the rats. Peripheral blood, liver, and cerebral cortex tissue samples were collected, and the total bile acid content in the serum and cerebral cortex was measured using an enzyme cycling method. The levels of inflammatory factors in the serum and cerebral cortex were analyzed using enzyme-linked immunosorbent assay. Liver histological examination was performed using the hematoxylin-eosin double-labeling method. Reverse transcription polymerase chain reaction, western blot, immunohistochemistry, and other techniques were employed to observe the expression of microglial activation marker ionized calcium-binding adaptor molecule-1 and Takeda G protein-coupled receptor 5 (TGR5) protein. RESULTS Compared to the VC group, the TAA group exhibited an exacerbation of HE in rats. The total bile acid content, pro-inflammatory factors [interleukin-1β (IL-1β), IL-6], and the anti-inflammatory factor IL-10 in both the serum and cerebral cortex were significantly elevated. Similarly, the expression of the TGR5 receptor in the cerebral cortex was upregulated. To investigate the impact of total bile acids on HE in rats, comparisons were made with the TAA group. In the TAAT group, the severity of HE was further aggravated, accompanied by increased total bile acid content in the serum and cerebral cortex, elevated pro-inflammatory factors (IL-1β, IL-6), reduced levels of the anti-inflammatory factor IL-10, and decreased expression of the TGR5 receptor in the cerebral cortex. In the TAAC group, the severity of HE was alleviated. This group showed reductions in total bile acid content in the serum and cerebral cortex, decreased pro-inflammatory factors (IL-1β, IL-6), increased levels of the anti-inflammatory factor IL-10, and enhanced expression of the TGR5 receptor in the cerebral cortex. CONCLUSION This study demonstrated that the total bile acid content in the serum and cerebral cortex of TAA-induced liver cirrhosis rats was elevated. Furthermore, total bile acids exacerbate the progression of HE in rats. This effect may be attributed to bile acids' involvement in the development of neurological dysfunction by mediating TGR5 expression and regulating neuroinflammation.
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Affiliation(s)
- Chao Ren
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Li Cha
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Shu-Yue Huang
- Department of Ultrasound, Qingdao Central Hospital, University of Health and Rehabilitation, Qingdao 266000, Shandong Province, China
| | - Guo-Hui Bai
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jin-Hui Li
- College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Xin Xiong
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yu-Xing Feng
- Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Dui-Ping Feng
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Long Gao
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China.
| | - Jin-Yu Li
- Department of Oncological and Vascular Intervention, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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Lopez VA, Lim JJ, Seguin RP, Dempsey JL, Kunzman G, Cui JY, Xu L. Oral exposure to benzalkonium chlorides in male and female mice reveals alteration of the gut microbiome and bile acid profile. Toxicol Sci 2024; 202:265-277. [PMID: 39363503 PMCID: PMC11589104 DOI: 10.1093/toxsci/kfae116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024] Open
Abstract
Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid (BA) homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 µg/g/d for 1 wk. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted BA quantitation analysis, we observed decreases in secondary BAs in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary BAs into secondary BAs, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.
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Affiliation(s)
- Vanessa A Lopez
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Joe J Lim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, United States
| | - Ryan P Seguin
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Joseph L Dempsey
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA 98195, United States
| | - Gabrielle Kunzman
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
| | - Julia Y Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, United States
| | - Libin Xu
- Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, United States
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, United States
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3
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Kwon SJ, Kim YS, Tak J, Lee SG, Lee EB, Kim SG. Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice. Sci Rep 2024; 14:19580. [PMID: 39179591 PMCID: PMC11344048 DOI: 10.1038/s41598-024-70254-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024] Open
Abstract
Inflammatory bowel disease is defined by inflammation and immune dysregulation. This study investigated the effects of Gα13 liver-specific knockout (LKO) on proximal and distal colons of dextran sodium sulfate (DSS)-induced mice in conjunction with a high-fat diet (HFD). HFD improved body weight gain and disease activity index scores. Gα13LKO exerted no improvement. In the proximal colon, HFD augmented the DSS effect on Il6, which was not observed in Gα13LKO mice. In the distal colon, HFD plus DSS oppositely fortified an increase in Tnfa and Cxcl10 mRNA in Gα13LKO but not WT. Il6 levels remained unchanged. Bioinformatic approaches using Gα13LKO livers displayed bile acid and cholesterol metabolism-related gene sets. Cholic acid and chenodeoxycholic acid levels were increased in the liver of mice treated with DSS, which was reversed by Gα13LKO. Notably, mice treated with DSS showed a reduction in hepatic ABCB11, CYP7B1, CYP7A1, and CYP8B1, which was reversed by Gα13LKO. Overall, feeding HFD augments the effect of DSS on Il6 in the proximal colon of WT, but not Gα13LKO mice, and enhances DSS effect on Tnfa and Cxcl10 in the distal colon of Gα13LKO mice, suggesting site-specific changes in the inflammatory cytokines, potentially resulting from changes in BA synthesis and excretion.
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Affiliation(s)
- Soon Jae Kwon
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Gil Lee
- Research and Development Institute, A Pharma Inc., Goyang-si, Gyeonggi-do, Republic of Korea
| | - Eun Byul Lee
- Research and Development Institute, A Pharma Inc., Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
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Newman NK, Monnier PM, Rodrigues RR, Gurung M, Vasquez-Perez S, Hioki KA, Greer RL, Brown K, Morgun A, Shulzhenko N. Host response to cholestyramine can be mediated by the gut microbiota. MICROBIOME RESEARCH REPORTS 2024; 3:40. [PMID: 39741955 PMCID: PMC11684918 DOI: 10.20517/mrr.2023.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/09/2024] [Accepted: 06/24/2024] [Indexed: 01/03/2025]
Abstract
Background: The gut microbiota has been implicated as a major factor contributing to metabolic diseases and the response to drugs used for the treatment of such diseases. In this study, we tested the effect of cholestyramine, a bile acid sequestrant that reduces blood cholesterol, on the murine gut microbiota and metabolism. We also explored the hypothesis that some effects of this drug on systemic metabolism can be attributed to alterations in the gut microbiota. Methods: We used a Western diet (WD) for 8 weeks to induce metabolic disease in mice, then treated some mice with cholestyramine added to WD. Metabolic phenotyping, gene expression in liver and ileum, and microbiota 16S rRNA genes were analyzed. Then, transkingdom network analysis was used to find candidate microbes for the cholestyramine effect. Results: We observed that cholestyramine decreased glucose and epididymal fat levels and detected dysregulation of genes known to be regulated by cholestyramine in the liver and ileum. Analysis of gut microbiota showed increased alpha diversity in cholestyramine-treated mice, with fourteen taxa showing restoration of relative abundance to levels resembling those in mice fed a control diet. Using transkingdom network analysis, we inferred two amplicon sequence variants (ASVs), one from the Lachnospiraceae family (ASV49) and the other from the Muribaculaceae family (ASV1), as potential regulators of cholestyramine effects. ASV49 was also negatively linked with glucose levels, further indicating its beneficial role. Conclusion: Our results indicate that the gut microbiota has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.
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Affiliation(s)
- Nolan K. Newman
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Philip M. Monnier
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Richard R. Rodrigues
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Manoj Gurung
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Stephany Vasquez-Perez
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kaito A. Hioki
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Renee L. Greer
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kevin Brown
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Andrey Morgun
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Natalia Shulzhenko
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
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Li H, Xiong H, Wang X, Xu T, Zhang C, Zhang W, Zhang Y. Ibuprofen induces hepatic Cyp7a1 expression in mice via the intestinal FXR-FGF15 signaling. Toxicol Lett 2024; 398:1-12. [PMID: 38815664 DOI: 10.1016/j.toxlet.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/13/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) may cause drug-induced liver injury (DILI). However, the molecular mechanisms underlying NSAIDs hepatotoxicity remain elusive. Dysregulations of bile acids (BAs) have been implicated in various DILI. In this study, we systematically investigated the effects of ibuprofen, the most commonly used NSAID, on BA metabolism and signaling in adult male C57/BL6 mice after oral administration of ibuprofen (IBU) at clinically relevant doses (30, 100, and 200 mg/kg) for one week. Notably, IBU significantly decreased BA concentrations in the liver in a dose-dependent manner, with a concomitant increase in both mRNA and protein expression of cholesterol 7alpha-hydoxylase (CYP7A1), the rate-limiting enzyme for BA synthesis. Mechanically, IBU altered the composition of gut microbiota and increased cecal BAs, leading to reduced intestinal absorption of BAs and thus deactivated ileal farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling. Additionally, diclofenac and indomethacin also induced hepatic Cyp7a1 expression in mice via their effects on gut microbiota and intestinal BA signaling. To conclude, the current findings suggest that NSAIDs-induced liver injury could be at least partially attributable to the dysregulation of BA metabolism and signaling.
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Affiliation(s)
- Huixiang Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Hui Xiong
- Department of Physiology and Pathophysiology, School of Basic Medicine, Tianjin Medical University, Tianjin 300070, China.
| | - Xue Wang
- Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Tong Xu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 30021, China
| | | | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
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Taylor R, Yang Z, Henry Z, Capece G, Meadows V, Otersen K, Basaly V, Bhattacharya A, Mera S, Zhou P, Joseph L, Yang I, Brinker A, Buckley B, Kong B, Guo GL. Characterization of individual bile acids in vivo utilizing a novel low bile acid mouse model. Toxicol Sci 2024; 199:316-331. [PMID: 38526215 DOI: 10.1093/toxsci/kfae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024] Open
Abstract
Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.
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Affiliation(s)
- Rulaiha Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Zakiyah Henry
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Gina Capece
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Vik Meadows
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Katherine Otersen
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Stephanie Mera
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Peihong Zhou
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Laurie Joseph
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Ill Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Anita Brinker
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Brian Buckley
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey 08854, USA
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey 08901, USA
- Veterans Administration Medical Center, VA New Jersey Health Care System, East Orange, New Jersey 07017, USA
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Lopez VA, Lim JL, Seguin RP, Dempsey JL, Kunzman G, Cui JY, Xu L. Oral Exposure to Benzalkonium Chlorides in Male and Female Mice Reveals Sex-Dependent Alteration of the Gut Microbiome and Bile Acid Profile. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593991. [PMID: 38798482 PMCID: PMC11118417 DOI: 10.1101/2024.05.13.593991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d 7 -C12- and d 7 -C16-BACs at 120 µg/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d 7 -C12- or d 7 -C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.
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He X, Gao X, Hong Y, Zhong J, Li Y, Zhu W, Ma J, Huang W, Li Y, Li Y, Wang H, Liu Z, Bao Y, Pan L, Zheng N, Sheng L, Li H. High Fat Diet and High Sucrose Intake Divergently Induce Dysregulation of Glucose Homeostasis through Distinct Gut Microbiota-Derived Bile Acid Metabolism in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:230-244. [PMID: 38079533 DOI: 10.1021/acs.jafc.3c02909] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
A high calorie diet such as excessive fat and sucrose intake is always accompanied by impaired glucose homeostasis such as T2DM (type 2 diabetes mellitus). However, it remains unclear how fat and sucrose individually affect host glucose metabolism. In this study, mice were fed with high fat diet (HFD) or 30% sucrose in drinking water (HSD) for 24 weeks, and glucose metabolism, gut microbiota composition, as well as bile acid (BA) profile were investigated. In addition, the functional changes of HFD or HSD-induced gut microbiota were further verified by fecal microbiota transplantation (FMT) and ex vivo culture of gut bacteria with BAs. Our results showed that both HFD and HSD caused dysregulated lipid metabolism, while HFD feeding had a more severe effect on impaired glucose homeostasis, accompanied by reduced hyocholic acid (HCA) levels in all studied tissues. Meanwhile, HFD had a more dramatic influence on composition and function of gut microbiota based on α diversity indices, β diversity analysis, as well as the abundance of secondary BA producers than HSD. In addition, the phenotypes of impaired glucose homeostasis and less formation of HCA caused by HFD can be transferred to recipient mice by FMT. Ex vivo culture with gut bacteria and BAs revealed HFD-altered gut bacteria produced less HCA than HSD, which might closely associate with reduced relative abundance of C7 epimerase-coding bacteria g_norank/unclassified_f_Eggerthellaceae and bile salt hydrolase-producing bacteria Lactobacillus and Bifidobacterium in HFD group. Our findings revealed that the divergent effects of different high-calorie diets on glucose metabolism may be due to the gut microbiota-mediated generation and metabolism of BAs, highlighting the importance of dietary management in T2DM.
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Affiliation(s)
- Xiaofang He
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xinxin Gao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ying Hong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jing Zhong
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China
| | - Yue Li
- Department of Endocrinology, Shanghai Fifth People's Hospital, Shanghai Medical School, Fudan University, Shanghai 200032, China
| | - Weize Zhu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junli Ma
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenjin Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yifan Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zekun Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yiyang Bao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lingyun Pan
- Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ningning Zheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Sheng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Houkai Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Liu Y, Zhang H, Lu W, Jiang T. Integrating metabolomics, 16S rRNA sequencing, network pharmacology, and metorigin to explore the mechanism of Cinnamomi Cortex in treating chronic atrophic gastritis rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155084. [PMID: 37722245 DOI: 10.1016/j.phymed.2023.155084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/08/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND Cinnamomi cortex called as Rougui (RG) in Chinese was a widely used food-medicine homology. RG has the potential to treat chronic atrophic gastritis (CAG), a disease with widespread impact in the Chinese population. PURPOSE This study aimed to explore its mechanism against CAG based on amalgamated strategies. METHODS Network pharmacology was used to predict the potential effective components and the core targets of RG against CAG based on the comprehensive chemical characterization using UHPLC-Q/TOF MS (ultra high performance liquid chromatogramphy-quadrupole/time-of-flight mass spectrometry). The CAG animals model were further used to validate its pharmacodynamics, of which gut microbiota of caecal contents were analyzed by integrating metabolomics, 16S rRNA sequencing, Metorigin metabolite traceability analysis and molecular docking to explore its action mechanism. RESULTS Network pharmacology firstly predicted the efficacy of RG was attributed to four effective components and seven targets. Metabolomics of caecal contents in CAG rats revealed primary bile acid biosynthesis was its targeted metabolic pathway associated with the metabolism of gut microbiota coupled with Metorigin traceability analysis. 16S rRNA sequencing showed that RG treated CAG by regulating the imbalance of gut microbiota. Molecular docking further confirmed that the effective components of RG could intervene with potential targets, metorigin analysis pathway, and key enzymes of gut microbiota metabolic pathways. CONCLUSION Our results proved that RG exerted favorable effect on CAG. The four active ingredients (quercetin, kaempferol, oleic acid, and (-)-epicatechin) of RG were the key to exert drug effect, which could targeted the core target of CAG, primary bile acid biosynthesis and intestinal flora metabolic pathways.
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Affiliation(s)
- Yuetao Liu
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China.
| | - Hui Zhang
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China
| | - Wentian Lu
- Modern Research Center for Traditional Chinese Medicine, the Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China; Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, No. 92, Wucheng Road, Taiyuan 030006, Shanxi, PR China
| | - Tao Jiang
- Institute of Cash Crops, Hebei Academy of Agricultural and Forestry Sciences, Shijiazhuang, 050051, Hebei, PR China.
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10
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Tan Y, Zhao N, Xie Q, Xu Z, Chai J, Zhang X, Li Y. Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. Mol Cell Biochem 2023; 478:2527-2537. [PMID: 36869985 DOI: 10.1007/s11010-023-04682-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 02/17/2023] [Indexed: 03/05/2023]
Abstract
Melatonin, an indole neurohormone secreted mainly by the pineal gland, has been found to be involved in a variety of liver diseases. However, the underlying mechanism by which melatonin ameliorates cholestatic liver injury is not fully understood. In this study, we investigated the mechanism by which melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. We measured the levels of serum melatonin in patients with obstructive cholestasis (n = 9), patients with primary biliary cholangitis (PBC) (n = 11), and control patients (n = 7). We performed experiments with C57BL/6 J mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and melatonin to verify the role of melatonin in the mouse model of cholestasis. Primary mouse hepatocytes were used for in vitro studies to study the mechanisms of action of melatonin in cholestasis. The levels of serum melatonin were markedly increased and negatively correlated with serum markers of liver injury in cholestatic patients. As expected, oral administration of melatonin significantly attenuated cholestasis-induced liver inflammation and fibrosis in 0.1% DDC diet-fed mice. Further mechanistic studies in cholestatic mice and primary hepatocytes revealed that melatonin reduced the conjugate BA-stimulated expression of cytokines (e.g. Ccl2, Tnfα, and Il6) through the ERK/Egr1 signalling pathway in these models. The levels of serum melatonin are significantly elevated in cholestatic patients. Melatonin treatment ameliorates cholestatic liver injury by suppressing the inflammatory response in vivo and in vitro. Therefore, melatonin is a promising novel therapeutic strategy for cholestasis.
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Affiliation(s)
- Ya Tan
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Nan Zhao
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qiaoling Xie
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Ziqian Xu
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Jin Chai
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Xiaoxun Zhang
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| | - Yan Li
- Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Cholestatic Liver Diseases Center, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
- Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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11
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Feng C, Yang Y, Lu A, Tan D, Lu Y, Qin L, He Y. Multi‑omics‑based analysis of the regulatory mechanism of gypenosides on bile acids in hypercholesterolemic mice. Exp Ther Med 2023; 26:438. [PMID: 37614436 PMCID: PMC10443059 DOI: 10.3892/etm.2023.12136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 06/22/2023] [Indexed: 08/25/2023] Open
Abstract
Gynostemma pentaphyllum is a traditional medicine used by ethnic minorities in southwest China and gypenosides are currently recognized as essential components of the pharmacological substances of Gynostemma pentaphyllum, which are effective in regulating metabolic syndrome, especially in improving hepatic metabolic disorders. The present study randomly divided C57BL/6J male mice into the normal diet control group (ND), high-fat diet modeling group (HFD) and gypenosides group (GP). Liquid chromatography-mass spectrometry (UPLC-MS) was applied to quantify bile acids in the liver, bile and serum of mice in ND, HFD and GP groups. Liver proteins were extracted for trypsin hydrolysis and analyzed quantitatively using UPLC-MS + MS/MS (timsTOF Pro 2). Total mouse liver RNA was extracted from ND, HFD and GP groups respectively, cDNA sequencing libraries constructed and sequenced using BGISEQ-500 sequencing platform. The expression of key genes Fxr, Shp, Cyp7a1, Cyp8b1, and Abab11 was detected by RT-qPCR. The results showed that gypenosides accelerated free bile acid synthesis by promoting the expression of bile acid synthase CYP7A1 and CYP8B1 genes and proteins and accelerating the secretion of conjugated bile acids from the liver to the bile ducts. GP inhibited the bile acid transporters solute carrier organic anion transporter family member (SLCO) 1A1 and SLCO1A4, reducing the reabsorption of free bile acids and accelerating the excretion of free bile acids from the blood to the kidneys. It also promoted the metabolic enzyme CYP3A11, which accelerated the metabolism and clearance of bile acids, thus maintaining the balance of the bile acid internal environment.
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Affiliation(s)
- Chengcheng Feng
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanping Yang
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Anjing Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Daopeng Tan
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yanliu Lu
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Lin Qin
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yuqi He
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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12
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Ge W, Sun Q, Yang Y, Ding Z, Liu J, Zhang J. Circadian PER1 controls daily fat absorption with the regulation of PER1-PKA on phosphorylation of bile acid synthetase. J Lipid Res 2023; 64:100390. [PMID: 37209828 PMCID: PMC10276160 DOI: 10.1016/j.jlr.2023.100390] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/10/2023] [Accepted: 05/11/2023] [Indexed: 05/22/2023] Open
Abstract
Several epidemiological studies suggest a correlation between eating time and obesity. Night eating syndrome characterized by a time-delayed eating pattern is positively associated with obesity in humans as well as in experimental animals. Here, we show that oil intake at night significantly makes more fat than that at day in wild-type mice, and circadian Period 1 (Per1) contributes to this day-night difference. Per1-knockout mice are protected from high-fat diet-induced obesity, which is accompanied by a reduction in the size of the bile acid pool, and the oral administration of bile acids restores fat absorption and accumulation. We identify that PER1 directly binds to the major hepatic enzymes involved in bile acid synthesis such as cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase. A biosynthesis rhythm of bile acids is accompanied by the activity and instability of bile acid synthases with PER1/PKA-mediated phosphorylation pathways. Both fasting and high fat stress enhance Per1 expression, increasing the fat absorption and accumulation. Our findings reveal that Per1 is an energy regulator and controls daily fat absorption and accumulation. Circadian Per1 controls daily fat absorption and accumulation, suggesting Per1 is a potential candidate of a key regulator in stress response and the relevant obesity risk.
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Affiliation(s)
- Wenhao Ge
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Qi Sun
- Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, China
| | - Yunxia Yang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Zhao Ding
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Junhao Liu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
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13
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Xu N, Bai Y, Han X, Yuan J, Wang L, He Y, Yang L, Wu H, Shi H, Wu X. Taurochenodeoxycholic acid reduces astrocytic neuroinflammation and alleviates experimental autoimmune encephalomyelitis in mice. Immunobiology 2023; 228:152388. [PMID: 37079985 DOI: 10.1016/j.imbio.2023.152388] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 04/22/2023]
Abstract
OBJECTIVE Multiple sclerosis (MS) is an immune regulatory disease that affects the central nervous system (CNS). The main pathological features include demyelination and neurodegeneration, and the pathogenesis is associated with astrocytic neuroinflammation. Taurochenodeoxycholic acid (TCDCA) is one of the conjugated bile acids in animal bile, and it is not clear whether TCDCA could improve MS by inhibiting the activation of astrocytes. This study was aimed to evaluate the effects of TCDCA on experimental autoimmune encephalomyelitis (EAE)-a classical animal model of MS, and to probe its mechanism from the aspect of suppressing astrocytic neuroinflammation. It is expected to prompt the potential application of TCDCA for the treatment of MS. RESULTS TCDCA effectively alleviated the progression of EAE and improved the impaired neurobehavior in mice. It mitigated the hyperactivation of astrocytes and down-regulated the mRNA expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the brain cortex. In the C6 astrocytic cell line induced by lipopolysaccharide (LPS), TCDCA treatment dose-dependently decreased the production of NO and the protein expression of iNOS and glial fibrillary acidic protein (GFAP). TCDCA consistently inhibited the mRNA expressions of COX2, iNOS and other inflammatory mediators. Furthermore, TCDCA decreased the protein expression of phosphorylated serine/threonine kinase (AKT), inhibitor of NFκB α (IκBα) and nuclear factor κB (NFκB). And TCDCA also inhibited the nuclear translocation of NFκB. Conversely, as an inhibitor of the G-protein coupled bile acid receptor Gpbar1 (TGR5), triamterene eliminated the effects of TCDCA in LPS-stimulated C6 cells. CONCLUSION TCDCA improves the progress of EAE by inhibiting the astrocytic neuroinflammation, which might be exerted by the regulation of TGR5 mediated AKT/NFκB signaling pathway. These findings may prompt the potential application of TCDCA for MS therapy by suppressing astrocyte inflammation.
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Affiliation(s)
- Nuo Xu
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuyan Bai
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinyan Han
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinfeng Yuan
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lupeng Wang
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yixin He
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liu Yang
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hui Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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14
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Hasan MN, Chen J, Matye D, Wang H, Luo W, Gu L, Clayton YD, Du Y, Li T. Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice. J Lipid Res 2023; 64:100340. [PMID: 36737039 PMCID: PMC9986646 DOI: 10.1016/j.jlr.2023.100340] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
Therapeutic reduction of hydrophobic bile acids exposure is considered beneficial in cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic acids and have a human-like hydrophobic bile acid pool resulting in hepatobiliary injury. This study investigates if combining an apical sodium-dependent bile acid transporter inhibitor GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of bile acid synthesis and gut bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, adeno-associated virus (AAV)-FGF15, and the combined treatment on bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal inflammation, ductular reaction, and fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-conjugated ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal fibrosis but the combined treatment was ineffective despite reducing bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing bile acid pool size and hydrophobicity.
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Affiliation(s)
- Mohammad Nazmul Hasan
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jianglei Chen
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - David Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Huaiwen Wang
- Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Wenyi Luo
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Lijie Gu
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yung Dai Clayton
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Yanhong Du
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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15
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Gillard J, Leclercq IA. Biological tuners to reshape the bile acid pool for therapeutic purposes in non-alcoholic fatty liver disease. Clin Sci (Lond) 2023; 137:65-85. [PMID: 36601783 PMCID: PMC9816373 DOI: 10.1042/cs20220697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/08/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023]
Abstract
Bile acids synthesized within the hepatocytes are transformed by gut microorganisms and reabsorbed into the portal circulation. During their enterohepatic cycling, bile acids act as signaling molecules by interacting with receptors to regulate pathways involved in many physiological processes. The bile acid pool, composed of a variety of bile acid species, has been shown to be altered in diseases, hence contributing to disease pathogenesis. Thus, understanding the changes in bile acid pool size and composition in pathological processes will help to elaborate effective pharmacological treatments. Five crucial steps along the enterohepatic cycle shape the bile acid pool size and composition, offering five possible targets for therapeutic intervention. In this review, we provide an insight on the strategies to modulate the bile acid pool, and then we discuss the potential benefits in non-alcoholic fatty liver disease.
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Affiliation(s)
- Justine Gillard
- Laboratory of Hepato‐Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepato‐Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
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16
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Vickers SD, Shumar SA, Saporito DC, Kunovac A, Hathaway QA, Mintmier B, King JA, King RD, Rajendran VM, Infante AM, Hollander JM, Leonardi R. NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet. J Biol Chem 2022; 299:102745. [PMID: 36436558 PMCID: PMC9792899 DOI: 10.1016/j.jbc.2022.102745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/25/2022] [Accepted: 11/22/2022] [Indexed: 11/26/2022] Open
Abstract
Nudix hydrolase 7 (NUDT7) is an enzyme that hydrolyzes CoA species, is highly expressed in the liver, and resides in the peroxisomes. Peroxisomes are organelles where the preferential oxidation of dicarboxylic fatty acids occurs and where the hepatic synthesis of the primary bile acids cholic acid and chenodeoxycholic acid is completed. We previously showed that liver-specific overexpression of NUDT7 affects peroxisomal lipid metabolism but does not prevent the increase in total liver CoA levels that occurs during fasting. We generated Nudt7-/- mice to further characterize the role that peroxisomal (acyl-)CoA degradation plays in the modulation of the size and composition of the acyl-CoA pool and in the regulation of hepatic lipid metabolism. Here, we show that deletion of Nudt7 alters the composition of the hepatic acyl-CoA pool in mice fed a low-fat diet, but only in males fed a Western diet does the lack of NUDT7 activity increase total liver CoA levels. This effect is driven by the male-specific accumulation of medium-chain dicarboxylic acyl-CoAs, which are produced from the β-oxidation of dicarboxylic fatty acids. We also show that, under conditions of elevated synthesis of chenodeoxycholic acid derivatives, Nudt7 deletion promotes the production of tauromuricholic acid, decreasing the hydrophobicity index of the intestinal bile acid pool and increasing fecal cholesterol excretion in male mice. These findings reveal that NUDT7-mediated hydrolysis of acyl-CoA pathway intermediates in liver peroxisomes contributes to the regulation of dicarboxylic fatty acid metabolism and the composition of the bile acid pool.
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Affiliation(s)
- Schuyler D Vickers
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Stephanie A Shumar
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Dominique C Saporito
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Amina Kunovac
- Division of Exercise Physiology, West Virginia University, Morgantown, West Virginia, USA
| | - Quincy A Hathaway
- Division of Exercise Physiology, West Virginia University, Morgantown, West Virginia, USA
| | - Breeanna Mintmier
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Judy A King
- Department of Pathology and Translational Pathobiology, LSU Health Shreveport, Shreveport, Louisiana, USA
| | - Rachel D King
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Vazhaikkurichi M Rajendran
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA
| | - Aniello M Infante
- Genomics Core Facility, West Virginia University, Morgantown, West Virginia, USA
| | - John M Hollander
- Division of Exercise Physiology, West Virginia University, Morgantown, West Virginia, USA
| | - Roberta Leonardi
- Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, West Virginia, USA.
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17
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High dose of bile acid enables the cellular entry and replication of hepatitis C virus in vitro. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00232-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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18
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Ueda H, Honda A, Miyazaki T, Morishita Y, Hirayama T, Iwamoto J, Nakamoto N, Ikegami T. Sex-, age-, and organ-dependent improvement of bile acid hydrophobicity by ursodeoxycholic acid treatment: A study using a mouse model with human-like bile acid composition. PLoS One 2022; 17:e0271308. [PMID: 35819971 PMCID: PMC9275687 DOI: 10.1371/journal.pone.0271308] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/27/2022] [Indexed: 12/15/2022] Open
Abstract
Cyp2a12-/-Cyp2c70-/- double knockout (DKO) mice have a human-like hydrophobic bile acid (BA) composition and show reduced fertility and liver injury. Ursodeoxycholic acid (UDCA) is a hydrophilic and cytoprotective BA used to treat various liver injuries in humans. This study investigated the effects of orally administered UDCA on fertility and liver injury in DKO mice. UDCA treatment prevented abnormal delivery (miscarriage and preterm birth) in pregnant DKO mice, presumably by increasing the hydrophilicity of serum BAs. UDCA also prevented liver damage in six-week-old DKO mice, however liver injury emerged in UDCA-treated 20-week-old female, but not male, DKO mice. In 20-week-old male UDCA-treated DKO mice, conjugated plus unconjugated UDCA proportions in serum, liver, and bile were 71, 64, and 71% of the total BAs, respectively. In contrast, conjugated plus unconjugated UDCA proportions in serum, liver, and bile of females were 56, 34, and 58% of the total BAs, respectively. The UDCA proportion was considerably low in female liver only and was compensated by highly hydrophobic lithocholic acid (LCA). Therefore, UDCA treatment markedly reduced the BA hydrophobicity index in the male liver but not in females. This appears to be why UDCA treatment causes liver injury in 20-week-old female mice. To explore the cause of LCA accumulation in the female liver, we evaluated the hepatic activity of CYP3A11 and SULT2A1, which metabolize LCAs to more hydrophilic BAs. However, there was no evidence to suggest that either enzyme activity was lower in females than in males. As female mice have a larger BA pool than males, excessive loading of LCAs on the hepatic bile salt export pump (BSEP) may be the reason for the hepatic accumulation of LCAs in female DKO mice with prolonged UDCA treatment. Our results suggest that the improvement of BA hydrophobicity in DKO mice by UDCA administration is sex-, age-, and organ-dependent.
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Affiliation(s)
- Hajime Ueda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.,Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Takeshi Hirayama
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Junichi Iwamoto
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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19
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Wang Q, Song GC, Weng FY, Zou B, Jin JY, Yan DM, Tan B, Zhao J, Li Y, Qiu FR. Hepatoprotective Effects of Glycyrrhetinic Acid on Lithocholic Acid-Induced Cholestatic Liver Injury Through Choleretic and Anti-Inflammatory Mechanisms. Front Pharmacol 2022; 13:881231. [PMID: 35712714 PMCID: PMC9194553 DOI: 10.3389/fphar.2022.881231] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022] Open
Abstract
Cholestasis is a clinical syndrome triggered by the accumulation and aggregation of bile acids by subsequent inflammatory responses. The present study investigated the protective effect of glycyrrhetinic acid (GA) on the cholestatic liver injury induced by lithocholic acid (LCA) from both anti-inflammatory and choleretic mechanistic standpoints. Male C57BL/6 mice were treated with LCA twice daily for 4 days to induce intrahepatic cholestasis. GA (50 mg/kg) and pregnenolone 16α-carbonitrile (PCN, 45 mg/kg) were intraperitoneally injected 3 days before and throughout the administration of LCA, respectively. Plasma biochemical indexes were determined by assay kits, and hepatic bile acids were quantified by LC-MS/MS. Hematoxylin and eosin staining of liver sections was performed for pathological examination. Protein expression of the TLRs/NF-κB pathway and the mRNA levels of inflammatory cytokines and chemokines were examined by Western blotting and PCR, respectively. Finally, the hepatic expression of pregnane X receptor (PXR) and farnesoid X receptor (FXR) and their target genes encoding metabolic enzymes and transporters was evaluated. GA significantly reversed liver necrosis and decreased plasma ALT and ALP activity. Plasma total bile acids, total bilirubin, and hepatic bile acids were also remarkably preserved. More importantly, the recruitment of inflammatory cells to hepatic sinusoids was alleviated. Additionally, the protein expression of TLR2, TLR4, and p-NF-κBp65 and the mRNA expression of CCL2, CXCL2, IL-1β, IL-6, and TNF-α were significantly decreased. Moreover, GA significantly increased the expression of hepatic FXR and its target genes, including BSEP, MRP3, and MRP4. In conclusion, GA protects against LCA-induced cholestatic liver injury by inhibiting the TLR2/NF-κB pathway and upregulating hepatic FXR expression.
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Affiliation(s)
- Qian Wang
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guo-Chao Song
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feng-Yi Weng
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bin Zou
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing-Yi Jin
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dong-Ming Yan
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bo Tan
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Zhao
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Li
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fu-Rong Qiu
- Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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20
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Choudhuri S, Klaassen CD. Molecular Regulation of Bile Acid Homeostasis. Drug Metab Dispos 2022; 50:425-455. [PMID: 34686523 DOI: 10.1124/dmd.121.000643] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022] Open
Abstract
Bile acids have been known for decades to aid in the digestion and absorption of dietary fats and fat-soluble vitamins in the intestine. The development of gene knockout mice models and transgenic humanized mouse models have helped us understand other functions of bile acids, such as their role in modulating fat, glucose, and energy metabolism, and in the molecular regulation of the synthesis, transport, and homeostasis of bile acids. The G-protein coupled receptor TGR5 regulates the bile acid induced alterations of intermediary metabolism, whereas the nuclear receptor FXR regulates bile acid synthesis and homeostasis. However, this review indicates that unidentified factors in addition to FXR must exist to aid in the regulation of bile acid synthesis and homeostasis. SIGNIFICANCE STATEMENT: This review captures the present understanding of bile acid synthesis, the role of bile acid transporters in the enterohepatic circulation of bile acids, the role of the nuclear receptor FXR on the regulation of bile acid synthesis and bile acid transporters, and the importance of bile acids in activating GPCR signaling via TGR5 to modify intermediary metabolism. This information is useful for developing drugs for the treatment of various hepatic and intestinal diseases, as well as the metabolic syndrome.
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Affiliation(s)
- Supratim Choudhuri
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
| | - Curtis D Klaassen
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
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21
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Guo S, Peng Y, Lou Y, Cao L, Liu J, Lin N, Cai S, Kang Y, Zeng S, Yu L. Downregulation of the farnesoid X receptor promotes colorectal tumorigenesis by facilitating enterotoxigenic Bacteroides fragilis colonization. Pharmacol Res 2022; 177:106101. [DOI: 10.1016/j.phrs.2022.106101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 12/24/2022]
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22
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Gillard J, Clerbaux LA, Nachit M, Sempoux C, Staels B, Bindels LB, Tailleux A, Leclercq IA. Bile acids contribute to the development of non-alcoholic steatohepatitis in mice. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2021; 4:100387. [PMID: 34825156 PMCID: PMC8604813 DOI: 10.1016/j.jhepr.2021.100387] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/20/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
Background & Aims Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition. Methods We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition. Results Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration. Conclusions BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH. Lay summary This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.
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Key Words
- ASBT, apical sodium-dependent BA transporter
- BA, bile acid
- CA, cholic acid
- CDCA, chenodeoxycholic acid
- CYP27A1, sterol 27-hydroxylase
- CYP2A12, bile acid 7α-hydroxylase
- CYP7A1, cholesterol 7α-hydroxylase
- CYP7B1, oxysterol 7α-hydroxylase
- CYP8B1, sterol 12α-hydroxylase
- DCA, deoxycholic acid
- FABP6, fatty acid binding protein 6
- FGF15, fibroblast growth factor 15
- FGFR4, fibroblast growth factor receptor 4
- FXR
- FXR, Farnesoid X receptor
- GLP-1, glucagon-like peptide-1
- HFD, high-fat diet
- LCA, lithocholic acid
- LPS, lipopolysaccharide
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH
- NASH, non-alcoholic steatohepatitis
- ND, normal diet
- OGTT, oral glucose tolerance test
- OST, organic solute transporter
- SHP, small heterodimer protein
- TGR5
- TGR5, Takeda G-protein coupled receptor 5
- TLCA, tauro-lithocholic acid
- TNFα, tumor necrosis factor α
- WDF, western and high-fructose diet
- WT, wild-type
- metabolic syndrome
- αMCA, α-muricholic acid
- βMCA, β-muricholic acid
- ωMCA, ω-muricholic acid
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Affiliation(s)
- Justine Gillard
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.,Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Laure-Alix Clerbaux
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Maxime Nachit
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Christine Sempoux
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Anne Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
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23
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Desai MS. Mechanistic insights into the pathophysiology of cirrhotic cardiomyopathy. Anal Biochem 2021; 636:114388. [PMID: 34587512 DOI: 10.1016/j.ab.2021.114388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/22/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023]
Abstract
Myocardial dysfunction in end stage cirrhotic liver disease, termed cirrhotic cardiomyopathy, is a long known, but little understood comorbidity seen in ∼50% of adults and children who present for liver transplantation. Structural, functional, hemodynamic and electrocardiographic aberrations that occur in the heart as a direct consequence of a damaged liver, is associated with multi-organ failure and increased mortality and morbidity in patients undergoing surgical procedures such as porto-systemic shunt placement and liver transplantation. Despite its clinical significance and rapid advances in science and pharmacotherapy, there is yet no specific treatment for this disease. This may be due to a lack of understanding of the pathogenesis and mechanisms behind how a cirrhotic liver causes cardiac pathology. This review will focus specifically on insights into the molecular mechanisms that drive this liver-heart interaction. Deeper understanding of the etio-pathogenesis of cirrhotic cardiomyopathy will allow us to design and test treatments that can be targeted to prevent and/or reverse this co-morbid consequence of liver failure and improve health care delivery and outcomes in patients with cirrhosis.
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Affiliation(s)
- Moreshwar S Desai
- Department of Pediatrics, Section of Pediatric Critical Care Medicine and Liver ICU. Baylor College of Medicine, Houston, TX, 77030, USA.
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24
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Reiter S, Dunkel A, Dawid C, Hofmann T. Targeted LC-MS/MS Profiling of Bile Acids in Various Animal Tissues. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:10572-10580. [PMID: 34490775 DOI: 10.1021/acs.jafc.1c03433] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Bile acids are being increasingly investigated in humans and laboratory animals as markers for various diseases in addition to their important functions, such as promoting the emulsification in fat digestion and preventing gallstone formation. In humans and animals, primary bile acids are formed from cholesterol in the liver, converted in the intestine into various secondary bile acids by the intestinal microbiota and reabsorbed in the terminal ileum, and partially returned to the liver. A universal high-throughput workflow, including a simple workup, was applied as a tool for bile acid analysis in animal studies. The complex bile acid profiles in various tissues, organs, and body fluids from different animals were mapped using a newly developed comprehensive liquid chromatography-tandem mass spectrometry method. The method can also be used in screening food to obtain information about the nutritional content of bile acids. This could be relevant to investigations on various animal diseases and on the bioavailability of bile acids that pass through the gastric tract.
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Affiliation(s)
- Sinah Reiter
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
- ZIEL-Institute for Food and Health, Technical University of Munich, Weihenstephaner Berg 1, 85354 Freising, Germany
| | - Andreas Dunkel
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Straße 34, 85354 Freising, Germany
| | - Corinna Dawid
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
| | - Thomas Hofmann
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
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25
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Taurochenodeoxycholic acid mediates cAMP-PKA-CREB signaling pathway. Chin J Nat Med 2021; 18:898-906. [PMID: 33357720 DOI: 10.1016/s1875-5364(20)60033-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Indexed: 12/12/2022]
Abstract
Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.
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26
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Pan L, Zhang XF, Wei WS, Zhang J, Li ZZ. The cardiovascular protective effect and mechanism of calycosin and its derivatives. Chin J Nat Med 2021; 18:907-915. [PMID: 33357721 DOI: 10.1016/s1875-5364(20)60034-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease is the main cause of mortality and morbidity in the world, especially in developing countries. Drug therapy is one of the main ways to treat cardiovascular diseases. Among them, great progress has been made in the treatment of cardiovascular diseases with traditional Chinese medicine. In terms of experimental research, the mechanism of traditional Chinese medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo. In terms of clinical treatment, traditional Chinese medicine with flavonoids, saponins and alkaloids as the main effective components has a definite effect on the treatment of cardiovascular diseases such as arrhythmia, myocardial ischemia, angina pectoris and myocardial infarction, with high safety and good application prospects. With the further research on the effective ingredients, mechanism and adverse reactions of traditional Chinese medicine, it will be beneficial to the effectiveness of traditional Chinese medicine, reduce side effects and promote the modernization of traditional Chinese medicine. Calycosin and its derivatives, the main bioactive flavonoids in Astragalus membranaceus have multiple biological effects, such as antioxidant, pro-angiogenesis, anti-tumour, and anti-inflammatory effects. Based on the above biological effects, calycosin has been shown to have good potential for cardiovascular protection. The potent antioxidant effect of calycosin may play an important role in the cardiovascular protective potential. For injured cardiac myocytes, calycosin and its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac myocytes mainly characterized by apoptosis through various mechanisms. For vascular endothelial cells, calycosin also has multiple effects and multiple mechanisms, such as promoting vascular endothelial cell proliferation, exerting vasodilating effect and directly affecting the synthesis function of endothelial cells. The present review will address the bioactivity of calycosin in cardiovascular diseases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its derivatives to exert the above biological effects.
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Affiliation(s)
- Li Pan
- Department of Cardiopulmonary Bypass, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Xuan-Fen Zhang
- Department of Orthopaedic Surgery, Lanzhou University Second Hospital, Lanzhou 730000, China.
| | - Wan-Sheng Wei
- Department of Cardiopulmonary Bypass, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Jing Zhang
- Department of Cardiopulmonary Bypass, Lanzhou University Second Hospital, Lanzhou 730000, China
| | - Zhen-Zhen Li
- Department of Cardiopulmonary Bypass, Lanzhou University Second Hospital, Lanzhou 730000, China
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27
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Liu J, Lickteig AJ, Zhang Y, Csanaky IL, Klaassen CD. Activation of Nrf2 decreases bile acid concentrations in livers of female mice. Xenobiotica 2021; 51:605-615. [PMID: 33522359 DOI: 10.1080/00498254.2021.1880033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
1. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of oxidative/electrophilic stress. Studies suggest a role of Nrf2 in regulating bile acid (BA) metabolism in male mice. However, whether Nrf2 is important for BA homeostasis in female mice remains undefined. In this study, we systematically investigated the effect of Nrf2 activation, either through CDDO-imidazolide (CDDO-Im) treatment or genetic modulation of Kelch-like ECH associating protein 1 (Keap1), on BA homeostasis in female mice.2. Both pharmacological and genetic Nrf2 activation increased mRNA levels of multidrug resistance-associated protein 2 and 3 (Mrp2 and Mrp3), two Nrf2 target genes, in livers and ilea of female mice. Both pharmacological and genetic activation of Nrf2 decreased BA concentrations in the liver, which did not appear to be due to increased biliary BA excretion or decreased ileal BA absorption. Importantly, both pharmacological and genetic activation of Nrf2 downregulated hepatic Cyp7a1 mRNA, which might be attributable to the upregulation of the Fxr-Fgf15 signalling in the ileum.3. To conclude, Nrf2 activation lowers BA concentrations in livers of female mice, which appears to be attributable to the decreased hepatic BA synthesis.
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Affiliation(s)
- Jing Liu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P.R.China
| | - Andrew J Lickteig
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P.R.China
| | - Iván L Csanaky
- Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Hospital and Clinics, Kansas City, MO, USA.,Division of Gastroenterology, Children's Mercy Hospital and Clinics, Kansas City, MO, USA.,Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Curtis D Klaassen
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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28
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Ma C, Guo Y, Klaassen CD. Effect of Gender and Various Diets on Bile Acid Profile and Related Genes in Mice. Drug Metab Dispos 2021; 49:62-71. [PMID: 33093018 PMCID: PMC7804885 DOI: 10.1124/dmd.120.000166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
Diet is an important factor for many diseases. Previous studies have demonstrated that several diets had remarkable effects on bile acid (BA) homeostasis, but no comprehensive information for both genders has been reported. Therefore, the current study characterized the nine most used laboratory animal diets fed to both genders of mice for a comparable evaluation of the topic. The results revealed that marked gender difference of BA homeostasis is ubiquitous in mice fed the various diets, and of the nine diets fed to mice, the atherogenic and calorie-restricted diets had the most marked effects on BA homeostasis, followed by the laboratory chow and essential fatty acid-deficient diets. More specifically, females had higher concentrations of total BAs in serum when fed six of the nine diets compared with male mice, and 26 of the 35 BA-related genes had marked gender difference in mice fed at least one diet. Although mice fed the calorie-restricted and atherogenic diets had increased BA, which was more pronounced in serum than liver, the intestinal farnesoid X nuclear receptor-fibroblast growth factor 15 axis changed in the opposite direction and resulted in different hepatic expression patterns of Cyp7a1 Compared with AIN-93M purified diet, higher hepatic expression of multidrug resistance-associated protein 3 was the only alteration in mice fed the laboratory chow diet. The other diets had little or no effect on BA concentrations in the liver and plasma or in the expression of BA-related genes. This study indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis. SIGNIFICANCE STATEMENT: Previous evidence suggested that various diets have effect on bile acid (BA) homeostasis; however, it is not possible to directly compare these findings, as they are all from different studies. The current study was the first to systematically investigate the influence of the nine most used experimental mouse diets on BA homeostasis and potential mechanism in both genders of mice and indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis, which will aid future investigations.
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Affiliation(s)
- Chong Ma
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
| | - Ying Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
| | - Curtis D Klaassen
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China (C.M., Y.G.); Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China (C.M., Y.G.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, P. R. China (C.M., Y.G.); National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China (C.M., Y.G.); and Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (C.D.K.)
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29
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Csanaky IL, Lickteig AJ, Zhang Y, Klaassen CD. Effects of patent ductus venosus on bile acid homeostasis in aryl hydrocarbon receptor (AhR)-null mice. Toxicol Appl Pharmacol 2020; 403:115136. [PMID: 32679164 DOI: 10.1016/j.taap.2020.115136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 12/20/2022]
Abstract
The Aryl hydrocarbon receptor (AhR) is primarily known as one of the xenosensors and regulators of drug-metabolizing genes. Bile acids (BAs) are synthesized in the liver, and undergo several enterohepatic recirculations in which the liver removes BAs from the portal blood, minimizing the BAs that spill over into the systemic circulation. Previous studies revealed a lifelong patent ductus venosus (PDV) in AhR-null mice. Increased concentration of total BAs (Σ-BAs) in AhR-null mice is known; however, the impact of PDV on BA homeostasis in liver and bile remains unclear. This work investigated the consequences of PDV on BA homeostasis by comparing AhR-null and wild-type (WT) mice of both genders. In serum, Σ-BAs were markedly higher (64-85-fold) in AhR-null mice than in WT mice, especially due to the increase of tri-OH primary BAs (86-142-fold). Despite the extremely high concentration of serum BAs, the concentration of BAs in livers of AhR-null mice remained similar to WT mice. AhR-null livers were protected against increased BA influx by downregulation of uptake transporters and BA synthetic enzymes in the alternative pathway. Although livers of AhR-null mice are 20-25% smaller than WT mice, biliary excretion of BAs was maintained in the AhR-null mice, and even tended to increase. Surprisingly, intestinal Fgf15 expression was not increased, even though there was a marked increase in serum BA concentrations. Although PDV resulted in extremely high BA concentrations in serum of AhR-null mice, they maintained a concentration of BAs in liver and biliary excretion of BAs similar to control mice.
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Affiliation(s)
- Iván L Csanaky
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri 64108, USA; Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
| | - Andrew J Lickteig
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Curtis D Klaassen
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
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Gutierrez D, Weinstock A, Antharam VC, Gu H, Jasbi P, Shi X, Dirks B, Krajmalnik-Brown R, Maldonado J, Guinan J, Thangamani S. Antibiotic-induced gut metabolome and microbiome alterations increase the susceptibility to Candida albicans colonization in the gastrointestinal tract. FEMS Microbiol Ecol 2020; 96:5643884. [PMID: 31769789 PMCID: PMC6934136 DOI: 10.1093/femsec/fiz187] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023] Open
Abstract
Antibiotic-induced alterations in the gut ecosystem increases the susceptibility to Candida albicans, yet the mechanisms involved remains poorly understood. Here we show that mice treated with the broad-spectrum antibiotic cefoperazone promoted the growth, morphogenesis and gastrointestinal (GI) colonization of C. albicans. Using metabolomics, we revealed that the cecal metabolic environment of the mice treated with cefoperazone showed a significant alteration in intestinal metabolites. Levels of carbohydrates, sugar alcohols and primary bile acids increased, whereas carboxylic acids and secondary bile acids decreased in antibiotic treated mice susceptible to C. albicans. Furthermore, using in-vitro assays, we confirmed that carbohydrates, sugar alcohols and primary bile acids promote, whereas carboxylic acids and secondary bile acids inhibit the growth and morphogenesis of C. albicans. In addition, in this study we report changes in the levels of gut metabolites correlated with shifts in the gut microbiota. Taken together, our in-vivo and in-vitro results indicate that cefoperazone-induced metabolome and microbiome alterations favor the growth and morphogenesis of C. albicans, and potentially play an important role in the GI colonization of C. albicans.
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Affiliation(s)
- Daniel Gutierrez
- College of Veterinary Medicine, Midwestern University, 19555 N. 59th Ave. Glendale, AZ 85308, USA
| | - Anthony Weinstock
- Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Ave. Glendale, AZ 85308, USA
| | - Vijay C Antharam
- Department of Chemistry, School of Science and Human Development, Methodist University, 5400 Ramsey St, Fayetteville, NC 28311, USA
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85259, USA
| | - Paniz Jasbi
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85259, USA
| | - Xiaojian Shi
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85259, USA
| | - Blake Dirks
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ 85280, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ 85280, USA.,School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85287, USA.,Biodesign Center for Fundamental and Applied Microbiomics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Juan Maldonado
- Biodesign Center for Fundamental and Applied Microbiomics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Jack Guinan
- College of Veterinary Medicine, Midwestern University, 19555 N. 59th Ave. Glendale, AZ 85308, USA
| | - Shankar Thangamani
- Department of Pathology and Population Medicine, College of Veterinary Medicine, Midwestern University, 19555 N. 59th Ave. Glendale, AZ 85308, USA
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Zhang Y, Lickteig AJ, Liu J, Csanaky IL, Klaassen CD. Effects of ablation and activation of Nrf2 on bile acid homeostasis in male mice. Toxicol Appl Pharmacol 2020; 403:115170. [PMID: 32738332 DOI: 10.1016/j.taap.2020.115170] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/23/2020] [Accepted: 07/27/2020] [Indexed: 01/16/2023]
Abstract
The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in bile acid (BA) homeostasis remains controversial. In this study, activation of Nrf2 was achieved either pharmacologically by CDDO-imidazolide (CDDO-Im) or genetically through a "gene dose-response" model consisting of Nrf2-null, wild-type (WT), Keap1-knockdown (Keap1-KD), and Keap1-hepatocyte knockout (Keap1-HKO) mice. In WT mice, CDDO-Im increased bile flow and decreased hepatic BAs, which was associated with a down-regulation of the canalicular BA efflux transporter Bsep and an increase in biliary BA excretion. In contrast, hepatic Bsep and biliary BA excretion were not altered in Keap1-KD or Keap1-HKO mice, suggesting that Nrf2 is not important for regulating Bsep or BA-dependent bile flow. In contrast, hepatic Mrp2 and Mrp3 were up-regulated by both pharmacological and genetic activations of Nrf2. Furthermore, ileal BA transporters (Asbt and Ostβ) and cholesterol transporters (Abcg5 and Abcg8) were down-regulated by both pharmacological and genetic activations of Nrf2, suggesting a role of Nrf2 in intestinal absorption of BAs and cholesterol. In Nrf2-null mice, CDDO-Im down-regulated hepatic BA uptake transporters (Ntcp, Oatp1a1, and Oatp1b2), leading to a 39-fold increase of serum BAs. To conclude, the present study demonstrates that activation of Nrf2 in mice up-regulates Mrp2 and Mrp3 in the liver and down-regulates BA and cholesterol transporters in the intestine.
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Affiliation(s)
- Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China.
| | - Andrew J Lickteig
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Jing Liu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
| | - Iván L Csanaky
- Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Division of Gastroenterology, Children's Mercy Hospital & Clinics, Kansas City, MO 64108, USA; Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Curtis D Klaassen
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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He Y, Yang T, Du Y, Qin L, Ma F, Wu Z, Ling H, Yang L, Wang Z, Zhou Q, Ge G, Lu Y. High fat diet significantly changed the global gene expression profile involved in hepatic drug metabolism and pharmacokinetic system in mice. Nutr Metab (Lond) 2020; 17:37. [PMID: 32489392 PMCID: PMC7245748 DOI: 10.1186/s12986-020-00456-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 05/07/2020] [Indexed: 12/25/2022] Open
Abstract
Background High fat diet impact transcription of hepatic genes responsible for drug metabolism and pharmacokinetics. Until now, researches just focused on a couple specific genes without a global profile showing. Age-dependent manner was also not noted well. This study aims to investigate the high fat diet effect on transcriptome of drug metabolism and pharmacokinetic system in mouse livers and show the age-dependent evidence. Methods C57BL/6 male mice were used in this experiment. High fat diet was used to treat mice for 16 and 38 weeks. Serum total cholesterol, low density lipoprotein cholesterol, aspartate transaminase, and alanine transaminaselevels were measured. Meanwhile, Histology, RNA-Seq, RT-PCR analysis and fourteen major hepatic bile acids quantification were performed for the liver tissues. Data was mined at levels of genes, drug metabolism and pharmacokinetic sysem, and genome wide. Results Treatment with high fat diet for 38 weeks significantly increased levels of serum lipids as well as aspartate transaminase, and alanine transaminase. Meanwhile, lipid accumulation in livers was observed. At week 38 of the experiment, the profile of 612 genes involved in drug metabolism and pharmacokinetics was significantly changed, indicated by a heatmap visulization and a principal component analysis. In total 210 genes were significantly regulated. Cyp3a11, Cyp4a10, and Cyp4a14 were down-regulated by 10–35 folds, while these three genes also were highly expressed in the liver. High fat diet regulated 11% of genome-wide gene while 30% of genes involved in the hepatic drug metabolism and pharmacokinetic system. Genes, including Adh4, Aldh1b1, Cyp3a11, Cyp4a10, Cyp8b1, Fmo2, Gsta3, Nat8f1, Slc22a7, Slco1a4, Sult5a1, and Ugt1a9, were regulated by high fat diet as an aging-dependent manner. Bile acids homeostasis, in which many genes related to metabolism and transportation were enriched, was also changed by high fat diet with an aging-dependet manner. Expression of genes in drug metabolism and disposition system significantly correlated to serum lipid profiles, and frequently correlated with each other. Conclusions High fat diet changed the global transcription profile of hepatic drug metabolism and pharmacokinetic system with a age-dependent manner.
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Affiliation(s)
- Yuqi He
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China.,Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription and the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines , Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Yang
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China
| | - Yimei Du
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China
| | - Lin Qin
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China
| | - Feifei Ma
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China
| | - Zunping Wu
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China
| | - Hua Ling
- School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA USA
| | - Li Yang
- Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription and the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines , Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengtao Wang
- Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription and the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines , Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qingdi Zhou
- School of Chemistry, The University of Sydney, Camperdown, NSW2006 Australia
| | - Guangbo Ge
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanliu Lu
- The Key Laboratory of the Minstry of Education of the Basic Pharmacology and the Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, School of Pharmacy, Zunyi Medical University, 6 West Xue-Fu Road, Zunyi City, 563009 Guizhou China.,Institute of Chinese Materia Medica, Shanghai Key Laboratory of Complex Prescription and the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines , Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Lee HJ, Shin BY, Moon JS, Fadriquela A, Nuwormegbe SA, Ho CC, Shin JS, Yoon JS, Lee SK, Kim SK. Critical role of bile acid (BA) in the cellular entry and permissiveness of Hepatitis B virus in vitro. Mol Cell Toxicol 2020. [DOI: 10.1007/s13273-020-00081-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Zhao Q, Gao X, Yan G, Zhang A, Sun H, Han Y, Li W, Liu L, Wang X. Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome. Front Med 2019; 14:335-356. [DOI: 10.1007/s11684-019-0705-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 06/25/2019] [Indexed: 01/16/2023]
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35
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Cheng SL, Li X, Lehmler HJ, Phillips B, Shen D, Cui JY. Gut Microbiota Modulates Interactions Between Polychlorinated Biphenyls and Bile Acid Homeostasis. Toxicol Sci 2019; 166:269-287. [PMID: 30496569 DOI: 10.1093/toxsci/kfy208] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The gut microbiome is increasingly recognized as a second genome that contributes to the health and diseases of the host. A major function of the gut microbiota is to convert primary bile acids (BAs) produced from cholesterol in the liver into secondary BAs that activate distinct host receptors to modulate xenobiotic metabolism and energy homeostasis. The goal of this study was to investigate to what extent oral exposure to an environmentally relevant polychlorinated biphenyl (PCBs mixture), namely the Fox River mixture, impacts gut microbiome and BA homeostasis. Ninety-day-old adult female conventional (CV) and germ-free (GF) C57BL/6 mice were orally exposed to corn oil (vehicle), or the Fox River mixture at 6 or 30 mg/kg once daily for 3 consecutive days. The PCB low dose profoundly increased BA metabolism related bacteria Akkermansia (A.) muciniphila, Clostridium (C.) scindens, and Enterococcus in the large intestinal pellet (LIP) of CV mice (16S rRNA sequencing/qPCR). This correlated with a PCB low dose-mediated increase in multiple BAs in serum and small intestinal content (SIP) in a gut microbiota-dependent manner (UPLC-MS/MS). Conversely, at PCB high dose, BA levels remained stable in CV mice correlated with an increase in hepatic efflux transporters and ileal Fgf15. Interestingly, lack of gut microbiota potentiated the PCB-mediated increase in taurine conjugated α and β muricholic acids in liver, SIP, and LIP. Pearson's correlation identified positive correlations between 5 taxa and most secondary BAs. In conclusion, PCBs dose-dependently altered BA homeostasis through a joint effort between host gut-liver axis and intestinal bacteria.
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Affiliation(s)
- Sunny Lihua Cheng
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
| | - Xueshu Li
- Department of Occupational & Environmental Health, University of Iowa, Iowa City, Iowa 52242
| | - Hans-Joachim Lehmler
- Department of Occupational & Environmental Health, University of Iowa, Iowa City, Iowa 52242
| | - Brian Phillips
- Department of Pharmaceutical Sciences, University of Washington, Seattle, Washington, 98105
| | - Danny Shen
- Department of Pharmaceutical Sciences, University of Washington, Seattle, Washington, 98105
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
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Honda A, Miyazaki T, Iwamoto J, Hirayama T, Morishita Y, Monma T, Ueda H, Mizuno S, Sugiyama F, Takahashi S, Ikegami T. Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition. J Lipid Res 2019; 61:54-69. [PMID: 31645370 DOI: 10.1194/jlr.ra119000395] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
The bile acid (BA) composition in mice is substantially different from that in humans. Chenodeoxycholic acid (CDCA) is an end product in the human liver; however, mouse Cyp2c70 metabolizes CDCA to hydrophilic muricholic acids (MCAs). Moreover, in humans, the gut microbiota converts the primary BAs, cholic acid and CDCA, into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In contrast, the mouse Cyp2a12 reverts this action and converts these secondary BAs to primary BAs. Here, we generated Cyp2a12 KO, Cyp2c70 KO, and Cyp2a12/Cyp2c70 double KO (DKO) mice using the CRISPR-Cas9 system to study the regulation of BA metabolism under hydrophobic BA composition. Cyp2a12 KO mice showed the accumulation of DCAs, whereas Cyp2c70 KO mice lacked MCAs and exhibited markedly increased hepatobiliary proportions of CDCA. In DKO mice, not only DCAs or CDCAs but also DCAs, CDCAs, and LCAs were all elevated. In Cyp2c70 KO and DKO mice, chronic liver inflammation was observed depending on the hepatic unconjugated CDCA concentrations. The BA pool was markedly reduced in Cyp2c70 KO and DKO mice, but the FXR was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/small heterodimer partner and FXR/fibroblast growth factor 15 pathways, for controlling BA synthesis under hydrophobic BA composition. From our results, we hypothesize that these KO mice can be novel and useful models for investigating the roles of hydrophobic BAs in various human diseases.
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Affiliation(s)
- Akira Honda
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan; Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Junichi Iwamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Takeshi Hirayama
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tadakuni Monma
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Hajime Ueda
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Fumihiro Sugiyama
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Tadashi Ikegami
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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Moore ES, Daugherity EK, Karambizi DI, Cummings BP, Behling-Kelly E, Schaefer DMW, Southard TL, McFadden JW, Weiss RS. Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge. J Biol Chem 2019; 294:15623-15637. [PMID: 31434739 DOI: 10.1074/jbc.ra118.005729] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 08/15/2019] [Indexed: 12/13/2022] Open
Abstract
Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2 -/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2 -/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2 -/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.
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Affiliation(s)
- Elizabeth S Moore
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853
| | - Erin K Daugherity
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853.,Center for Animal Resources and Education, Cornell University, Ithaca, New York 14853
| | - David I Karambizi
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853
| | - Bethany P Cummings
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853
| | - Erica Behling-Kelly
- Department of Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, New York 14853
| | - Deanna M W Schaefer
- Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, Tennessee 37996
| | - Teresa L Southard
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853
| | - Joseph W McFadden
- Department of Animal Science, Cornell University, Ithaca, New York 14853
| | - Robert S Weiss
- Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853
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Rizzolo D, Buckley K, Kong B, Zhan L, Shen J, Stofan M, Brinker A, Goedken M, Buckley B, Guo GL. Bile Acid Homeostasis in a Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Double Knockout Mouse Model. Hepatology 2019; 70:389-402. [PMID: 30864232 PMCID: PMC7893641 DOI: 10.1002/hep.30612] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 03/01/2019] [Indexed: 12/31/2022]
Abstract
Bile acids (BAs) are diverse molecules that are synthesized from cholesterol in the liver. The synthesis of BAs has traditionally been shown to occur through two pathways. Cholesterol 7α-hydroxylase (CYP7A1) performs the initial and rate-limiting step in the classical pathway, and sterol 27-hydroxylase (CYP27A1) initiates the hydroxylation of cholesterol in the alternative pathway. While the role of individual BA species as physiological detergents is relatively ubiquitous, their endocrine functions as signaling molecules and roles in disease pathogenesis have been emerging to be BA species-specific. In order to better understand the pharmacologic and toxicologic roles of individual BA species in an in vivo model, we created cholesterol 7α-hydroxylase (Cyp7a1) and sterol 27-hydroxylase (Cyp27a1) double knockout (DKO) mice by cross-breeding single knockout mice (Cyp7a1-/- and Cyp27a1-/- ). BA profiling and quantification by liquid chromatography-mass spectrometry of serum, gallbladder, liver, small intestine, and colon of wild-type, Cyp7a1-/- , Cyp27a1-/- , and DKO mice showed that DKO mice exhibited a reduction of BAs in the plasma (45.9%), liver (60.2%), gallbladder (76.3%), small intestine (88.7%), and colon (93.6%), while maintaining a similar BA pool composition compared to wild-type mice. The function of the farnesoid X receptor (FXR) in DKO mice was lower, revealed by decreased mRNA expression of well-known FXR target genes, hepatic small heterodimer partner, and ileal fibroblast growth factor 15. However, response to FXR synthetic ligands was maintained in DKO mice as treatment with GW4064 resulted in similar changes in gene expression in all strains of mice. Conclusion: We provide a useful tool for studying the role of individual BAs in vivo; DKO mice have a significantly reduced BA pool, have a similar BA profile, and maintained response to FXR activation.
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Affiliation(s)
- Daniel Rizzolo
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Kyle Buckley
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Bo Kong
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Le Zhan
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States
| | - Julia Shen
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Mary Stofan
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Anita Brinker
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States
| | - Michael Goedken
- Office of Research and Economic Development, Research Pathology Services, Rutgers University, Piscataway, NJ 08854, United States
| | - Brian Buckley
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States,Environmental and Occupational Health Institute, Rutgers University, Piscataway NJ 08854, United States
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, School of Pharmacy, EOHSI, Rutgers University, Piscataway, NJ 08854, United States,Environmental and Occupational Health Institute, Rutgers University, Piscataway NJ 08854, United States.,VA NJ Health Care Systems, East Orange NJ 07018, United States.,Corresponding Author Information: Grace L. Guo; EOHSI Room 322, 170 Frelinghuysen Rd, Piscataway, NJ 08854; ; Phone: 848-445-8186; Fax: 732-445-4161
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Lickteig AJ, Zhang Y, Klaassen CD, Csanaky IL. Effects of Absence of Constitutive Androstane Receptor (CAR) on Bile Acid Homeostasis in Male and Female Mice. Toxicol Sci 2019; 171:132-145. [PMID: 31225615 PMCID: PMC6735724 DOI: 10.1093/toxsci/kfz143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 01/05/2023] Open
Abstract
Accumulation of BAs in hepatocytes has a role in liver disease and also in drug-induced liver injury. The Constitutive Androstane Receptor (CAR) has been shown to protect against BA-induced liver injury. The polymorphism of CAR has recently been shown to modify the pharmacokinetics and pharmacodynamics of various drugs. Thus it was hypothesized that polymorphism of CAR may also influence BA homeostasis. Using CAR-null and WT mice, this study modeled the potential consequences of CAR polymorphism on BA homeostasis. Our previous study showed that chemical activation of CAR decreases the total BA concentrations in livers of mice. Surprisingly the absence of CAR also decreased the BA concentrations in livers of mice, but to a lesser extent than in CAR-activated mice. Neither CAR activation nor elimination of CAR altered the biliary excretion of total BAs, but CAR activation increased the proportion of 6-OH BAs (TMCA), whereas the lack of CAR increased the excretion of TCA, TCDCA and TDCA. Serum BA concentrations did not parallel the decrease in BA concentrations in the liver in either the mice after CAR activation or mice lacking CAR. Gene expression of BA synthesis, transporter and regulator genes were mainly similar in livers of CAR-null and WT mice. In summary, CAR activation decreases primarily the 12-OH BA concentrations in liver, whereas lack of CAR decreases the concentrations of 6-OH BAs in liver. In bile, CAR activation increases the biliary excretion of 6-OH BAs, whereas absence of CAR increases the biliary excretion of 12-OH BAs and TCDCA.
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Affiliation(s)
- Andrew J Lickteig
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. China
| | - Curtis D Klaassen
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Iván L Csanaky
- Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Division of Gastroenterology, Children's Mercy Hospital, Kansas City, Missouri, USA.,Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas, USA
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Wei J, Chen J, Fu L, Han L, Gao X, Sarhene M, Hu L, Zhang Y, Fan G. Polygonum multiflorum Thunb suppress bile acid synthesis by activating Fxr-Fgf15 signaling in the intestine. JOURNAL OF ETHNOPHARMACOLOGY 2019; 235:472-480. [PMID: 30528660 DOI: 10.1016/j.jep.2018.12.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/29/2018] [Accepted: 12/05/2018] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Polygonum multiflorum Thunb (Heshouwu, HSW) is commonly used in clinical medicine, while the hepatotoxicities of HSW are reported increasingly in recent years. Currently, researchers have demonstrated an essential role of Bile Acids (BAs) in liver diseases. The occurrence of hepatotoxicity cases linked to HSW are characterized by jaundice and cholestasis, suggesting an interaction that between BAs and HSW AIM OF THE STUDY: This study was designed to investigate the HSW-induced liver functional and histological changes in mice and the role of HSW on bile acid synthesis, metabolism, clearance and intestinal absorption. MATERIALS AND METHODS The mice were intragastrically (i.g.) given HSW at doses of 1.275 and 3.825 g/kg (Crude extracts /body weight) once a day for seven days. Liver function was evaluated by measuring the serum levels of enzymes and analyzing the liver histology. The LC/MS analysis was performed to quantify BAs from liver, ileum and serum. Moreover, the expression of bile metabolic-related transporters and metabolic enzymes at both protein and mRNA levels were observed to elucidate the underlying mechanisms. RESULTS Oral administration of HSW for 7 days could not cause liver damage. A significant change was observed for the concentrations of liver and serum BAs in treatment groups compared with normal control. The mRNA expression levels of bile acid excretory transporter (Bsep) and basolateral uptake transporter (Ntcp) were increased with the development of HSW. The concentrations of unconjugated BAs increased in mice intestines after the administration of HSW. Western blot and qRT-PCR analyses showed that HSW upregulated the protein and mRNA expression of Shp and Fgf15 in the ileum of the mice. CONCLUSION HSW treatment for 7days did not cause liver damage. HSW accelerated bile acid enterohepatic circulation and changed the composition of intestinal BAs, leding to the activation of Fxr-Fgf15 signal in intestines, and further inhibited the expression of Cyp7a1 in the liver.
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Affiliation(s)
- Jing Wei
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China; Medical Experiment Center, The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingrui Chen
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Lingling Fu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Xiumei Gao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Michael Sarhene
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Limin Hu
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, #312 Anshanxi Road, Nankai District, Tianjin 300193, China
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai Disctrict, Tianjin 300072, China.
| | - Guanwei Fan
- Medical Experiment Center, The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
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Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration. Cell Stem Cell 2019; 25:23-38.e8. [PMID: 31080134 DOI: 10.1016/j.stem.2019.04.004] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 02/04/2019] [Accepted: 04/04/2019] [Indexed: 12/19/2022]
Abstract
The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program. This transcriptional signature defines a dynamic cellular state during homeostasis and is highly responsive to injury. YAP signaling is induced by physiological bile acids (BAs), required for BEC survival in response to BA exposure, and is necessary for hepatocyte reprogramming into biliary progenitors upon injury. Together, these findings uncover molecular heterogeneity within the ductal epithelium and reveal YAP as a protective rheostat and regenerative regulator in the mammalian liver.
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Dempsey JL, Wang D, Siginir G, Fei Q, Raftery D, Gu H, Yue Cui J. Pharmacological Activation of PXR and CAR Downregulates Distinct Bile Acid-Metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis. Toxicol Sci 2019; 168:40-60. [PMID: 30407581 PMCID: PMC6821357 DOI: 10.1093/toxsci/kfy271] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, 9-week-old male conventional and germ-free mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for 4 days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content of germ-free mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation downregulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner.
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Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
| | - Dongfang Wang
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
- Chongqing Blood Center, Chongqing 400015, P.R. China
| | - Gunseli Siginir
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
| | - Qiang Fei
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
- Department of Chemistry, Jilin University, Changchun, Jilin Province 130061, P.R. China
| | - Daniel Raftery
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona 85004
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
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43
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Pearson T, Caporaso JG, Yellowhair M, Bokulich NA, Padi M, Roe DJ, Wertheim BC, Linhart M, Martinez JA, Bilagody C, Hornstra H, Alberts DS, Lance P, Thompson PA. Effects of ursodeoxycholic acid on the gut microbiome and colorectal adenoma development. Cancer Med 2019; 8:617-628. [PMID: 30652422 PMCID: PMC6382922 DOI: 10.1002/cam4.1965] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/10/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022] Open
Abstract
It has been previously reported that ursodeoxycholic acid (UDCA), a therapeutic bile acid, reduced risk for advanced colorectal adenoma in men but not women. Interactions between the gut microbiome and fecal bile acid composition as a factor in colorectal cancer neoplasia have been postulated but evidence is limited to small cohorts and animal studies. Using banked stool samples collected as part of a phase III randomized clinical trial of UDCA for the prevention of colorectal adenomatous polyps, we compared change in the microbiome composition after a 3-year intervention in a subset of participants randomized to oral UDCA at 8-10 mg/kg of body weight per day (n = 198) or placebo (n = 203). Study participants randomized to UDCA experienced compositional changes in their microbiome that were statistically more similar to other individuals in the UDCA arm than to those in the placebo arm. This reflected a UDCA-associated shift in microbial community composition (P < 0.001), independent of sex, with no evidence of a UDCA effect on microbial richness (P > 0.05). These UDCA-associated shifts in microbial community distance metrics from baseline to end-of-study were not associated with risk of any or advanced adenoma (all P > 0.05) in men or women. Separate analyses of microbial networks revealed an overrepresentation of Faecalibacterium prausnitzii in the post-UDCA arm and an inverse relationship between F prausnitzii and Ruminococcus gnavus. In men who received UDCA, the overrepresentation of F prausnitzii and underrepresentation of R gnavus were more prominent in those with no adenoma recurrence at follow-up compared to men with recurrence. This relationship was not observed in women. Daily UDCA use modestly influences the relative abundance of microbial species in stool and affects the microbial network composition with suggestive evidence for sex-specific effects of UDCA on stool microbial community composition as a modifier of colorectal adenoma risk.
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Affiliation(s)
- Talima Pearson
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
- Department of Biological SciencesNorthern Arizona UniversityFlagstaffArizona
| | - J. Gregory Caporaso
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
- Department of Biological SciencesNorthern Arizona UniversityFlagstaffArizona
| | - Monica Yellowhair
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | | | - Megha Padi
- Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonArizona
| | - Denise J. Roe
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Betsy C. Wertheim
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Mark Linhart
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - Jessica A. Martinez
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
- Department of Nutritional SciencesUniversity of ArizonaTucsonArizona
| | - Cherae Bilagody
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - Heidie Hornstra
- Pathogen and Microbiome InstituteNorthern Arizona UniversityFlagstaffArizona
| | - David S. Alberts
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Peter Lance
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
| | - Patricia A. Thompson
- University of Arizona Cancer CenterUniversity of ArizonaTucsonArizona
- Stony Brook School of MedicineStony BrookNew York
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Marion S, Studer N, Desharnais L, Menin L, Escrig S, Meibom A, Hapfelmeier S, Bernier-Latmani R. In vitro and in vivo characterization of Clostridium scindens bile acid transformations. Gut Microbes 2018; 10:481-503. [PMID: 30589376 PMCID: PMC6748637 DOI: 10.1080/19490976.2018.1549420] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The human gut hosts trillions of microorganisms that exert a profound influence on human biology. Gut bacteria communicate with their host by secreting small molecules that can signal to distant organs in the body. Bile acids are one class of these signaling molecules, synthesized by the host and chemically transformed by the gut microbiota. Among bile acid metabolizers, bile acid 7-dehydroxylating bacteria are commensals of particular importance as they carry out the 7-dehydroxylation of liver-derived primary bile acids to 7-dehydroxylated bile acids. The latter represents a major fraction of the secondary bile acid pool. The microbiology of this group of gut microorganisms is understudied and warrants more attention. Here, we detail the bile acid transformations carried out by the 7-dehydroxylating bacterium Clostridium scindens in vitro and in vivo. In vitro, C. scindens exhibits not only 7α-dehydroxylating capabilities but also, the ability to oxidize other hydroxyl groups and reduce ketone groups in primary and secondary bile acids. This study revealed 12-oxolithocholic acid as a major transient product in the 7α-dehydroxylation of cholic acid. Furthermore, the in vivo study included complementing a gnotobiotic mouse line (devoid of the ability to 7-dehydroxylate bile acids) with C. scindens and investigating its colonization dynamics and bile acid transformations. Using NanoSIMS (Nanoscale Secondary Ion Mass Spectrometry), we demonstrate that the large intestine constitutes a niche for C. scindens, where it efficiently 7-dehydroxylates cholic acid to deoxycholic acid. Overall, this work reveals a novel transient species during 7-dehydroxylation as well as provides direct evidence for the colonization and growth of 7-dehydroxylating bacteria in the large intestine.
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Affiliation(s)
- Solenne Marion
- Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Nicolas Studer
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - Lyne Desharnais
- Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Laure Menin
- Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Stéphane Escrig
- Laboratory for Biological Geochemistry, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Anders Meibom
- Laboratory for Biological Geochemistry, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland,Center for Advanced Surface Analysis, Université de Lausanne, Lausanne, Switzerland
| | | | - Rizlan Bernier-Latmani
- Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland,CONTACT Rizlan Bernier-Latmani Environmental Microbiology Laboratory, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
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Wang X, Han L, Bi Y, Li C, Gao X, Fan G, Zhang Y. Paradoxical Effects of Emodin on ANIT-Induced Intrahepatic Cholestasis and Herb-Induced Hepatotoxicity in Mice. Toxicol Sci 2018; 168:264-278. [DOI: 10.1093/toxsci/kfy295] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Xue Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Yajuan Bi
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Caiyu Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Xiumei Gao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Guanwei Fan
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
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46
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Abstract
PURPOSE OF REVIEW Herein, we review the role of FXR and TGR5 in the regulation of hepatic bile acid metabolism, with a focus on how our understanding of bile acid metabolic regulation by these receptors has evolved in recent years and how this improved understanding may facilitate targeting bile acids for type 2 diabetes treatment. RECENT FINDINGS Bile acid profile is a key regulator of metabolic homeostasis. Inhibition of expression of the enzyme that is required for cholic acid synthesis and thus determines bile acid profile, Cyp8b1, may be an effective target for type 2 diabetes treatment. FXR and, more recently, TGR5 have been shown to regulate bile acid metabolism and Cyp8b1 expression and, therefore, may provide a mechanism with which to target bile acid profile for type 2 diabetes treatment. Inhibition of Cyp8b1 expression is a promising therapeutic modality for type 2 diabetes; however, further work is needed to fully understand the pathways regulating Cyp8b1 expression.
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Affiliation(s)
- Karolina E Zaborska
- Department of Biomedical Sciences, Cornell University, T3 014A Veterinary Research Tower, Ithaca, NY, 14853, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, Cornell University, T3 014A Veterinary Research Tower, Ithaca, NY, 14853, USA.
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47
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Wang X, Wang F, Lu Z, Jin X, Zhang Y. Semi-quantitative profiling of bile acids in serum and liver reveals the dosage-related effects of dexamethasone on bile acid metabolism in mice. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1095:65-74. [DOI: 10.1016/j.jchromb.2018.07.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 07/06/2018] [Accepted: 07/15/2018] [Indexed: 12/11/2022]
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48
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Grefhorst A, van den Beukel JC, Dijk W, Steenbergen J, Voortman GJ, Leeuwenburgh S, Visser TJ, Kersten S, Friesema ECH, Themmen APN, Visser JA. Multiple effects of cold exposure on livers of male mice. J Endocrinol 2018; 238:91-106. [PMID: 29743343 DOI: 10.1530/joe-18-0076] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 05/09/2018] [Indexed: 02/02/2023]
Abstract
Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole-body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete TGs in VLDL particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed. Here, we report the effects of 24-h exposure to 4°C on parameters of hepatic lipid metabolism of male C57BL/6J mice. Cold exposure increased hepatic TG concentrations by 2-fold (P < 0.05) but reduced hepatic lipogenic gene expression. Hepatic expression of genes encoding proteins involved in cholesterol synthesis and uptake such as the LDL receptor (LDLR) was significantly increased upon cold exposure. Hepatic expression of Cyp7a1 encoding the rate-limiting enzyme in the classical bile acid (BA) synthesis pathway was increased by 4.3-fold (P < 0.05). Hepatic BA concentrations and fecal BA excretion were increased by 2.8- and 1.3-fold, respectively (P < 0.05 for both). VLDL-TG secretion was reduced by approximately 50% after 24 h of cold exposure (P < 0.05). In conclusion, cold exposure has various, likely intertwined effects on the liver that should be taken into account when studying the effects of cold exposure on whole-body metabolism.
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Affiliation(s)
- Aldo Grefhorst
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Johanna C van den Beukel
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Wieneke Dijk
- Division of Human NutritionNutrition, Metabolism, and Genomics Group, Wageningen University, Wageningen, The Netherlands
| | - Jacobie Steenbergen
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Gardi J Voortman
- Section of PharmacologyVascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Selmar Leeuwenburgh
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Theo J Visser
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Sander Kersten
- Division of Human NutritionNutrition, Metabolism, and Genomics Group, Wageningen University, Wageningen, The Netherlands
| | - Edith C H Friesema
- Section of PharmacologyVascular and Metabolic Diseases, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Axel P N Themmen
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Jenny A Visser
- Section of EndocrinologyDepartment of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Li CY, Dempsey JL, Wang D, Lee S, Weigel KM, Fei Q, Bhatt DK, Prasad B, Raftery D, Gu H, Cui JY. PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice. Drug Metab Dispos 2018; 46:1226-1240. [PMID: 29769268 PMCID: PMC6053593 DOI: 10.1124/dmd.118.081547] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 05/11/2018] [Indexed: 12/14/2022] Open
Abstract
Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs that may be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis. Nine-week-old male C57BL/6 conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil (10 mg/kg), BDE-47 (100 μmol/kg), or BDE-99 (100 μmol/kg) once daily for 4 days (n = 3-5/group). Gut microbiome was characterized using 16S rRNA sequencing of the large intestinal content in CV mice. Both BDE-47 and BDE-99 profoundly decreased the alpha diversity of gut microbiome and differentially regulated 45 bacterial species. Both PBDE congeners increased Akkermansia muciniphila and Erysipelotrichaceae Allobaculum spp., which have been reported to have anti-inflammatory and antiobesity functions. Targeted metabolomics of 56 BAs was conducted in serum, liver, and small and large intestinal content of CV and GF mice. BDE-99 increased many unconjugated BAs in multiple biocompartments in a gut microbiota-dependent manner. This correlated with an increase in microbial 7α-dehydroxylation enzymes for secondary BA synthesis and increased expression of host intestinal transporters for BA absorption. Targeted proteomics showed that PBDEs downregulated host BA-synthesizing enzymes and transporters in livers of CV but not GF mice. In conclusion, there is a novel interaction between PBDEs and the endogenous BA-signaling through modification of the "gut-liver axis".
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Affiliation(s)
- Cindy Yanfei Li
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Joseph L Dempsey
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Dongfang Wang
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - SooWan Lee
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Kris M Weigel
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Qiang Fei
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Deepak Kumar Bhatt
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Bhagwat Prasad
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Daniel Raftery
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Haiwei Gu
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Julia Yue Cui
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
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50
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Zaborska KE, Lee SA, Garribay D, Cha E, Cummings BP. Deoxycholic acid supplementation impairs glucose homeostasis in mice. PLoS One 2018; 13:e0200908. [PMID: 30059528 PMCID: PMC6066200 DOI: 10.1371/journal.pone.0200908] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 05/22/2018] [Indexed: 12/14/2022] Open
Abstract
Bile acids are critical contributors to the regulation of whole body glucose homeostasis; however, the mechanisms remain incompletely defined. While the hydrophilic bile acid subtype, ursodeoxycholic acid, has been shown to attenuate hepatic endoplasmic reticulum (ER) stress and thereby improve glucose regulation in mice, the effect of hydrophobic bile acid subtypes on ER stress and glucose regulation in vivo is unknown. Therefore, we investigated the effect of the hydrophobic bile acid subtype, deoxycholic acid (DCA), on ER stress and glucose regulation. Eight week old C57BL/6J mice were fed a high fat diet supplemented with or without DCA. Glucose regulation was assessed by oral glucose tolerance and insulin tolerance testing. In addition, circulating bile acid profile and hepatic insulin and ER stress signaling were measured. DCA supplementation did not alter body weight or food intake, but did impair glucose regulation. Consistent with the impairment in glucose regulation, DCA increased the hydrophobicity of the circulating bile acid profile, decreased hepatic insulin signaling and increased hepatic ER stress signaling. Together, these data suggest that dietary supplementation of DCA impairs whole body glucose regulation by disrupting hepatic ER homeostasis in mice.
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Affiliation(s)
- Karolina E. Zaborska
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States of America
| | - Seon A. Lee
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States of America
| | - Darline Garribay
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States of America
| | - Eumee Cha
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States of America
| | - Bethany P. Cummings
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States of America
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