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Yang M, Li A, Mei Y, Li H, An Z, Zhou Q, Zhao J, Li Y, Li K, Zhao M, Xu J, Guo H, Xu Q. Effect of PFAS serum exposure pattern on the lipid metabolism: Time to step-forward in causal inference in epidemiology. J Environ Sci (China) 2025; 155:163-176. [PMID: 40246456 DOI: 10.1016/j.jes.2024.12.029] [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: 06/25/2024] [Revised: 12/22/2024] [Accepted: 12/25/2024] [Indexed: 04/19/2025]
Abstract
Associations of per- and polyfluoroalkyl substances (PFAS) on lipid metabolism have been documented but research remains scarce regarding effect of PFAS on lipid variability. To deeply understand their relationship, a step-forward in causal inference is expected. To address these, we conducted a longitudinal study with three repeated measurements involving 201 participants in Beijing, among which 100 eligible participants were included for the present study. Twenty-three PFAS and four lipid indicators were assessed at each visit. We used linear mixed models and quantile g-computation models to investigate associations between PFAS and blood lipid levels. A latent class growth model described PFAS serum exposure patterns, and a generalized linear model demonstrated associations between these patterns and lipid variability. Our study found that PFDA was associated with increased TC (β = 0.083, 95% CI: 0.011, 0.155) and HDL-C (β = 0.106, 95% CI: 0.034, 0.178). The PFAS mixture also showed a positive relationship with TC (β = 0.06, 95% CI: 0.02, 0.10), with PFDA contributing most positively. Compared to the low trajectory group, the middle trajectory group for PFDA was associated with VIM of TC (β = 0.756, 95% CI: 0.153, 1.359). Furthermore, PFDA showed biological gradients with lipid metabolism. This is the first repeated-measures study to identify the impact of PFAS serum exposure pattern on the lipid metabolism and the first to estimate the association between PFAS and blood lipid levels in middle-aged and elderly Chinese and reinforce the evidence of their causal relationship through epidemiological studies.
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Affiliation(s)
- Ming Yang
- Medical Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Ang Li
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Yayuan Mei
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Haoran Li
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China; Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
| | - Ziwen An
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Environment and Human Health, Hebei Province, Shijiazhuang 050017, China
| | - Quan Zhou
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Jiaxin Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Yanbing Li
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Kai Li
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Meiduo Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Jing Xu
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China
| | - Huicai Guo
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Environment and Human Health, Hebei Province, Shijiazhuang 050017, China.
| | - Qun Xu
- Medical Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China; Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China; Center of Environmental and Health Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China.
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Lin X, Xia L, Zhou Y, Xie J, Tuo Q, Lin L, Liao D. Crosstalk Between Bile Acids and Intestinal Epithelium: Multidimensional Roles of Farnesoid X Receptor and Takeda G Protein Receptor 5. Int J Mol Sci 2025; 26:4240. [PMID: 40362481 PMCID: PMC12072030 DOI: 10.3390/ijms26094240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/22/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.
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Affiliation(s)
| | | | | | | | | | | | - Duanfang Liao
- Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (X.L.); (L.X.); (Y.Z.); (J.X.); (Q.T.); (L.L.)
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Girisa S, Aswani BS, Manickasamy MK, Hegde M, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. Expert Opin Ther Targets 2025; 29:193-221. [PMID: 40169227 DOI: 10.1080/14728222.2025.2487465] [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: 12/08/2024] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
INTRODUCTION Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions. AREAS COVERED This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed. EXPERT OPINION It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
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Li Y, Wang L, Yi Q, Luo L, Xiong Y. Regulation of bile acids and their receptor FXR in metabolic diseases. Front Nutr 2024; 11:1447878. [PMID: 39726876 PMCID: PMC11669848 DOI: 10.3389/fnut.2024.1447878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 11/13/2024] [Indexed: 12/28/2024] Open
Abstract
High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.
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Affiliation(s)
| | | | | | | | - Yuxia Xiong
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
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5
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Liu P, Jin M, Hu P, Sun W, Tang Y, Wu J, Zhang D, Yang L, He H, Xu X. Gut microbiota and bile acids: Metabolic interactions and impacts on diabetic kidney disease. CURRENT RESEARCH IN MICROBIAL SCIENCES 2024; 7:100315. [PMID: 39726973 PMCID: PMC11670419 DOI: 10.1016/j.crmicr.2024.100315] [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] [Indexed: 12/28/2024] Open
Abstract
The intestinal microbiota comprises approximately 1013-1014 species of bacteria and plays a crucial role in host metabolism by facilitating various chemical reactions. Secondary bile acids (BAs) are key metabolites produced by gut microbiota.Initially synthesized by the liver, BA undergoes structural modifications through the activity of various intestinal microbiota enzymes, including eukaryotic, bacterial, and archaeal enzymes. These modified BA then activate specific receptors that regulate multiple metabolic pathways in the host, such as lipid and glucose metabolism, energy balance, inflammatory response, and cell proliferation and death. Recent attention has been given to intestinal flora disorders in diabetic kidney disease (DKD), where activation of BA receptors has shown promise in alleviating diabetic kidney damage by modulating renal lipid metabolism and mitochondrial production. Imbalances in the intestinal flora can influence the progression of DKD through the regulation of bile acid and its receptor pathways. This review aims to propose a mechanism involving the gut-BA-diabetes and nephropathy axes with the goal of optimizing new strategies for treating DKD.
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Affiliation(s)
| | | | - Ping Hu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Weiqian Sun
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Yuyan Tang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Jiajun Wu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Dongliang Zhang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Licai Yang
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Haidong He
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
| | - Xudong Xu
- Division of Nephrology, Minhang Hospital, Fudan University, Shanghai, China
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6
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Herrmann M, Rodriguez-Blanco G, Balasso M, Sobolewska K, Semeraro MD, Alonso N, Herrmann W. The role of bile acid metabolism in bone and muscle: from analytics to mechanisms. Crit Rev Clin Lab Sci 2024; 61:510-528. [PMID: 38488591 DOI: 10.1080/10408363.2024.2323132] [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: 12/06/2023] [Revised: 02/09/2024] [Accepted: 02/21/2024] [Indexed: 08/25/2024]
Abstract
Osteoporosis and sarcopenia are both common age-related disorders that are associated with increased morbidity and mortality. Bone and muscle are metabolically very active tissues that require large amounts of energy. Bile acids (BAs), a group of liver-derived steroid compounds, are primarily known as emulsifiers that facilitate the resorption of dietary fat and lipids. In addition, they have pleiotropic metabolic functions in lipoprotein and glucose metabolism, inflammation, and intestinal bacterial growth. Through these effects, they are related to metabolic diseases, such as diabetes, hypertriglyceridemia, atherosclerosis, and nonalcoholic steatohepatitis. BAs mediate their metabolic effects through receptor dependent and receptor-independent mechanisms. Emerging evidence suggests that BAs are also involved in bone and muscle metabolism. Under normal circumstances, BAs support bone health by shifting the delicate equilibrium of bone turnover toward bone formation. In contrast, low or excessive amounts of BAs promote bone resorption. In cholestatic liver disease, BAs accumulate in the liver, reach toxic concentrations in the circulation, and thus may contribute to bone loss and muscle wasting. In addition, the measurement of BAs is in rapid evolution with modern mass spectrometry techniques that allow for the detection of a continuously growing number of BAs. This review provides a comprehensive overview of the biochemistry, physiology and measurement of bile acids. Furthermore, it summarizes the existing literature regarding their role in bone and muscle.
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Affiliation(s)
- Markus Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Giovanny Rodriguez-Blanco
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Marco Balasso
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Katarzyna Sobolewska
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Maria Donatella Semeraro
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Nerea Alonso
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Wolfgang Herrmann
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
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7
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Guo X, Xu J, Lu X, Zheng X, Chen X, Sun Z, Shen B, Tang H, Duan Y, Zhou Z, Feng X, Chen Y, Wang J, Pang J, Jiang Q, Huang B, Gu N, Li J. Chenodeoxycholic Acid-Modified Polyethyleneimine Nano-Composites Deliver Low-Density Lipoprotein Receptor Genes for Lipid-Lowering Therapy by Targeting the Liver. Adv Healthc Mater 2024; 13:e2400254. [PMID: 38857027 DOI: 10.1002/adhm.202400254] [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: 01/25/2024] [Revised: 06/03/2024] [Indexed: 06/11/2024]
Abstract
Lipid-lowering drugs, especially statins, are extensively utilized in clinical settings for the prevention of hyperlipidemia. Nevertheless, prolonged usage of current lipid-lowering medications is associated with significant adverse reactions. Therefore, it is imperative to develop novel therapeutic agents for lipid-lowering therapy. In this study, a chenodeoxycholic acid and lactobionic acid double-modified polyethyleneimine (PDL) nanocomposite as a gene delivery vehicle for lipid-lowering therapy by targeting the liver, are synthesized. Results from the in vitro experiments demonstrate that PDL exhibits superior transfection efficiency compared to polyethyleneimine in alpha mouse liver 12 (AML12) cells and effectively carries plasmids. Moreover, PDL can be internalized by AML12 cells and rapidly escape lysosomal entrapment. Intravenous administration of cyanine5.5 (Cy5.5)-conjugated PDL nanocomposites reveals their preferential accumulation in the liver compared to polyethyleneimine counterparts. Systemic delivery of low-density lipoprotein receptor plasmid-loaded PDL nanocomposites into mice leads to reduced levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TC) in the bloodstream without any observed adverse effects on mouse health or well-being. Collectively, these findings suggest that low-density lipoprotein receptor plasmid-loaded PDL nanocomposites hold promise as potential therapeutics for lipid-lowering therapy.
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Affiliation(s)
- Xiaotang Guo
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Jiming Xu
- School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China
| | - Xiyuan Lu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Xiaoyan Zheng
- School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China
| | - Xi Chen
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, P. R. China
- Department of Ophthalmology, Northern Jiangsu People's Hospital, Yangzhou, 225001, P. R. China
| | - Zhenning Sun
- School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China
| | - Beilei Shen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Hao Tang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Yiman Duan
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Zhengwei Zhou
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Xu Feng
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Yang Chen
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Junjie Wang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Jing Pang
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Qin Jiang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, P. R. China
| | - Bin Huang
- School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Ning Gu
- Medical School, Nanjing University, Nanjing, 210093, P. R. China
| | - Juxue Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, P. R. China
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, P. R. China
- School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, 210029, P. R. China
- The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, P. R. China
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Wei X, Yao C, He X, Li J, Wang Y, Wang C, Chen Q, Ma X, Guo DA. Biotransformation of chenodeoxycholic acid by human intestinal fungi and the agonistic effects on FXR. PHYTOCHEMISTRY 2024; 224:114162. [PMID: 38797255 DOI: 10.1016/j.phytochem.2024.114162] [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: 02/20/2024] [Revised: 05/13/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024]
Abstract
Bile acids play a vital role in modulating host metabolism, with chenodeoxycholic acid (CDCA) standing out as a primary bile acid that naturally activates farnesoid X receptor (FXR). In this study, we investigated the microbial transformations of CDCA by seven human intestinal fungal species. Our findings revealed that hydroxylation and dehydrogenation were the most prevalent metabolic pathways. Incubation of CDCA with Rhizopus microspores (PT2906) afforded eight undescribed compounds (6-13) alongside five known analogs (1-5) which were elucidated by HRESI-MS and NMR data. Notably, compounds 8, 12 and 13 exhibited an inhibitory effect on FXR in contrast to the FXR activation observed with CDCA in vitro assays. This study shone a light on the diverse transformations of CDCA by intestinal fungi, unveiling potential modulators of FXR activity with implications for host metabolism.
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Affiliation(s)
- Xuemei Wei
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Changliang Yao
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xin He
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiayuan Li
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yulu Wang
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Chao Wang
- College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, 116044, China
| | - Qinhua Chen
- Shenzhen Baoan Authentic TCM Therapy Hospital, Shenzhen, 518101, China
| | - Xiaochi Ma
- College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
| | - De-An Guo
- National Engineering Research Center of TCM Standardization Technology, Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
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9
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [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: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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Wang K, Zhang Y, Wang G, Hao H, Wang H. FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid. Med Res Rev 2024; 44:568-586. [PMID: 37899676 DOI: 10.1002/med.21991] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/06/2023] [Accepted: 10/17/2023] [Indexed: 10/31/2023]
Abstract
Nonalcoholic fatty liver disease, also called metabolic dysfunction-associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction-associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR-based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR-based therapy for NASH/MASH, hoping to support a successful bench-to-clinic transition.
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Affiliation(s)
- Kang Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yuecan Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Hong Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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11
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Chen Z, Shao W, Li Y, Zhang X, Geng Y, Ma X, Tao B, Ma Y, Yi C, Zhang B, Zhang R, Lin J, Chen J. Inhibition of PCSK9 prevents and alleviates cholesterol gallstones through PPARα-mediated CYP7A1 activation. Metabolism 2024; 152:155774. [PMID: 38191052 DOI: 10.1016/j.metabol.2023.155774] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/28/2023] [Accepted: 12/31/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND & AIMS Dysregulated cholesterol metabolism is the major factor responsible for cholesterol gallstones (CGS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis and its inhibitors secure approval for treating various cholesterol metabolic disorders such as hypercholesterolemia and cardiovascular diseases, but its role in CGS remains unclear. Our study aims to clarify mechanisms by which PCSK9 promotes CGS formation and explore the application of the PCSK9 inhibitor, alirocumab, in preventing and treating CGS. APPROACH & RESULTS The expressions of PCSK9 were notably increased in CGS patients' serum, bile, and liver tissues compared to those without gallstones. Moreover, among CGS patients, hepatic PCSK9 was positively correlated with hepatic cholesterol and negatively correlated with hepatic bile acids (BAs), suggesting PCSK9 was involved in disrupted hepatic cholesterol metabolism related to CGS. Mechanistically, in vitro experiments demonstrated that inhibition of PCSK9 enhanced nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Finally, inhibition of PCSK9 prevented CGS formation and dissolved the existing stones in CGS mice by elevating the conversion of cholesterol into BAs through PPARα-mediated CYP7A1 activation. Additionally, serum PCSK9 level may function as a prognostic signature to evaluate the therapeutic efficacy of PCSK9 inhibitors. CONCLUSIONS Inhibition of PCSK9 exerts preventive and therapeutic effects on CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs, which highlights the potential of PCSK9 inhibition as a promising candidate for preventing and treating CGS in clinical applications. IMPACT AND IMPLICATIONS PCSK9 plays a pivotal role in cholesterol metabolism and its inhibitors are approved for clinical use in cardiovascular diseases. Our study observes inhibition of PCSK9 prevents and dissolves CGS by activating PPARα-mediated CYP7A1 expression and facilitating the conversion of cholesterol into BAs. Mechanistically, PCSK9 inhibition enhanced the nuclear expression of PPARα by diminishing its lysosomal degradation and subsequently activated CYP7A1 transcription. Our study sheds light on the new function and mechanism of PCSK9 in CGS, providing a novel preventive and therapeutic target with potential clinical applications.
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Affiliation(s)
- Zhenmei Chen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China; Shanghai Institute of Infectious Disease and Biosecurity, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Weiqing Shao
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Yitong Li
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Xiandi Zhang
- Department of Ultrasound, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Yan Geng
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Xiaochen Ma
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Baorui Tao
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Yue Ma
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Chenhe Yi
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Bo Zhang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Rui Zhang
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China
| | - Jing Lin
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China.
| | - Jinhong Chen
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road, Shanghai 200040, China.
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12
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Hu Y, Zou J, Wang Q, Chen Y, Wang H, Li J. Lipoprotein-mimicking nanotherapeutics reconstituted with chenodeoxycholic acid modified protein for efficient tumor targeting. Eur J Pharm Biopharm 2024; 196:114184. [PMID: 38244896 DOI: 10.1016/j.ejpb.2024.114184] [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: 08/26/2023] [Revised: 12/12/2023] [Accepted: 01/14/2024] [Indexed: 01/22/2024]
Abstract
Lipoprotein-derived nanotherapeutics based on endogenous lipid supramolecules have been regarded as an exceptional and promising approach for anti-tumor drug delivery. However, certain challenges associated with the main component apolipoprotein, such as limited availability, high cost, and insufficient specificity of relevant receptor expression, pose significant barriers to its widespread development and application. The objective of this study is to fabricate lipoprotein-mimicking nanocomposites, denoted as CA-P-rHDL by substituting apolipoprotein with chenodeoxycholic acid (CA) modified bovine serum albumin (BSA), and subsequently assess their tumor-targeting capability and anti-tumor efficacy. CA modified BSA (CA-BSA) was successfully synthesized and characterized by quantifying the degree of protein substitution. Subsequently, a nanostructured lipid carrier (NLC) mimicking the hydrophobic core of natural lipoproteins was attached with CA-BSA to form a lipoprotein-mimic nanocomplex termed as CA-rHDL. CA-rHDL was endowed with lipoprotein-like structures, favorable particle size, zeta potential and excellent paclitaxel encapsulation (termed as CA-P-rHDL). The internalization of CA-rHDL by HepG2 cells exhibited significantly superior efficiency, with a notably higher in HepG2 cells compared to LO2 cells. Confocal laser scanning microscopy revealed that CA-rHDL evaded lysosomal degradation and was evenly distributed throughout the cells. CCK-8 studies demonstrated that CA-P-rHDL exhibited significantly superior inhibition of tumor cells growth compared to other paclitaxel formulations in vitro. Moreover, in vivo imaging observation in H22 tumor-bearing mouse models exhibited a rapid and consistent accumulation of CA-rHDL within tumors, while CA-P-rHDL demonstrated remarkable efficacy against cancer in these mice. These exceptional capabilities of CA-P-rHDL can be attributed to the synergistic targeting effect facilitated by the combination of CA and BSA, rendering it a promising and versatile drug delivery system for targeted anticancer therapy. Consequently, CA-P-rHDL established a highly potential platform for simulating the reconstitution of supramolecular nanovehicles.
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Affiliation(s)
- Yunfeng Hu
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Jiahui Zou
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Qianqian Wang
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Yang Chen
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Hui Wang
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China
| | - Jin Li
- School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, PR China.
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13
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Li R, Zhang Z, Xuan Y, Wang Y, Zhong Y, Zhang L, Zhang J, Chen Q, Yu S, Yuan J. HNF4A as a potential target of PFOA and PFOS leading to hepatic steatosis: Integrated molecular docking, molecular dynamic and transcriptomic analyses. Chem Biol Interact 2024; 390:110867. [PMID: 38199259 DOI: 10.1016/j.cbi.2024.110867] [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: 11/20/2023] [Revised: 12/30/2023] [Accepted: 01/08/2024] [Indexed: 01/12/2024]
Abstract
Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are indeed among the most well known and extensively studied Per- and polyfluoroalkyl substances (PFASs), and increasing evidence confirm their effects on human health, especially liver steatosis. Nonetheless, the molecular mechanisms of their initiation of hepatic steatosis is still elusive. Therefore, potential targets of PFOA/PFOS must be explored to ameliorate its adverse consequences. This research aims to investigate the molecular mechanisms of PFOA and PFOS-induced liver steatosis, with emphasis on identifying a potential target that links these PFASs to liver steatosis. The potential target that causes PFOA and PFOS-induced liver steatosis have been explored and determined based on molecular docking, molecular dynamics (MD) simulation, and transcriptomics analysis. In silico results show that PFOA/PFOS can form a stable binding conformation with HNF4A, and PFOA/PFOS may interact with HNF4A to affect the downstream conduction mechanism. Transcriptome data from PFOA/PFOS-induced human stem cell spheres showed that HNF4A was inhibited, suggesting that PFOA/PFOS may constrain its function. PFOS mainly down-regulated genes related to cholesterol synthesis while PFOA mainly up-regulated genes related to fatty acid β-oxidation. This study explored the toxicological mechanism of liver steatosis caused by PFOA/PFOS. These compounds might inhibit and down-regulate HNF4A, which is the molecular initiation events (MIE) that induces liver steatosis.
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Affiliation(s)
- Rui Li
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Zijing Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Yuxin Xuan
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Yulu Wang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Yuyan Zhong
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Lingyin Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Jinrui Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Qian Chen
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Shuling Yu
- Key Laboratory of Natural Medicine and Immune-Engineering of Henan Province, Henan University, Kaifeng, Henan, 475004, PR China
| | - Jintao Yuan
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, PR China.
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14
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Wang A, Guan B, Zhang H, Xu H. Danger-associated metabolites trigger metaflammation: A crowbar in cardiometabolic diseases. Pharmacol Res 2023; 198:106983. [PMID: 37931790 DOI: 10.1016/j.phrs.2023.106983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/12/2023] [Accepted: 11/03/2023] [Indexed: 11/08/2023]
Abstract
Cardiometabolic diseases (CMDs) are characterized by a series of metabolic disorders and chronic low-grade inflammation. CMDs contribute to a high burden of mortality and morbidity worldwide. Host-microbial metabolic regulation that triggers metaflammation is an emerging field of study that promotes a new perspective for perceiving cardiovascular risks. The term metaflammation denotes the entire cascade of immune responses activated by a new class of metabolites known as "danger-associated metabolites" (DAMs). It is being proposed by the present review for the first time. We summarize current studies covering bench to bedside aspects of DAMs to better understand CMDs in the context of DAMs. We have focused on the involvement of DAMs in the pathophysiological development of CMDs, including the disruption of immune homeostasis and chronic inflammation-triggered damage leading to CMD-related adverse events, as well as emerging therapeutic approaches for targeting DAM metabolism in CMDs.
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Affiliation(s)
- Anlu Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Baoyi Guan
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China
| | - He Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Hao Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China.
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15
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Yang Y, Hsiao YC, Liu CW, Lu K. The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice. TOXICS 2023; 11:833. [PMID: 37888683 PMCID: PMC10611046 DOI: 10.3390/toxics11100833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/28/2023]
Abstract
Inorganic arsenic in drinking water is prioritized as a top environmental contaminant by the World Health Organization, with over 230 million people potentially being exposed. Arsenic toxicity has been well documented and is associated with a plethora of human diseases, including diabetes, as established in numerous animal and epidemiological studies. Our previous study revealed that arsenic exposure leads to the inhibition of nuclear receptors, including LXR/RXR. To this end, FXR is a nuclear receptor central to glucose and lipid metabolism. However, limited studies are available for understanding arsenic exposure-FXR interactions. Herein, we report that FXR knockout mice developed more profound glucose intolerance than wild-type mice upon arsenic exposure, supporting the regulatory role of FXR in arsenic-induced glucose intolerance. We further exposed mice to arsenic and tested if GW4064, a FXR agonist, could improve glucose intolerance and dysregulation of hepatic proteins and serum metabolites. Our data showed arsenic-induced glucose intolerance was remarkably diminished by GW4064, accompanied by a significant ratio of alleviation of dysregulation in hepatic proteins (83%) and annotated serum metabolites (58%). In particular, hepatic proteins "rescued" from arsenic toxicity by GW4064 featured members of glucose and lipid utilization. For instance, the expression of PCK1, a candidate gene for diabetes and obesity that facilitates gluconeogenesis, was repressed under arsenic exposure in the liver, but revived with the GW4064 supplement. Together, our comprehensive dataset indicates FXR plays a key role and may serve as a potential therapeutic for arsenic-induced metabolic disorders.
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Affiliation(s)
| | | | | | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
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16
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Wang Y, Li J, Wu L, Qin X, Xie C, Gao X. Saikosaponins regulate bile acid excretion in mice liver and ileum by activating farnesoid X receptor and bile acid transporter. Phytother Res 2023; 37:4572-4586. [PMID: 37318212 DOI: 10.1002/ptr.7927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 05/10/2023] [Accepted: 06/03/2023] [Indexed: 06/16/2023]
Abstract
Radix Bupleuri exerts effective hepatoprotective and cholagogic effects through its Saikosaponins (SSs) component. Therefore, we attempted to determine the mechanism of saikosaponins used to promote bile excretion by studying their effects on intrahepatic bile flow, focusing on the synthesis, transport, excretion, and metabolism of bile acids. C57BL/6N mice were continuously gavaged with saikosaponin a (SSa), saikosaponin b2 (SSb2 ), or saikosaponin D (SSd) (200 mg/kg) for 14 days. Liver and serum biochemical indices were determined using Enzyme-linked immunosorbent assay (ELISA) kits. In addition, an ultra-performance liquid chromatography-mass spectrometer (UPLC-MS) was used to measure the levels of the 16 bile acids in the liver, gallbladder, and cecal contents. Furthermore, SSs pharmacokinetics and docking between SSs and farnesoid X receptor (FXR)-related proteins were analyzed to investigate the underlying molecular mechanisms. Administration of SSs and Radix Bupleuri alcohol extract (ESS) did not cause significant changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) levels. Saikosaponin-regulated changes in bile acid (BA) levels in the liver, gallbladder, and cecum were closely related to genes involved in BA synthesis, transport, and excretion in the liver. Pharmacokinetic studies indicated that SSs were characterized by rapid elimination (t1/2 as 0.68-2.47 h), absorption (Tmax as 0.47-0.78 h), and double peaks in the drug-time curves of SSa and SSb2 . A molecular docking study revealed that SSa, SSb2 , and SSd docked well with the 16 protein FXR molecules and target genes (<-5.2 kcal/mol). Collectively, saikosaponins may maintain BA homeostasis in mice by regulating FXR-related genes and transporters in the liver and intestine.
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Affiliation(s)
- YuKun Wang
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, PR China
| | - Jing Li
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, PR China
| | - Li Wu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, PR China
| | - XueMei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, PR China
| | - Cen Xie
- State Key Lab Drug Res, Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, PR China
| | - XiaoXia Gao
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, PR China
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17
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Ho TM, Arman HD, Yoshimoto FK. Synthesis of Hyocholic Acid and Its Derivatization with Sodium Periodate to Distinguish It from Cholic Acid by Mass Spectrometry. Steroids 2023:109260. [PMID: 37336340 DOI: 10.1016/j.steroids.2023.109260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 06/15/2023] [Accepted: 06/16/2023] [Indexed: 06/21/2023]
Abstract
Low concentrations of hyocholic acid in human serum has been linked to diabetes. Due to its important role in human health, we were interested in synthesizing hyocholic acid to explore potential biochemical properties of this bile acid. Here, a synthesis of hyocholic acid is reported from chenodeoxycholic acid. The key step was a Rubottom oxidation of a silyl enol ether intermediate to directly incorporate the oxygen at C6. Furthermore, the synthesized hyocholic acid product was treated with NaIO4 to cleave the C6-C7 bond to yield a hemiacetal at C6. This C-C bond cleavage reaction using NaIO4 was used to develop an ultra-performance liquid chromatography mass spectrometry method to distinguish between a 1 to 1 mixture of hyocholic acid and cholic acid (a 12α-hydroxylated bile acid), two bile acid regioisomers with identical masses. Upon treatment of the mixture with NaIO4, hyocholic acid was selectively cleaved in the B ring (C6-C7 bond) to yield the hemiacetal that formed between the C3-hydroxy and the C6-aldehyde moiety with an m/z 405 while cholic acid remained intact with an m/z 407 in the negative electrospray ionization mode. Subsequently, a commercially available ox bile extract was treated with NaIO4 to detect bile acid derivatives by mass spectrometry. Two possible hyocholic acid derivatives conjugated to serine and gamma-glutamic semialdehyde were detected in electrospray ionization positive mode, which oxidatively cleaved with NaIO4 (m/z 496 and 522 to m/z 494 and 520, respectively).
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Affiliation(s)
- Tu M Ho
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
| | - Hadi D Arman
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
| | - Francis K Yoshimoto
- Department of Chemistry, The University of Texas at San Antonio (UTSA), San Antonio, TX 78249
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18
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Xie Y, Shen F, He Y, Guo C, Yang R, Cao H, Pan Q, Fan J. Gamma-Muricholic Acid Inhibits Nonalcoholic Steatohepatitis: Abolishment of Steatosis-Dependent Peroxidative Impairment by FXR/SHP/LXRα/FASN Signaling. Nutrients 2023; 15:1255. [PMID: 36904254 PMCID: PMC10005659 DOI: 10.3390/nu15051255] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/23/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) reflects the outcome of steatosis-based peroxidative impairment. Here, the effect and mechanism of γ-muricholic acid (γ-MCA) on NASH were investigated on the basis of its actions in hepatic steatosis, lipid peroxidation, peroxidative injury, hepatocyte apoptosis, and its NAFLD activity score (NAS). The agonist action of γ-MCA on farnesoid X receptor (FXR) upregulated the small heterodimer partner (SHP) expression of hepatocytes. An increase in SHP attenuated the triglyceride-dominated hepatic steatosis which was induced in vivo by a high-fat high-cholesterol (HFHC) diet and in vitro by free fatty acids depending on the inhibition of liver X receptor α (LXRα) and fatty acid synthase (FASN). In contrast, FXR knockdown abrogated the γ-MCA-dependent lipogenic inactivation. When compared to their excessive production in HFHC diet-induced rodent NASH, products of lipid peroxidation (MDA and 4-HNE) exhibited significant reductions upon γ-MCA treatment. Moreover, the decreased levels of serum alanine aminotransferases and aspartate aminotransferases demonstrated an improvement in the peroxidative injury of hepatocytes. By TUNEL assay, injurious amelioration protected the γ-MCA-treated mice against hepatic apoptosis. The abolishment of apoptosis prevented lobular inflammation, which downregulated the incidence of NASH by lowering NAS. Collectively, γ-MCA inhibits steatosis-induced peroxidative injury to ameliorate NASH by targeting FXR/SHP/LXRα/FASN signaling.
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Affiliation(s)
- Yang Xie
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Feng Shen
- Endoscopy Center, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Yafang He
- Department of Pediatric Respiratory, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Canjie Guo
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Ruixu Yang
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Haixia Cao
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
| | - Qin Pan
- Research Center, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
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19
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Chew NW, Muthiah MD, Sanyal AJ. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: pathophysiology and implications for cardiovascular disease. CARDIOVASCULAR ENDOCRINOLOGY AND METABOLISM 2023:137-173. [DOI: 10.1016/b978-0-323-99991-5.00003-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Nestel P, Loh WJ, Ward NC, Watts GF. New Horizons: Revival of Lipoprotein (a) as a Risk Factor for Cardiovascular Disease. J Clin Endocrinol Metab 2022; 107:e4281-e4294. [PMID: 36108076 DOI: 10.1210/clinem/dgac541] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Indexed: 02/13/2023]
Abstract
The status of lipoprotein (a) [Lp(a)] as a cardiovascular risk factor has been resurrected by advances in genetics. Mendelian randomization studies show a causal link of Lp(a) with coronary artery disease (CAD), peripheral artery disease (PAD), and calcific aortic valve stenosis (CAVS). The genetics of Lp(a) is complex and extends beyond the kringle-IV type 2, as it is also dependent on ancestry. The plasma concentration of Lp(a) is determined by the hepatic production of apolipoprotein(a) [apo(a)] component of Lp(a), supporting the use of nucleic acids that inhibit the messenger RNA (mRNA) gene transcript for apo(a). Analytical barriers to measurement of Lp(a) are being addressed using isoform independent assays and a traceable standard. The association of Lp(a) and atherosclerotic cardiovascular disease is higher for myocardial infarction than PAD and CAVS. Increased risk of type 2 diabetes mellitus associated with low Lp(a) levels is perplexing and requires further investigation. The greatest advancement in Lp(a)-lowering therapies is based on using RNA therapeutics that are now being investigated in clinical trials. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition lowers Lp(a) modestly, but whether cardiovascular benefit is independent of low-density lipoprotein lowering remains unclear. Opportunistic and selective testing for Lp(a) is supported by moderate evidence, with the case for universal screening premature. Modification of behavioral and clinical risk factors may be targeted to mitigate Lp(a)-mediated risk of cardiovascular disease. Clinical practice guidelines have been developed to address gaps in care of high Lp(a), but full implementation awaits the findings of clinical outcome trials using RNA-directed therapies currently underway.
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Affiliation(s)
- Paul Nestel
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Wann Jia Loh
- School of Medicine, University of Western Australia, Perth, Australia
- Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Australia
- Department of Endocrinology, Changi General Hospital, Singapore
- Duke-NUS Medical School, Singapore
| | - Natalie C Ward
- School of Medicine, University of Western Australia, Perth, Australia
| | - Gerald F Watts
- School of Medicine, University of Western Australia, Perth, Australia
- Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Australia
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21
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Handelman SK, Puentes YM, Kuppa A, Chen Y, Du X, Feitosa MF, Palmer ND, Speliotes EK. Population-based meta-analysis and gene-set enrichment identifies FXR/RXR pathway as common to fatty liver disease and serum lipids. Hepatol Commun 2022; 6:3120-3131. [PMID: 36098472 PMCID: PMC9592792 DOI: 10.1002/hep4.2066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 02/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide. NAFLD is associated with elevated serum triglycerides (TG), low-density lipoprotein cholesterol (LDL), and reduced high-density lipoprotein cholesterol (HDL). Both NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology. We used genome-wide association studies (GWAS)-ranked genes and gene-set enrichment analysis to identify pathways that affect serum lipids and NAFLD. We identified credible genes in these pathways and characterized missense variants in these for effects on serum traits. We used MAGENTA to identify 58 enriched pathways from publicly available TG, LDL, and HDL GWAS (n = 99,000). Three of these pathways were also enriched for associations with European-ancestry NAFLD GWAS (n = 7176). One pathway, farnesoid X receptor (FXR)/retinoid X receptor (RXR) activation, was replicated for association in an African-ancestry NAFLD GWAS (n = 3214) and plays a role in serum lipids and NAFLD. Credible genes (proteins) in FXR/RXR activation include those associated with cholesterol/bile/bilirubin transport/absorption (ABCC2 (MRP2) [ATP binding cassette subfamily C member (multidrug resistance-associated protein 2)], ABCG5, ABCG8 [ATP-binding cassette (ABC) transporters G5 and G8], APOB (APOB) [apolipoprotein B], FABP6 (ILBP) [fatty acid binding protein 6 (ileal lipid-binding protein)], MTTP (MTP) [microsomal triglyceride transfer protein], SLC4A2 (AE2) [solute carrier family 4 member 2 (anion exchange protein 2)]), nuclear hormone-mediated control of metabolism (NR0B2 (SHP) [nuclear receptor subfamily 0 group B member 2 (small heterodimer partner)], NR1H4 (FXR) [nuclear receptor subfamily 1 group H member 4 (FXR)], PPARA (PPAR) [peroxisome proliferator activated receptor alpha], FOXO1 (FOXO1A) [forkhead box O1]), or other pathways (FETUB (FETUB) [fetuin B]). Missense variants in ABCC2 (MRP2), ABCG5 (ABCG5), ABCG8 (ABCG8), APOB (APOB), MTTP (MTP), NR0B2 (SHP), NR1H4 (FXR), and PPARA (PPAR) that associate with serum LDL levels also associate with serum liver function tests in UK Biobank. Conclusion: Genetic variants in NR1H4 (FXR) that protect against liver steatosis increase serum LDL cholesterol while variants in other members of the family have congruent effects on these traits. Human genetic pathway enrichment analysis can help guide therapeutic development by identifying effective targets for NAFLD/serum lipid manipulation while minimizing side effects. In addition, missense variants could be used in companion diagnostics to determine their influence on drug effectiveness.
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Affiliation(s)
- Samuel K. Handelman
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Yindra M. Puentes
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Annapurna Kuppa
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Yanhua Chen
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Xiaomeng Du
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
| | - Mary F. Feitosa
- Division of Statistical Genomics, Department of GeneticsWashington UniversitySt. LouisMissouriUSA
| | - Nicholette D. Palmer
- Department of BiochemistryWake Forest School of MedicineWinston‐SalemNorth CarolinaUSA
| | - Elizabeth K. Speliotes
- Division of Gastroenterology and HepatologyUniversity of Michigan Health SystemAnn ArborMichiganUSA
- Department of Computational Medicine and BioinformaticsUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
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22
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Santos Silva E, Rocha S, Candeias Ramos R, Coutinho H, Catarino C, Teixeira F, Henriques G, Lopes AI, Santos-Silva A, Brites D. Bile acids profile and redox status in healthy infants. Pediatr Res 2022:10.1038/s41390-022-02350-y. [PMID: 36272998 DOI: 10.1038/s41390-022-02350-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 09/20/2022] [Accepted: 09/24/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND At birth, human neonates are more likely to develop cholestasis and oxidative stress due to immaturity or other causes. We aimed to search for a potential association between bile acids profile, redox status, and type of diet in healthy infants. METHODS A cross-sectional, exploratory study enrolled 2-month-old full-term infants (n = 32). We measured plasma bile acids (total and conjugated), and red blood cell (RBC) oxidative stress biomarkers. The type of diet (breastfeeding, mixed, formula) was used as an independent variable. RESULTS Plasma total bile acids medium value was 14.80 µmol/L (IQR: 9.25-18.00). The plasma-conjugated chenodeoxycholic acid percentage (CDCA%) correlated significantly and negatively with RBCs membrane-bound hemoglobin percentage (MBH%) (r = -0.635, p < 0.01) and with RBC-oxidized glutathione (r = -0.403, p < 0.05) levels. RBC oxidative stress biomarkers (especially MBH%) were predictors of conjugated CDCA%, and this predictive ability was enhanced when adjusted for the type of diet (MBH, r = 0.452, p < 0.001). CONCLUSIONS Our data suggest that the bile acid profile might play a role in the regulation of redox status (or vice versa) in early postnatal life. Eventually, the type of diet may have some impact on this process. IMPACT The conjugated CDCA% in plasma is negatively correlated with biomarkers of RBC oxidative stress in healthy infants. Specific biomarkers of RBC oxidative stress (e.g. MBH, GSH, GSSG) may be promising predictors of conjugated CDCA% in plasma. The type of diet may influence the predictive ability of hit RBC oxidative stress biomarkers (e.g. MBH, GSH, GSSG). Our findings suggest a link between plasma bile acids profile and the RBC redox status in healthy infants, eventually modulated by the type of diet. The recognition of this link may contribute to the development of preventive and therapeutic strategies for neonatal cholestasis.
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Affiliation(s)
- Ermelinda Santos Silva
- Gastroenterology Unit, Pediatrics Division, Child and Adolescent Department, Centro Materno Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal. .,Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. .,UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal. .,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
| | - Susana Rocha
- UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Rita Candeias Ramos
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Helena Coutinho
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Cristina Catarino
- UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Fernanda Teixeira
- CoreLab, Pathology Department, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Graça Henriques
- CoreLab, Pathology Department, Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Ana Isabel Lopes
- Clínica Universitária de Pediatria, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.,Pediatric Gastroenterology Unit, Pediatrics Department, Hospital Universitário de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
| | - Alice Santos-Silva
- UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.,Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Dora Brites
- Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
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23
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Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
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24
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Guan B, Tong J, Hao H, Yang Z, Chen K, Xu H, Wang A. Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases. Acta Pharm Sin B 2022; 12:2129-2149. [PMID: 35646540 PMCID: PMC9136572 DOI: 10.1016/j.apsb.2021.12.011] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 02/08/2023] Open
Abstract
Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.
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Key Words
- AS, atherosclerosis
- ASBT, apical sodium-dependent bile salt transporter
- BAs, bile acids
- BSEP, bile salt export pump
- BSH, bile salt hydrolases
- Bile acid
- CA, cholic acid
- CAR, constitutive androstane receptor
- CCs, cholesterol crystals
- CDCA, chenodeoxycholic acid
- CMD, cardiometabolic disease
- CVDs, cardiovascular diseases
- CYP7A1, cholesterol 7 alpha-hydroxylase
- CYP8B1, sterol 12α-hydroxylase
- Cardiometabolic diseases
- DAMPs, danger-associated molecular patterns
- DCA, deoxycholic acid
- DCs, dendritic cells
- ERK, extracellular signal-regulated kinase
- FA, fatty acids
- FFAs, free fatty acids
- FGF, fibroblast growth factor
- FMO3, flavin-containing monooxygenase 3
- FXR, farnesoid X receptor
- GLP-1, glucagon-like peptide 1
- HCA, hyocholic acid
- HDL, high-density lipoprotein
- HFD, high fat diet
- HNF, hepatocyte nuclear receptor
- IL, interleukin
- IR, insulin resistance
- JNK, c-Jun N-terminal protein kinase
- LCA, lithocholic acid
- LDL, low-density lipoprotein
- LDLR, low-density lipoprotein receptor
- LPS, lipopolysaccharide
- NAFLD, non-alcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-κB
- NLRP3, NLR family pyrin domain containing 3
- Nuclear receptors
- OCA, obeticholic acid
- PKA, protein kinase A
- PPARα, peroxisome proliferator-activated receptor alpha
- PXR, pregnane X receptor
- RCT, reverses cholesterol transportation
- ROR, retinoid-related orphan receptor
- S1PR2, sphingosine-1-phosphate receptor 2
- SCFAs, short-chain fatty acids
- SHP, small heterodimer partner
- Systemic immunometabolism
- TG, triglyceride
- TGR5, takeda G-protein receptor 5
- TLR, toll-like receptor
- TMAO, trimethylamine N-oxide
- Therapeutic opportunities
- UDCA, ursodeoxycholic acid
- VDR, vitamin D receptor
- cAMP, cyclic adenosine monophosphate
- mTOR, mammalian target of rapamycin
- ox-LDL, oxidated low-density lipoprotein
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Affiliation(s)
- Baoyi Guan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Jinlin Tong
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zhixu Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Keji Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Hao Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
| | - Anlu Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China
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25
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Yang Y, Wu C. Targeting gut microbial bile salt hydrolase (BSH) by diet supplements: new insights into dietary modulation of human health. Food Funct 2022; 13:7409-7422. [DOI: 10.1039/d2fo01252a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Dietary supplements could modulate the abundance of BSH-producing bacteria to regulate the BSH enzyme activity, thereby change the BAs composition to regulate FXR signaling, which then regulate human health.
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Affiliation(s)
- Yanan Yang
- Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China
| | - Chongming Wu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
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26
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Mooranian A, Foster T, Ionescu CM, Carey L, Walker D, Jones M, Wagle SR, Kovacevic B, Chester J, Johnstone E, Kuthubutheen J, Brown D, Atlas MD, Mikov M, Al-Salami H. The Effects of Primary Unconjugated Bile Acids on Nanoencapsulated Pharmaceutical Formulation of Hydrophilic Drugs: Pharmacological Implications. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:4423-4434. [PMID: 34720580 PMCID: PMC8550211 DOI: 10.2147/dddt.s328526] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/10/2021] [Indexed: 01/13/2023]
Abstract
Introduction In a recent study, in our laboratory, primary unconjugated bile acids, commonly found in humans, chenodeoxycholic acid (CDCA), have been shown to improve stability of nanoencapsulated lipophilic drugs and improve their release profile after oral administration likely via electrokinetic stabilisation. Hence, this study aimed to examine the effects of CDCA on exerting similar effects on hydrophilic drugs. Methods Various CDCA-based formulations were produced for the orally administered hydrophilic drug, metformin. Analyses of these formulations included electrokinetic potentials, topography, drug and CDCA formulation contents, nano size distribution, heat-induced deformation and outer-core expansion indices, release profiles, shell-resistance ratio, and thermal and chemical indices. With the drug’s main target being pancreatic beta-cells, the formulations’ effects on cell viability, functions and inflammatory profiles were also investigated. Results and Conclusions CDCA-based metformin formulations exhibited improved stability and release profiles via thermal, chemical and electrokinetic effects, which were formulation-dependent suggesting potential applications of CDCA in the oral targeted delivery of hydrophilic drugs.
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Affiliation(s)
- Armin Mooranian
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Thomas Foster
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Corina M Ionescu
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Louise Carey
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Daniel Walker
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Melissa Jones
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Susbin Raj Wagle
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Bozica Kovacevic
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Jacqueline Chester
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Edan Johnstone
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | | | - Daniel Brown
- Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Marcus D Atlas
- Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, 21101, Serbia
| | - Hani Al-Salami
- The Biotechnology and Drug Development Research Laboratory, Curtin Medical School & Curtin Health Innovation Research Institute, Curtin University, Bentley, Perth, 6102, WA, Australia.,Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands, Perth, 6009, WA, Australia
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27
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Gaillard D, Masson D, Garo E, Souidi M, Pais de Barros JP, Schoonjans K, Grober J, Besnard P, Thomas C. Muricholic Acids Promote Resistance to Hypercholesterolemia in Cholesterol-Fed Mice. Int J Mol Sci 2021; 22:7163. [PMID: 34281217 PMCID: PMC8269105 DOI: 10.3390/ijms22137163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. METHODS Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. RESULTS Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. CONCLUSIONS These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.
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Affiliation(s)
- Dany Gaillard
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- Department of Cell & Developmental Biology, and The Rocky Mountain Taste & Smell Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - David Masson
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- LipSTIC LabEx, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France
- Biochemistry Department, University Hospital François Mitterrand, 21000 Dijon, France
| | - Erwan Garo
- IGBMC, CNRS UMR 7104, INSERM U 1258, 67400 Illkirch, France;
| | - Maamar Souidi
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 92260 Fontenay-aux-Roses, France;
| | - Jean-Paul Pais de Barros
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- LipSTIC LabEx, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France
- Lipidomic Facility, Université de Bourgogne Franche-Comté (UBFC), 21078 Dijon, France
| | - Kristina Schoonjans
- Institute of Bioengineering, Life Science Faculty, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland;
| | - Jacques Grober
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- LipSTIC LabEx, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France
| | - Philippe Besnard
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- LipSTIC LabEx, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France
- Physiologie de la Nutrition, AgroSup Dijon, 21000 Dijon, France
| | - Charles Thomas
- Center for Translational Medicine, UMR1231 INSERM-uB-AgroSupDijon, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France; (D.G.); (D.M.); (J.-P.P.d.B.); (J.G.)
- LipSTIC LabEx, Université de Bourgogne Franche-Comté (UBFC), 21000 Dijon, France
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Beyond Lipoprotein(a) plasma measurements: Lipoprotein(a) and inflammation. Pharmacol Res 2021; 169:105689. [PMID: 34033878 PMCID: PMC9247870 DOI: 10.1016/j.phrs.2021.105689] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/18/2021] [Accepted: 05/19/2021] [Indexed: 12/20/2022]
Abstract
Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD.
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Total flavonoids of Astragalus Ameliorated Bile Acid Metabolism Dysfunction in Diabetes Mellitus. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6675567. [PMID: 33953787 PMCID: PMC8057874 DOI: 10.1155/2021/6675567] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/27/2021] [Accepted: 04/02/2021] [Indexed: 12/14/2022]
Abstract
Astragalus Radix is one of the common traditional Chinese medicines used to treat diabetes. However, the underlying mechanism is not fully understood. Flavones are a class of active components that have been reported to exert various activities. Existing evidence suggests that flavones from Astragalus Radix may be pivotal in modulating progression of diabetes. In this study, total flavones from Astragalus Radix (TFA) were studied to observe its effects on metabolism of bile acids both in vivo and in vitro. C57BL/6J mice were treated with STZ and high-fat feeding to construct diabetic model, and HepG2 cell line was applied to investigate the influence of TFA on liver cells. We found a serious disturbance of bile acids and lipid metabolism in diabetic mice, and oral administration or cell incubation with TFA significantly reduced the production of total cholesterol (TCHO), total triglyceride, glutamic oxalacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), and low-density lipoprotein (LDL-C), while it increased the level of high-density lipoprotein (HDL-C). The expression of glucose transporter 2 (GLUT2) and cholesterol 7α-hydroxylase (CYP7A1) was significantly upregulated on TFA treatment, and FXR and TGR5 play pivotal role in modulating bile acid and lipid metabolism. This study supplied a novel understanding towards the mechanism of Astragalus Radix on controlling diabetes.
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Girisa S, Rana V, Parama D, Dutta U, Kunnumakkara AB. Differential roles of farnesoid X receptor (FXR) in modulating apoptosis in cancer cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 126:63-90. [PMID: 34090620 DOI: 10.1016/bs.apcsb.2021.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is one of the leading causes of mortality in the world. The conventional treatment strategies of cancer are surgery, radiation, and chemotherapy. However, in the advanced stage of the disease chemotherapy is the prime treatment and it is effective in only less than 10% of the patients. Therefore, there is an urgent need to find out novel therapeutic targets and delineate the mechanism of action of these targets for better management of this disease. Recent studies have shown that some of the proteins have differential role in different cancers. Therefore, it is pertinent that the targeting of these proteins should be based on the type of cancer. The nuclear receptor, FXR, is one of the vital proteins that regulate cell apoptosis. Besides, it also regulates other processes such as cell proliferation, angiogenesis, invasion, and migration. Studies suggest that the low or high expression of FXR is associated with the progression of carcinogenesis depending on the cancer types. Due to the diverse expression, it functions as both tumor suppressor and promoter. Previous studies suggest the overexpression of FXR in breast, lung, esophageal, and prostate cancer, which is related to poor survival and poor prognosis in patients. Therefore, targeting FXR with agonists and antagonists play different outcome in different cancers. Hence, this review describes the role of FXR in different cancers and the role of its inhibitors and activators for the prevention and treatment of various cancers.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Uma Dutta
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Guwahati, Assam, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166133. [PMID: 33771667 DOI: 10.1016/j.bbadis.2021.166133] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
The liver is the central metabolic hub which coordinates nutritional inputs and metabolic outputs. Food intake releases bile acids which can be sensed by the bile acid receptor FXR in the liver and the intestine. Hepatic and intestinal FXR coordinately regulate postprandial nutrient disposal in a network of interacting metabolic nuclear receptors. In this review we summarize and update the "classical roles" of FXR as a central integrator of the feeding state response, which orchestrates the metabolic processing of carbohydrates, lipids, proteins and bile acids. We also discuss more recent and less well studied FXR effects on amino acid, protein metabolism, autophagic turnover and inflammation. In addition, we summarize the recent understanding of how FXR signaling is affected by posttranslational modifications and by different FXR isoforms. These modifications and variations in FXR signaling might be considered when FXR is targeted pharmaceutically in clinical applications.
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Selicean S, Wang C, Guixé-Muntet S, Stefanescu H, Kawada N, Gracia-Sancho J. Regression of portal hypertension: underlying mechanisms and therapeutic strategies. Hepatol Int 2021; 15:36-50. [PMID: 33544313 PMCID: PMC7886770 DOI: 10.1007/s12072-021-10135-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/05/2021] [Indexed: 12/12/2022]
Abstract
Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible.
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Affiliation(s)
- Sonia Selicean
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Cong Wang
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Sergi Guixé-Muntet
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland
| | - Horia Stefanescu
- Department of Hepatology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Liver Research Club, Cluj-Napoca, Romania
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Jordi Gracia-Sancho
- Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland.
- Liver Vascular Biology Research Group, IDIBAPS Research Institute, CIBEREHD, Barcelona, Spain.
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 237] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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Shah RA, Alkhouri N, Kowdley KV. Emerging drugs for the treatment of non-alcoholic steatohepatitis: a focused review of farnesoid X receptor agonists. Expert Opin Emerg Drugs 2020; 25:251-260. [DOI: 10.1080/14728214.2020.1796968] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Ni Z, Sun S, Bi Y, Ding J, Cheng W, Yu J, Zhou L, Li M, Yu C. Correlation of fecal metabolomics and gut microbiota in mice with endometriosis. Am J Reprod Immunol 2020; 84:e13307. [PMID: 32681566 DOI: 10.1111/aji.13307] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/07/2020] [Accepted: 07/13/2020] [Indexed: 12/21/2022] Open
Abstract
PROBLEM Endometriosis (EMS) is a chronic inflammatory disease with unclear pathogenesis. Three studies have uncovered the influence of gut microbiota on mice with EMS, but no study has investigated the characteristics of fecal metabolomics to determine some important clues on EMS. This research aims to uncover the interaction between fecal metabolomics and gut microbiota in EMS mice. METHOD OF STUDY Female C57BL/6J mice were used to construct the EMS model. Non-target metabolomics was applied to detect the fecal metabolites of EMS mice. The 16s rRNA sequencing was used for clarifying the composition of the gut microbiota. The functional characteristics of gut microbiota were analyzed using the PICRUSt. The receiver operator characteristic curve (ROC) analysis was utilized for determining the potential important differential metabolites, and the Spearman correlation coefficient was applied for expressing the correlation between the important differential metabolites and gut microbiota. RESULTS A total of 156 named differential metabolites were screened. The diversity and the abundance of gut microbiota in EMS mice decreased. Eleven pathways were involved in the differential metabolites and the functional prediction of gut microbiota, among which the second bile acid biosynthesis and alpha-linolenic acid (ALA) metabolism were the significant enrichment pathways. The increased abundance of chenodeoxycholic and ursodeoxycholic acids and the decreased abundance of ALA and 12,13-EOTrE were found in the feces of EMS mice. CONCLUSION The abnormal fecal metabolites, which are influenced by dysbacteriosis, may be the characteristics of EMS mice and can be the potential important indices to distinguish the disease.
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Affiliation(s)
- Zhexin Ni
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shuai Sun
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yanli Bi
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jie Ding
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Wen Cheng
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jin Yu
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Ling Zhou
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Mingqing Li
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China
| | - Chaoqin Yu
- Department of Gynecology of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University, Shanghai, China
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Connelly MA, Velez Rivera J, Guyton JR, Siddiqui MS, Sanyal AJ. Review article: the impact of liver-directed therapies on the atherogenic risk profile in non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020; 52:619-636. [PMID: 32638417 PMCID: PMC7497003 DOI: 10.1111/apt.15935] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/23/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Patients with non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, are at higher risk of cardiovascular disease (CVD) and associated mortality. Therefore, it is important to understand how new therapies for non-alcoholic steatohepatitis (NASH) may impact CVD risk factors in these patients. AIMS To summarise the effects of drug therapies on lipid and lipoprotein levels in patients with NASH and provide insight into the potential mechanisms for the observed changes. METHODS PubMed searches of the literature were performed and results were compiled. RESULTS Recent clinical trials have highlighted the safety and efficacy of drug candidates for the treatment of NASH. Several agents have shown improvements in the histological features of NASH and liver function. Pioglitazone, a drug that is currently available for type 2 diabetes and may be useful for NASH, exhibits beneficial effects on lipids. However, agents such as farnesoid X receptor agonists, which are in development for NASH, may adversely affect circulating lipids and lipoproteins. CONCLUSIONS NASH is a multi-system disease with a disproportionate CVD burden. Current and future drugs for NASH have had variable impact on the atherogenic risk profile. Potential co-administration of a statin may help mitigate the negative impact of some of these therapies on lipid and lipoprotein levels.
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Affiliation(s)
| | - Jonathan Velez Rivera
- Division of Endocrinology, Metabolism, and NutritionDepartment of MedicineDuke University Medical CenterDurhamNCUSA
| | - John R. Guyton
- Division of Endocrinology, Metabolism, and NutritionDepartment of MedicineDuke University Medical CenterDurhamNCUSA
| | | | - Arun J. Sanyal
- Division of Gastroenterology and HepatologyVirginia Commonwealth UniversityRichmondVAUSA
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Abstract
INTRODUCTION NAFLD has grown to become the most prevalent liver disease in the world, with a quarter of the general population estimated to have the disease. NASH, characterized as NAFLD with inflammation, is associated with worsening fibrosis along with increased incidence of HCC. Despite high prevalence of this disease, no pharmacologic treatments approved by regulatory agencies are available. AREAS COVERED This review briefly discusses present understanding of NASH pathology and currently available treatments. We also discuss data on the role of OCA as an FXR agonist in modulating disease in NASH. A comprehensive literature search of review articles, original research articles, and prospective clinical trials from 1998 to the present was performed. EXPERT OPINION Based on 18-month interim findings of the REGENERATE trial, OCA likely improves fibrosis in NASH and therefore may have a beneficial effect in delaying or even preventing cirrhosis. The side effect of an atherogenic lipoprotein profile may adversely affect long-term outcomes, though studies have shown that co-administration of statins is able to mitigate this effect. OCA is likely to become an option for treatment, but the specific context within which it may be prescribed still needs to be clarified.
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Affiliation(s)
- Raj A Shah
- Liver Institute Northwest , Seattle, WA, USA
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Effect of rhTSH on Lipids. J Clin Med 2020; 9:jcm9020515. [PMID: 32074945 PMCID: PMC7073530 DOI: 10.3390/jcm9020515] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/02/2020] [Accepted: 02/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Subclinical hypothyroidism is associated with increased blood lipid levels. However, the exact role of thyrotropin (TSH) alone is not clear. In order to clarify this point, we analysed the acute effect of recombinant human TSH (rhTSH) administration on lipid levels. METHODS Sera of 27 premenopausal women with well-differentiated thyroid cancer were analysed. Patients that underwent a total thyroidectomy, ablation with 131I (Iodine 131) and rhTSH administration as a part of routine follow-up American Thyroid Association guidelines were included. The protocol consists of 2 intramuscular injections of 0.9 mg of rhTSH, performed on day 1 day and day 2, with blood collection on day 1 (before rhTSH administration), and day 5. TSH, free thyroxine, total cholesterol, low-density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), and triglycerides were assessed in all the samples, before and four days after the first administration of rhTSH. RESULTS Total cholesterol and triglycerides significantly increased after stimulation of rhTSH (respectively, 192 ± 33 vs. 207 ± 26, p = 0.036 and 72 ± 23 vs. 85 ± 23, p = 0.016). LDLc and HDLc showed comparable concentrations before and after the test (respectively, 115 ± 27 vs. 126 ± 22, p = 0.066, and 62 ± 15 vs. 64 ± 15, p = 0.339), while non-HDLc increased after stimulation (130 ± 30 vs. 143 ± 25, p = 0.045). CONCLUSION TSH has a direct effect on total cholesterol, triglycerides, and nonHDLc. Explanation of these phenomena will require additional studies.
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Blanchard C, Ledoux S, Verhaegen A, Wargny M, Letessier E, Stepanian A, Huten N, Jacobi D, Krempf M, Le Bras M, Perrocheau Guillouche M, Arnaud L, Pichelin M, Van Gaal L, Cariou B, Le May C. Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients. DIABETES & METABOLISM 2020; 46:480-487. [PMID: 32032671 DOI: 10.1016/j.diabet.2020.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 12/11/2022]
Abstract
AIM Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. METHODS Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). RESULTS A total of 156 patients (34SG, 122RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P<0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r=0.22, P=0.007), HOMA-IR (r=0.24, P=0.005), total cholesterol (r=0.17, P=0.037) and non-HDL-C (r=0.17, P=0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. CONCLUSION RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.
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Affiliation(s)
- C Blanchard
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France; Clinical Department of Digestive and Endocrine Surgery, CHU of Nantes, Nantes, France
| | - S Ledoux
- Department of Functional Explorations, North Francilien Integrated Obesity Centre (CINFO), Hôpital Louis Mourier (AP-HP.7), University of Paris, Paris, France
| | - A Verhaegen
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - M Wargny
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France; Thorax Institute, Department of Endocrinology, CIC 1413 Inserm, CHU Nantes, Nantes, France
| | - E Letessier
- Clinical Department of Digestive and Endocrine Surgery, CHU of Nantes, Nantes, France
| | - A Stepanian
- AP-HP, Hôpital Lariboisière, Department of Biological Haematology, Paris, France
| | - N Huten
- Digestive, Endocrine, Oncology and Liver Transplantation Department, CHU of Tours, Tours, France
| | - D Jacobi
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France; Digestive, Endocrine, Oncology and Liver Transplantation Department, CHU of Tours, Tours, France
| | - M Krempf
- Thorax Institute, Department of Endocrinology, CIC 1413 Inserm, CHU Nantes, Nantes, France; INRA, UMR 1280, Physiology of Nutritional Adaptations, CHU Hôtel-Dieu, 44000 Nantes, France
| | - M Le Bras
- Thorax Institute, Department of Endocrinology, CIC 1413 Inserm, CHU Nantes, Nantes, France
| | | | - L Arnaud
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France
| | - M Pichelin
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France; Thorax Institute, Department of Endocrinology, CIC 1413 Inserm, CHU Nantes, Nantes, France
| | - L Van Gaal
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - B Cariou
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France; Thorax Institute, Department of Endocrinology, CIC 1413 Inserm, CHU Nantes, Nantes, France
| | - C Le May
- University of Nantes, CNRS, Inserm, Thorax Institute, 44000 Nantes, France.
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Tanaka M, Kanasaki A, Hayashi N, Iida T, Murao K. Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels. ACTA ACUST UNITED AC 2020. [DOI: 10.2131/fts.7.15] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Misuzu Tanaka
- Research and Development, Matsutani Chemical Industry Co., Ltd
| | - Akane Kanasaki
- Research and Development, Matsutani Chemical Industry Co., Ltd
| | - Noriko Hayashi
- Research and Development, Matsutani Chemical Industry Co., Ltd
| | - Tetsuo Iida
- Research and Development, Matsutani Chemical Industry Co., Ltd
| | - Koji Murao
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University
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Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol 2020; 72:25-33. [PMID: 31634532 PMCID: PMC6920569 DOI: 10.1016/j.jhep.2019.10.006] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/04/2019] [Accepted: 10/07/2019] [Indexed: 01/27/2023]
Abstract
BACKGROUND & AIMS Obeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles. METHOD This study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72 weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72 weeks after randomization, and 24 weeks following EOT. RESULTS Baseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12 weeks (baseline-adjusted mean: 6.8 vs. 8.9 nmol/L; p = 0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0 nmol/L; p = 0.02). After 12 weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329 nmol/L; p <0.0001), characterized by corresponding increases in both less atherogenic, large-buoyant LDL (475 vs. 308 nmol/L; p ≤0.001) and more atherogenic small-dense LDL particles (1,015 vs. 872 nmol/L; p = 0.002). The changes in LDL particle concentrations were similar between treatment groups (OCA and placebo) 24 weeks following EOT due to improvement in the OCA cohort. Compared to placebo, a reduction in total HDL particle concentration, particularly large and medium HDL particles, was noted in the OCA-treated patients, but this resolved after drug discontinuation. CONCLUSION OCA therapy is associated with increases in small VLDL particles, large and small LDL particles, and a reduction in HDL particles at 12 weeks. These lipoprotein concentrations reverted to baseline values 24 weeks after drug discontinuation. LAY SUMMARY Non-alcoholic steatohepatitis is a chronic liver disease that is associated with an increased risk of developing cirrhosis and cardiovascular disease. Recently, obeticholic acid (OCA), a farnesoid X receptor agonist, improved liver disease but led to an increase in cholesterol. However, the impact of OCA on cholesterol is not well understood. In the present study, we show that OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.
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Paredes S, Alves M, Pereira ML, Marques O, Ribeiro L. Lipoprotein(a) Change After Sleeve Gastrectomy Is Affected by the Presence of Metabolic Syndrome. Obes Surg 2019; 30:545-552. [PMID: 31625055 DOI: 10.1007/s11695-019-04212-9] [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] [Indexed: 12/23/2022]
Abstract
BACKGROUND Patients with metabolic syndrome (MetS) are at high risk of developing cardiovascular disease (CVD) and lipoprotein(a) (Lp(a)) is an independent risk factor for CVD. This study aimed to determine the effect of vertical sleeve gastrectomy (VSG)-induced weight loss on Lp(a) levels in obese individuals. METHODS Patients submitted to VSG from January 2011 to July 2015 were included. Anthropometric and metabolic parameters were recorded before and 12 months after surgery. Univariate analysis identified associations between Lp(a) and anthropometry and metabolic parameters, and the logistic regression predictors of Lp(a) decrease after VSG. RESULTS MetS was present in 47% of the 330 patients involved. Patients with MetS had higher body mass index (BMI) and triglyceride levels and were more insulin-resistant. No differences were found between groups respecting Lp(a) levels prior to surgery (15.2 mg/dL vs. 15.0 mg/dL, p = 0.795). After surgery, patients without MetS had a decrease in Lp(a) levels (14.7 mg/dL vs. 12.3 mg/dL, p = 0.006), while MetS patients showed no differences (13.9 mg/dL vs. 14.6 mg/dL, p = 0.302). The regression model evidenced that older age and Δ HDL-c were predictors of Lp(a) decrease, whereas the greater the number of MetS components and lower estimated BF% loss, the lesser odds of decreasing Lp(a) after surgery. CONCLUSIONS Despite a global improvement of conventional CVD risk factors, only individuals without MetS showed a decrease of Lp(a) levels after VSG. Further studies should explore not only the pathophysiological mechanisms underlying the absence of decrease of Lp(a) levels in MetS patients, but also its impact on the metabolic beneficial changes usually observed after VSG.
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Affiliation(s)
- Silvia Paredes
- Endocrinology Department, Hospital de Braga, Sete Fontes, São Victor, 4710-243, Braga, Portugal. .,Department of Public Health and Forensic Sciences, and Medical Education, Medical Education Unit, Faculty of Medicine of the University of Porto, 4200-319, Porto, Portugal.
| | - Marta Alves
- Endocrinology Department, Hospital de Braga, Sete Fontes, São Victor, 4710-243, Braga, Portugal
| | - Maria Lopes Pereira
- Endocrinology Department, Hospital de Braga, Sete Fontes, São Victor, 4710-243, Braga, Portugal
| | - Olinda Marques
- Endocrinology Department, Hospital de Braga, Sete Fontes, São Victor, 4710-243, Braga, Portugal
| | - Laura Ribeiro
- Department of Public Health and Forensic Sciences, and Medical Education, Medical Education Unit, Faculty of Medicine of the University of Porto, 4200-319, Porto, Portugal.,I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-319, Porto, Portugal
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Ghaffarzadegan T, Essén S, Verbrugghe P, Marungruang N, Hållenius FF, Nyman M, Sandahl M. Determination of free and conjugated bile acids in serum of Apoe(-/-) mice fed different lingonberry fractions by UHPLC-MS. Sci Rep 2019; 9:3800. [PMID: 30846721 PMCID: PMC6405994 DOI: 10.1038/s41598-019-40272-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/08/2019] [Indexed: 12/13/2022] Open
Abstract
Bile acids (BAs) are known to be involved in cholesterol metabolism but interactions between the diet, BA profiles, gut microbiota and lipid metabolism have not been extensively explored. In the present study, primary and secondary BAs including their glycine and taurine-conjugated forms were quantified in serum of Apoe−/− mice by protein precipitation followed by reversed phase ultra-high-performance liquid chromatography and QTOF mass spectrometry. The mice were fed different lingonberry fractions (whole, insoluble and soluble) in a high-fat setting or cellulose in a high and low-fat setting. Serum concentrations of BAs in mice fed cellulose were higher with the high-fat diet compared to the low-fat diet (20–70%). Among the lingonberry diets, the diet containing whole lingonberries had the highest concentration of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA), tauro-ursodeoxycholic acid (T-UDCA), α and ω-muricholic acids (MCA) and tauro-α-MCA (T-α-MCA), and the lowest concentration of tauro-cholic acid (T-CA), deoxycholic acid (DCA) and tauro-deoxycholic acid (T-DCA). The glycine-conjugated BAs were very similar with all diets. CDCA, UDCA and α-MCA correlated positively with Bifidobacterium and Prevotella, and T-UDCA, T-α-MCA and ω-MCA with Bacteroides and Parabacteroides.
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Affiliation(s)
- Tannaz Ghaffarzadegan
- Food for Health Science Centre, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden. .,Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden.
| | - Sofia Essén
- Centre for Analysis and Synthesis, Department of Chemistry, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
| | - Phebe Verbrugghe
- Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
| | - Nittaya Marungruang
- Food for Health Science Centre, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden.,Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
| | - Frida Fåk Hållenius
- Food for Health Science Centre, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden.,Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
| | - Margareta Nyman
- Food for Health Science Centre, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden.,Food Technology, Engineering and Nutrition, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
| | - Margareta Sandahl
- Centre for Analysis and Synthesis, Department of Chemistry, Kemicentrum, Lund University, PO Box 124, SE-221 00, Lund, Sweden
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Momtazi-Borojeni AA, Katsiki N, Pirro M, Banach M, Rasadi KA, Sahebkar A. Dietary natural products as emerging lipoprotein(a)-lowering agents. J Cell Physiol 2019; 234:12581-12594. [PMID: 30637725 DOI: 10.1002/jcp.28134] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 12/07/2018] [Indexed: 12/13/2022]
Abstract
Elevated plasma lipoprotein(a) (Lp(a)) levels are associated with an increased risk of cardiovascular disease (CVD). Hitherto, niacin has been the drug of choice to reduce elevated Lp(a) levels in hyperlipidemic patients but its efficacy in reducing CVD outcomes has been seriously questioned by recent clinical trials. Additional drugs may reduce to some extent plasma Lp(a) levels but the lack of a specific therapeutic indication for Lp(a)-lowering limits profoundly reduce their use. An attractive therapeutic option is natural products. In several preclinical and clinical studies as well as meta-analyses, natural products, including l-carnitine, coenzyme Q 10 , and xuezhikang were shown to significantly decrease Lp(a) levels in patients with Lp(a) hyperlipoproteinemia. Other natural products, such as pectin, Ginkgo biloba, flaxseed, red wine, resveratrol and curcuminoids can also reduce elevated Lp(a) concentrations but to a lesser degree. In conclusion, aforementioned natural products may represent promising therapeutic agents for Lp(a) lowering.
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Affiliation(s)
- Amir Abbas Momtazi-Borojeni
- Department of Medical Biotechnology, Nanotechnology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Lodz, Poland.,Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Khalid Al Rasadi
- Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Study of the Treatment Effects of Compound Tufuling Granules in Hyperuricemic Rats Using Serum Metabolomics. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:3458185. [PMID: 30410553 PMCID: PMC6206513 DOI: 10.1155/2018/3458185] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 09/04/2018] [Accepted: 09/30/2018] [Indexed: 01/18/2023]
Abstract
The study aimed to investigate the mechanism of the effect of Compound Tufuling Granules (CTG) to lower the serum uric acid level in a rat model of hyperuricemia. The rat model was established by administering hypoxanthine through oral gavage and potassium oxonate through intraperitoneal injection. Rats were divided into the normal group, model group, CTG group, and allopurinol group. Serum uric acid, creatinine, urea nitrogen, and inflammatory cytokine levels were determined in each group. In the model group, ultrahigh performance liquid chromatography-mass spectrometry was used to analyze the metabolic profiles and delineate the action mechanism of CTG; in addition, the orthogonal projection method was used to perform latent structure-discrimination analysis to screen the related metabolites. The results indicated significant differences in the metabolic profiles between the model and normal groups. A total of seven related metabolites were identified through screening in the model group, mainly related to the pathways of bile secretion, pyrimidine, purine, and phenylalanine metabolism, pantothenate and CoA biosynthesis, and pentose and glucuronate interconversions; these related pathways were reversed in the CTG group. In the metabolic networks, uracil and acetyl-coenzyme A were the nodal molecules. In addition, the test results of the evaluation of serum biochemical and inflammatory factors confirmed that CTG had significant effect in reducing the levels of serum uric acid and protecting renal function. These results confirmed that CTG primarily regulated the recruitment of nodal molecules to achieve anti-inflammatory effects, reduced uric acid level, and renal protection.
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Al-Khaifi A, Rudling M, Angelin B. An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers. Gastroenterology 2018; 155:1012-1016. [PMID: 29928896 DOI: 10.1053/j.gastro.2018.06.038] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/12/2018] [Accepted: 06/13/2018] [Indexed: 01/07/2023]
Abstract
Bile acid (BA) synthesis is regulated through suppression of hepatic cholesterol 7α-hydroxylase via farnesoid X receptor (FXR) activation in hepatocytes and/or enterocytes; in enterocytes, this process requires FGF19 signaling. To study these pathways, we quantified markers of BA synthesis (7α-hydroxy-4-cholesten-3-one [C4]) and cholesterol production (lathosterol), fibroblast growth factor (FGF)19, and BAs in serum from healthy male volunteers given 1 oral dose of the nonsteroidal FXR agonist Px-102 (0.15 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.12 mg/kg, 2.25 mg/kg, 3.38 mg/kg, or 4.5 mg/kg). After 8 hours, serum levels of C4 decreased by 80% in volunteers given 0.15 mg/kg, whereas serum levels of FGF19 were unchanged. Serum levels of FGF19 increased significantly, in a dose-dependent manner, in volunteers given >0.3 mg/kg Px-102, up to as much as 1600%, whereas C4 levels remained significantly reduced (by >80%). For all doses, FGF19 levels returned to normal 24 hours after administration of Px-102. Serum levels of C4 decreased before levels of FGF19 levels increased, and were still reduced by 95% 24 hours after the highest dose (4.5 mg/kg) of Px-102, even though levels of FGF19 had returned to baseline. Our findings indicate that activation of hepatic FXR is able to suppress BA synthesis, independent of FGF19.
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Affiliation(s)
- Amani Al-Khaifi
- Metabolism Unit and Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Biochemistry, College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Mats Rudling
- Metabolism Unit and Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Bo Angelin
- Metabolism Unit and Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Abstract
Lipoprotein (a) is a low-density lipoprotein-like particle covalently bound to a glycoprotein called apolipoprotein(a) that is under potent genetic control. Plasma levels of lipoprotein (a) vary by up to 1000-fold among individuals, with 1 in 4 having levels that increase the risk of atherosclerotic cardiovascular disease. New evidence supports a causal role for lipoprotein (a) in atherosclerotic cardiovascular disease and aortic valve stenosis. Individuals with elevated lipoprotein (a) have a high life-time burden of atherosclerotic cardiovascular disease. This notion is important for coronary prevention. But is lipoprotein (a) ready for prime-time use in coronary prevention clinics?
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Affiliation(s)
- Katrina L Ellis
- School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; School of Biomedical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
| | - Gerald F Watts
- School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia; Department of Cardiology, Lipid Disorders Clinic, Royal Perth Hospital, GPO Box X2213, Perth, WA 6001, Australia.
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Malivindi R, Santoro M, De Rose D, Panza S, Gervasi S, Rago V, Aquila S. Activated-farnesoid X receptor (FXR) expressed in human sperm alters its fertilising ability. Reproduction 2018; 156:249-259. [DOI: 10.1530/rep-18-0203] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/18/2018] [Indexed: 12/12/2022]
Abstract
The farnesoid X receptor alpha (FXR) is a bile acid sensor activated by binding to endogenous bile acids including chenodeoxycholic acid (CDCA). Although, FXR is expressed in male reproductive tissue, the relevance of the receptor on reproduction is scarcely known. Here, we demonstrated the FXR presence and its action on several human sperm features. Western blot and immunofluorescence assays evidenced the FXR expression in human spermatozoa and the localisation in the middle piece. CDCA increasing concentrations and GW4064, synthetic ligand of FXR, were used to study the FXR influence on sperm motility, survival, capacitation, acrosome reaction and on glucose as well as lipid metabolism. Interestingly, our data showed that increasing concentrations of CDCA negatively affected sperm parameters, while the receptor blockage by (Z)-Guggulsterone and by the anti-FXR Ab reversed the effects. Intriguingly, elevated CDCA levels increased triglyceride content, while lipase and G6PDH activities were reduced with respect to untreated samples, thus impeding the metabolic reprogramming typical of the capacitated sperm. In conclusion, in this study, we demonstrated for the first time a novel target for FXR and that the activated receptor alters the acquisition of sperm fertilising ability. We showed that sperm itself express the FXR and it is responsive to specific ligands of the receptor; therefore, bile acids influence this cell both in male and in female genital tracts. It might be hypothesized that bile acid levels could be involved in infertility with idiopathic origin as these compounds are not systematically measured in men undergoing medically assisted procreation.
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Papazyan R, Liu X, Liu J, Dong B, Plummer EM, Lewis RD, Roth JD, Young MA. FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver. J Lipid Res 2018; 59:982-993. [PMID: 29559521 PMCID: PMC5983391 DOI: 10.1194/jlr.m081935] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 03/01/2018] [Indexed: 12/15/2022] Open
Abstract
Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.
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Affiliation(s)
| | - Xueqing Liu
- Intercept Pharmaceuticals, Inc., San Diego, CA 92121
| | - Jingwen Liu
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
| | - Bin Dong
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
| | | | | | | | - Mark A Young
- Intercept Pharmaceuticals, Inc., San Diego, CA 92121.
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Beukhof CM, Massolt ET, Visser TJ, Korevaar TIM, Medici M, de Herder WW, Roeters van Lennep JE, Mulder MT, de Rijke YB, Reiners C, Verburg FA, Peeters RP. Effects of Thyrotropin on Peripheral Thyroid Hormone Metabolism and Serum Lipids. Thyroid 2018; 28:168-174. [PMID: 29316865 DOI: 10.1089/thy.2017.0330] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.
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Affiliation(s)
- Carolien M Beukhof
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | - Elske T Massolt
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | - Theo J Visser
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | - Tim I M Korevaar
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | - Marco Medici
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | - Wouter W de Herder
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
| | | | - Monique T Mulder
- 2 Department of Vascular Medicine, University Medical Center , Rotterdam, The Netherlands
| | - Yolanda B de Rijke
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
- 3 Department of Clinical Chemistry, Erasmus MC, University Medical Center , Rotterdam, The Netherlands
| | - Christoph Reiners
- 4 Department of Nuclear Medicine, University Hospital Wuerzburg , Wuerzburg, Germany
| | - Frederik A Verburg
- 4 Department of Nuclear Medicine, University Hospital Wuerzburg , Wuerzburg, Germany
- 5 Department of Nuclear Medicine, University Hospital Marburg , Marburg, Germany
| | - Robin P Peeters
- 1 Department of Internal Medicine, Academic Center for Thyroid Diseases, University Medical Center , Rotterdam, The Netherlands
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