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Taylor R, Basaly V, Kong B, Yang I, Brinker AM, Capece G, Bhattacharya A, Henry ZR, Otersen K, Yang Z, Meadows V, Mera S, Joseph LB, Zhou P, Aleksunes LM, Roepke T, Buckley B, Guo GL. Effects of therapeutically approved individual bile acids on the development of metabolic dysfunction-associated steatohepatitis a low bile acid mouse model. Toxicol Sci 2024; 202:179-195. [PMID: 39302723 DOI: 10.1093/toxsci/kfae110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Abstract
Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet.
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Affiliation(s)
- Rulaiha Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Ill Yang
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Anita M Brinker
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Gina Capece
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Zakiyah R Henry
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Katherine Otersen
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Vik Meadows
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
| | - Stephanie Mera
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
| | - Laurie B Joseph
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Peihong Zhou
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Troy Roepke
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Brian Buckley
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
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Zhang L, Shi Y, Liang B, Li X. An overview of the cholesterol metabolism and its proinflammatory role in the development of MASLD. Hepatol Commun 2024; 8:e0434. [PMID: 38696365 PMCID: PMC11068152 DOI: 10.1097/hc9.0000000000000434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 03/05/2024] [Indexed: 05/04/2024] Open
Abstract
Cholesterol is an essential lipid molecule in mammalian cells. It is not only involved in the formation of cell membranes but also serves as a raw material for the synthesis of bile acids, vitamin D, and steroid hormones. Additionally, it acts as a covalent modifier of proteins and plays a crucial role in numerous life processes. Generally, the metabolic processes of cholesterol absorption, synthesis, conversion, and efflux are strictly regulated. Excessive accumulation of cholesterol in the body is a risk factor for metabolic diseases such as cardiovascular disease, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we first provide an overview of the discovery of cholesterol and the fundamental process of cholesterol metabolism. We then summarize the relationship between dietary cholesterol intake and the risk of developing MASLD, and also the animal models of MASLD specifically established with a cholesterol-containing diet. In the end, the role of cholesterol-induced inflammation in the initiation and development of MASLD is discussed.
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Affiliation(s)
- Linqiang Zhang
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Yongqiong Shi
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
| | - Bin Liang
- Center for Life Sciences, Yunnan Key Laboratory of Cell Metabolism and Diseases, School of Life Sciences, Yunnan University, Kunming, Yunnan, China
| | - Xi Li
- Institute of Life Sciences, School of Basic Medicine, Chongqing Medical University, Chongqing, China
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Novel Insights into Total Flavonoids of Rhizoma Drynariae against Meat Quality Deterioration Caused by Dietary Aflatoxin B1 Exposure in Chickens. Antioxidants (Basel) 2022; 12:antiox12010083. [PMID: 36670945 PMCID: PMC9854432 DOI: 10.3390/antiox12010083] [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: 10/31/2022] [Revised: 12/22/2022] [Accepted: 12/23/2022] [Indexed: 12/31/2022] Open
Abstract
Aflatoxin B1 (AFB1) is a group of highly toxic mycotoxins that are commonly found in human and animal foods and threaten animal and human food safety. Total flavonoids of Rhizoma Drynaria (TFRD), a traditional Chinese medicinal herb, exert multiple biological activities such as immunomodulatory, anti-inflammatory, and anti-oxidation effects. Here, a total of 160 healthy 21-day-old male broilers were randomly divided into four groups: the CON group, the TFRD group, the AFB1 group, and the AFB1 + TFRD group. The study found that AFB1 exposure altered the breast meat quality-related indicators, including meat sensory and physical indicators. Metabolomics analysis further showed that the change in meat quality was closely associated with significantly differential metabolites of breast muscle. Furthermore, spotlighted amino acid content contributes to changes in the secondary structure of the myofibrillar protein by Raman spectroscopy analysis, which was associated with the oxidative stress and inflammatory response in AFB1-exposed breast meat. Meanwhile, dietary 125 mg/kg TFRD supplementation could effectively restore the changes in breast meat quality. Taken together, these results by multi-technical analysis revealed that AFB1 exposure causes deterioration of chicken meat quality and that TFRD may be a potential herbal extract to antagonize mycotoxicity.
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Wang O, Zhang N, Han C, Huang J. Regular exercise combined with ferulic acid exhibits antiobesity effect and regulates metabolic profiles in high-fat diet-induced mice. Front Nutr 2022; 9:957321. [PMID: 35967808 PMCID: PMC9363793 DOI: 10.3389/fnut.2022.957321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/20/2022] [Indexed: 11/20/2022] Open
Abstract
Exercise (Ex) has been recognized as an effective way of obesity prevention, but it shows a dual effect on the body's antioxidant system. Ferulic acid (FA) is a kind of phenolic acid with well-known antioxidant capacity and numerous health benefits. Therefore, the aim of the study was to compare the antiobesity effect of Ex, FA, and Ex combined with FA (Ex-FA) in vivo and to illustrate the potential mechanisms. Mice were fed a high-fat diet (HFD) with or without administration of Ex, FA, and Ex-FA for 13 weeks. The body weight, antioxidant ability, Ex performance, and lipid profiles in the serum, liver, and skeletal muscle were compared among the groups, and serum metabolomics analysis was conducted. The results showed that Ex, FA, and Ex-FA exhibited a similar effect on body weight management. Ex had a more beneficial function by alleviating HFD-induced dyslipidemia than FA, while FA exerted a more efficient effect in mitigating lipid deposition in the liver and skeletal muscle. Ex-FA showed comprehensive effects in the regulation of the lipid contents in serum, liver, and skeletal muscle, and provoked enhancement effects on antioxidant ability and Ex capacity. Mice administered with Ex, FA, and Ex-FA showed different metabolic profiles, which might be achieved through different metabolic pathways. The findings of this research implied that Ex coupled with FA could become an effective and safe remedy for the management of dietary-induced obesity.
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Affiliation(s)
- Ou Wang
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China
- Key Laboratory of Trace Element Nutrition of National Health Commission of People's Republic of China, Beijing, China
| | - Nanhai Zhang
- Beijing Key Laboratory of Functional Food From Plant Resources, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Chao Han
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China
- Key Laboratory of Trace Element Nutrition of National Health Commission of People's Republic of China, Beijing, China
| | - Jian Huang
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, Beijing, China
- Key Laboratory of Trace Element Nutrition of National Health Commission of People's Republic of China, Beijing, China
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Abshirini M, Cabrera D, Fraser K, Siriarchavatana P, Wolber FM, Miller MR, Tian HS, Kruger MC. Mass Spectrometry-Based Metabolomic and Lipidomic Analysis of the Effect of High Fat/High Sugar Diet and Greenshell TM Mussel Feeding on Plasma of Ovariectomized Rats. Metabolites 2021; 11:metabo11110754. [PMID: 34822412 PMCID: PMC8622240 DOI: 10.3390/metabo11110754] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/24/2021] [Accepted: 10/27/2021] [Indexed: 12/05/2022] Open
Abstract
This study aimed to examine the changes in lipid and metabolite profiles of ovariectomized (OVX) rats with diet-induced metabolic syndrome-associated osteoarthritis (MetOA) after supplementation with greenshell mussel (GSM) using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach. Ninety-six rats were fed with one of four diets: control, control supplemented with GSM + GSM, high fat/high sugar (HFHS), or high fat/high sugar enriched with GSM (HFHS + GSM). After 8 weeks on experimental diets, half of the rats in each group underwent OVX and the other half were sham operated. After being fed for an additional 28 weeks, blood samples were collected for the metabolomics analysis. Lipid and polar metabolites were extracted from plasma and analysed by LC-MS. We identified 29 lipid species from four lipid subclasses (phosphatidylcholine, lysophosphatidylcholine, diacylglycerol, and triacylglycerol) and a set of eight metabolites involved in amino acid metabolism (serine, threonine, lysine, valine, histidine, pipecolic acid, 3-methylcytidine, and cholic acid) as potential biomarkers for the effect of HFHS diet and GSM supplementation. GSM incorporation more specifically in the control diet generated significant alterations in the levels of several lipids and metabolites. Further studies are required to validate these findings that identify potential biomarkers to follow OA progression and to monitor the impact of GSM supplementation.
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Affiliation(s)
- Maryam Abshirini
- School of Health Sciences, College of Health, Massey University, Palmerston North 4442, New Zealand;
| | - Diana Cabrera
- Food Chemistry and Structure, AgResearch Grasslands, Palmerston North 4442, New Zealand; (D.C.); (K.F.)
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
| | - Karl Fraser
- Food Chemistry and Structure, AgResearch Grasslands, Palmerston North 4442, New Zealand; (D.C.); (K.F.)
- High-Value Nutrition National Science Challenge, Auckland 1023, New Zealand
- Riddet Institute, Massey University, Palmerston North 4442, New Zealand
| | - Parkpoom Siriarchavatana
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (P.S.); (F.M.W.)
| | - Frances M. Wolber
- School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand; (P.S.); (F.M.W.)
- Centre for Metabolic Health Research, Massey University, Palmerston North 4442, New Zealand
| | | | | | - Marlena C. Kruger
- School of Health Sciences, College of Health, Massey University, Palmerston North 4442, New Zealand;
- Correspondence:
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Li W, Sun Z, Wu M, Deng Z, Zheng M, Kuang Z, Liu Y, He G. Deficiency of coiled-coil domain containing 80 increases plasma cholesterol by decreasing fecal sterols excretion in hypercholesterolemic mice. J Nutr Biochem 2021; 98:108868. [PMID: 34563664 DOI: 10.1016/j.jnutbio.2021.108868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 06/16/2021] [Accepted: 09/20/2021] [Indexed: 11/26/2022]
Abstract
Disorders in cholesterol and bile acid metabolism have been acknowledged as critical in pathogenesis of hypercholesterolemia. Coiled-coil domain containing 80 (CCDC80) has been closely linked to lipid homeostasis in mice, with its role in cholesterol metabolism yet to be fully elucidated. This study aims to uncover the regulatory mechanisms of CCDC80 in diet-induced hypercholesterolemia. We generated a CCDC80 knockout (CCDC80-/-) model in C57BL/6 mouse. The initial transcriptional and metabolic consequences of removing CCDC80 were accessed at baseline by gene expression microarrays and gas chromatography-mass spectrometry / ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, respectively. The hepatic cholesterol was investigated in both CCDC80+/+ and CCDC80-/- male mice at baseline and after feeding a high-cholesterol diet for 12 weeks. The regulatory effects of CCDC80 on gene expressions and protein masses were measured by RT-qPCR and western blot, respectively. At baseline, the KEGG pathway enrichment analysis combining metabolomics, lipidomics and transcriptomics, revealed a down-regulation of hepatic bile acid biosynthesis by CCDC80-knockout, especially for primary bile acids. In the hypercholesterolemic models, our results showed that deficiency of CCDC80 increased plasma and liver cholesterol levels, but decreased fecal neutral and acidic sterols excretion in mice. Mechanistically, we found that such effects were partly mediated by attenuating the alternative pathway of bile acid synthesis catalyzed by oxysterol 7-alpha-hydroxylase (CYP7B1). In conclusion, our results suggest CCDC80 as a novel modulator of cholesterol homeostasis in male mice. Deficiency of CCDC80 could further impair fecal sterols excretion in diet-induced hypercholesterolemia.
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Affiliation(s)
- Wenyun Li
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Zhuo Sun
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Min Wu
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Zequn Deng
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Mengman Zheng
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Zhichao Kuang
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Yuwei Liu
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
| | - Gengsheng He
- School of Public Health / Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
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Xu E, Wang B, Lu S, Zhang C, Zhu L, Liu X, Bai M, Li Y. Tandem mass tag-based quantitative proteomic analysis of the liver reveals potential protein targets of Xiaochaihutang in CUMS model of depression. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1181:122898. [PMID: 34479180 DOI: 10.1016/j.jchromb.2021.122898] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/06/2021] [Accepted: 08/11/2021] [Indexed: 10/20/2022]
Abstract
Depression is a global mental disorder disease and greatly threatened human health. Xiaochaihutang (XCHT) has been used successfully in treatment of depression for many years in China, but the mechanism is unclear. Using the chronic unpredictable mild stress (CUMS) mice model of depression, the present study aimed to reveal possible antidepressant mechanisms of XCHT from the perspective of liver by analyzing hepatic proteomics in mice. Bioinformatics analysis identified 31 differentially expressed proteins (DEPs), including 5 upregulated and 26 downregulated proteins, between the CUMS model and XCHT groups. The bile secretion pathway was found by KEGG pathway analysis of these DEPs. Four of the 31 differentially expressed proteins, including 2 active proteins involved in bile secretion, carbonic anhydrase 2 (CA2) and cystic fibrosis transmembrane conductance regulator (CFTR), were selected to verify their genes. Four genes (Cyp7a1, Fxr, Shp and Ntcp) related to bile acid synthesis and transport were further investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Both biochemical tests and gene studies demonstrated that CUMS affected bile acid synthesis and transport, while XCHT regulated this pathway. The results indicated that there may be a potential relationship between CUMS induced depression and hepatic injury caused by increased bile acid, and also provide a novel insight to understand the underlying anti-depression mechanisms of XCHT.
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Affiliation(s)
- Erping Xu
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China
| | - Baoying Wang
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China
| | - Shuaifei Lu
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China; School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Changjing Zhang
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China; School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Leilei Zhu
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China; School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Xueying Liu
- Basic Medical School, Henan University of Chinese Medicine, Zhengzhou, China
| | - Ming Bai
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China.
| | - Yucheng Li
- Henan Key Laboratory for Modern Research on Zhongjing's Herbal Formulae, Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, China.
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Asano T, Taki K, Kitamori K, Naito H, Nakajima T, Tsuchihashi H, Ishii A, Zaitsu K. One-Pot Extraction and Quantification Method for Bile Acids in the Rat Liver by Capillary Liquid Chromatography Tandem Mass Spectrometry. ACS OMEGA 2021; 6:8588-8597. [PMID: 33817519 PMCID: PMC8015121 DOI: 10.1021/acsomega.1c00403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/05/2021] [Indexed: 06/12/2023]
Abstract
We developed a highly sensitive method for quantifying 21 bile acids (BAs) in the rat liver by capillary liquid chromatography tandem mass spectrometry (cLC/MS/MS) with one-pot extraction. High recovery rates were obtained for the one-pot methods with either methanol (MeOH) extraction or MeOH/acetonitrile (ACN) (1:1, v/v) mixture extraction; the results obtained for the MeOH/ACN mixture solution were better than the results obtained for MeOH. Thus, we determined that the one-pot method with MeOH/ACN was the most suitable method for the efficient extraction of BAs in the liver. Targeted BAs were well separated by cLC with gradient elution using ammonium acetate (NH4OAc)-MeOH mobile phases. Method validation proved that the intra-day and inter-day accuracies and precisions were primarily less than ±20 and 20% relative standard deviation, respectively. Also, the limit of detection (LOD) and the limit of quantitation (LOQ) were 0.9-10 and 2.3-27 ng/g liver, which proves the high sensitivity of the method. Finally, we quantitated 21 BA concentrations in the liver samples of normal and nonalcoholic steatohepatitis (NASH) rats, both of which were derived from stroke-prone spontaneously hypertensive five (SHRSP5) /Dmcr rat. The hepatic BA profiles were found to be substantially different between the normal and NASH groups; the two groups were clearly separated along the first component axis in the score plots of the principal component analysis. In particular, 10 BAs (β-muricholic acid (MCA), glyco (G-) cholic acid (CA), G-chenodeoxycholic acid (CDCA), tauro (T-) CA, T-CDCA, T-ursodeoxycholic acid (UDCA), T-lithocholic acid (LCA), T-hiodeoxycholic acid (HDCA), T-α-MCA, and T-β-MCA) were significantly different between the two groups using Welch's t-test with the false discovery rate correction method, demonstrating BA disruption in the NASH model rat. In conclusion, this method was able to quantify 21 BAs in the rat liver and will evaluate the hepatic BA pathophysiology of rat disease models.
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Affiliation(s)
- Tomomi Asano
- Department
of Human Life and Environment, Kinjo Gakuin
University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan
- Department
of Legal Medicine & Bioethics, Nagoya
University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Kentaro Taki
- Department
of Legal Medicine & Bioethics, Nagoya
University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Kazuya Kitamori
- Department
of Human Life and Environment, Kinjo Gakuin
University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan
| | - Hisao Naito
- Department
of Human Life and Environment, Kinjo Gakuin
University, 2-1723 Omori, Moriyama-ku, Nagoya 463-8521, Japan
| | - Tamie Nakajima
- College
of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
| | - Hitoshi Tsuchihashi
- Department
of Legal Medicine & Bioethics, Nagoya
University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Akira Ishii
- Department
of Legal Medicine & Bioethics, Nagoya
University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Kei Zaitsu
- Department
of Legal Medicine & Bioethics, Nagoya
University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
- In
Vivo Real-time Omics Laboratory, Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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9
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Chandra A, Sharma K, Pratap K, Singh V, Saini N. Inhibition of microRNA-128-3p attenuates hypercholesterolemia in mouse model. Life Sci 2020; 264:118633. [PMID: 33190783 DOI: 10.1016/j.lfs.2020.118633] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/03/2020] [Accepted: 10/18/2020] [Indexed: 12/22/2022]
Abstract
AIMS Hypercholesterolemia remains a critical risk factor for cardiovascular diseases and there is an urgent need to develop effective alternative therapeutics. Herein, we investigated the effects of miR-128-3p inhibition on serum cholesterol levels using a hypercholesterolemic mouse model. MATERIALS AND METHODS Five injections of anti-miR-128-3p (AM-128) treatment were given, and the cholesterol profile in serum and liver was quantified. We validated the underlying gene network using qRT-PCR, western blotting, ELISA, and dual luciferase assays. KEY FINDINGS AM-128 treatment inhibits cholesterol biosynthesis by upregulating INSIG1 and downregulating HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) expression. The serum cholesterol clearance by SR-B1 (scavenger receptor class B member 1) and LDLR (low density lipoprotein receptors) was also increased. Furthermore, the catabolism of cholesterol by CYP7A1 (cytochrome P450 family 7 subfamily A member 1) was increased. SIGNIFICANCE Our results confirmed a critical role of miR-128-3p inhibition in lowering serum cholesterol and suggest its potential therapeutic implications in reversing hypercholesterolemia.
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Affiliation(s)
- Amit Chandra
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
| | - Kritika Sharma
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India
| | - Kunal Pratap
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India
| | - Vijaypal Singh
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India
| | - Neeru Saini
- CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India.
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10
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Mohanty SK, Lobeck I, Donnelly B, Dupree P, Walther A, Mowery S, Coots A, Bondoc A, Sheridan RM, Poling HM, Temple H, McNeal M, Sestak K, Bansal R, Tiao G. Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia. Hepatology 2020; 71:1316-1330. [PMID: 31442322 PMCID: PMC7384231 DOI: 10.1002/hep.30907] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 08/15/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. APPROACH AND RESULTS In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV-infected pups succumb by day of life 14. Thus, in this study we generated an RRV-TUCH rotavirus reassortant (designated as TR(VP2,VP4) ) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. CONCLUSIONS This model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.
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Affiliation(s)
- Sujit K. Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Inna Lobeck
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Phylicia Dupree
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Ashley Walther
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Sarah Mowery
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Abigail Coots
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Alexander Bondoc
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Rachel M. Sheridan
- Division of Pathology and Laboratory MedicineCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Holly M. Poling
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Haley Temple
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Monica McNeal
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOH,Division of Infectious DiseasesCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Karol Sestak
- Tulane National Primate Research CenterCovingtonLA
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical CentreUniversity of TwenteEnschedethe Netherlands
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
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11
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High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver. Sci Rep 2019; 9:12514. [PMID: 31467308 PMCID: PMC6715744 DOI: 10.1038/s41598-019-48973-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 08/14/2019] [Indexed: 12/19/2022] Open
Abstract
Precise molecular pathways involved in the progression of non-alcoholic steatohepatitis (NASH) remain to be elucidated. As Mallory–Denk bodies were occasionally observed in the enlarged hepatocytes in NASH model rat (SHRSP5/Dmcr) fed high-fat and high-cholesterol (HFC) diet, we aimed to clarify the roles of autophagy and endoplasmic reticulum (ER) stress in NASH progression. Male SHRSP5/Dmcr were randomly divided into 4 groups. Two groups were fed a control diet; the other two groups were fed a HFC diet for 2 and 8 weeks, respectively. The HFC diet increased the autophagy-related proteins levels and microtubule-associated protein 1 light chain 3-II/I ratio after 2 and 8 weeks, respectively. However, regarding ER stress-related proteins, the HFC diet decreased the levels of phosphorylated (p-) inositol-requiring kinase-1 (p-IRE-1) and p-protein kinase RNA-like ER kinase after 2 weeks. Additionally, the HFC diet increased anti-ubiquitin-positive cells and the level of the autophagy substrate p62, suggesting that the HFC diet induced dysfunction in ubiquitin-dependent protein degradation pathways. In conclusion, the HFC diet arrested the autophagy process in the liver; this was particularly associated with decreases in p-IRE-1 expression.
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12
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Watanabe S, Kumazaki S, Yamamoto S, Sato I, Kitamori K, Mori M, Yamori Y, Hirohata S. Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model. Int J Exp Pathol 2019; 99:282-294. [PMID: 30680827 DOI: 10.1111/iep.12301] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 11/29/2018] [Accepted: 12/09/2018] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.
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Affiliation(s)
- Shogo Watanabe
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
| | - Shota Kumazaki
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
| | - Shusei Yamamoto
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
| | - Ikumi Sato
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
| | - Kazuya Kitamori
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Mari Mori
- Department of Health Management, School of Health Studies, Tokai University, Kanagawa, Japan
| | - Yukio Yamori
- Institute for World Health Development, Mukogawa Women's University, Hyogo, Japan
| | - Satoshi Hirohata
- Department of Medical Technology, Graduate School of Health Sciences, Okayama University, Okayama, Japan
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13
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Ying F, Cai Y, Wong HK, Chen XY, Huang IB, Vanhoutte PM, Xia Z, Xu A, Tang EHC. EP4 emerges as a novel regulator of bile acid synthesis and its activation protects against hypercholesterolemia. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:1029-1040. [DOI: 10.1016/j.bbalip.2018.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/16/2018] [Accepted: 06/03/2018] [Indexed: 12/17/2022]
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14
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Yetti H, Naito H, Yuan Y, Jia X, Hayashi Y, Tamada H, Kitamori K, Ikeda K, Yamori Y, Nakajima T. Bile acid detoxifying enzymes limit susceptibility to liver fibrosis in female SHRSP5/Dmcr rats fed with a high-fat-cholesterol diet. PLoS One 2018; 13:e0192863. [PMID: 29438418 PMCID: PMC5811017 DOI: 10.1371/journal.pone.0192863] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 01/31/2018] [Indexed: 02/07/2023] Open
Abstract
During middle age, women are less susceptible to nonalcoholic steatohepatitis (NASH) than men. Thus, we investigated the underlying molecular mechanisms behind these sexual differences using an established rat model of NASH. Mature female and male stroke-prone spontaneously hypertensive 5/Dmcr rats were fed control or high-fat-cholesterol (HFC) diets for 2, 8, and 14 weeks. Although HFC-induced hepatic fibrosis was markedly less severe in females than in males, only minor gender differences were observed in expression levels of cytochrome P450 enzymes (CYP)7A1, CYP8B1 CYP27A1, and CYP7B1, and multidrug resistance-associated protein 3, and bile salt export pump, which are involved in fibrosis-related bile acid (BA) kinetics. However, the BA detoxification-related enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) 2A1, and the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), were strongly suppressed in HFC-fed males, and were only slightly changed in HFC-diet fed females. Expression levels of the farnesoid X receptor and its small heterodimer partner were similarly regulated in a gender-dependent fashion following HFC feeding. Hence, the pronounced female resistance to HFC-induced liver damage likely reflects sustained expression of the nuclear receptors CAR and PXR and the BA detoxification enzymes UGT and SULT.
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MESH Headings
- Animals
- Bile Acids and Salts/metabolism
- Cholesterol, Dietary/administration & dosage
- Cholesterol, Dietary/adverse effects
- Constitutive Androstane Receptor
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Disease Susceptibility
- Female
- Gene Expression
- Glucuronosyltransferase/metabolism
- Liver Cirrhosis/etiology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Male
- Non-alcoholic Fatty Liver Disease/etiology
- Non-alcoholic Fatty Liver Disease/metabolism
- Non-alcoholic Fatty Liver Disease/pathology
- Pregnane X Receptor
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Rats, Inbred SHR
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, Steroid/genetics
- Receptors, Steroid/metabolism
- Sex Characteristics
- Sulfotransferases/metabolism
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Affiliation(s)
- Husna Yetti
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Toyoake, Japan
| | - Yuan Yuan
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
| | - Xiaofang Jia
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yumi Hayashi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hazuki Tamada
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuya Kitamori
- College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Katsumi Ikeda
- School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, Nishinomiya, Japan
| | - Yukio Yamori
- Institute for World Health Development, Mukogawa Women’s University, Nishinomiya, Japan
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, Kasugai, Japan
- * E-mail:
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15
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Lee EA, Lee DI, Kim HY, Ahn SH, Seong HR, Jung WH, Kim KY, Kim S, Rhee SD. Cyp7a1 is continuously increased with disrupted Fxr-mediated feedback inhibition in hypercholesterolemic TALLYHO/Jng mice. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863:20-25. [DOI: 10.1016/j.bbalip.2017.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/18/2017] [Accepted: 08/22/2017] [Indexed: 10/19/2022]
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16
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Jia HM, Yu M, Ma LY, Zhang HW, Zou ZM. Chaihu-Shu-Gan-San regulates phospholipids and bile acid metabolism against hepatic injury induced by chronic unpredictable stress in rat. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1064:14-21. [DOI: 10.1016/j.jchromb.2017.08.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/25/2017] [Accepted: 08/02/2017] [Indexed: 01/12/2023]
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17
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Yuan Y, Naito H, Jia X, Kitamori K, Nakajima T. Combination of Hypertension Along with a High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways. Nutrients 2017; 9:nu9091018. [PMID: 28906458 PMCID: PMC5622778 DOI: 10.3390/nu9091018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 08/29/2017] [Accepted: 09/11/2017] [Indexed: 02/07/2023] Open
Abstract
Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. An increased activation of proinflammatory signaling (transforming growth factor-β1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH.
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Affiliation(s)
- Yuan Yuan
- College of Life and Health Sciences, Chubu University, 487-8501 Kasugai, Japan.
| | - Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, 470-1192 Toyoake, Japan.
| | - Xiaofang Jia
- National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 100050 Beijing, China.
| | - Kazuya Kitamori
- College of Human Life and Environment, Kinjo Gakuin University, 463-8521 Nagoya, Japan.
| | - Tamie Nakajima
- College of Life and Health Sciences, Chubu University, 487-8501 Kasugai, Japan.
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18
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Yang N, Sun R, Liao X, Aa J, Wang G. UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine. Pharmacol Res 2017; 121:169-183. [PMID: 28479371 DOI: 10.1016/j.phrs.2017.05.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Abstract
UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating their clearance. The UGTs belong to a superfamily that consists of diverse isoforms possessing distinct but overlapping metabolic activity. The abnormality or deficiency of UGTs in vivo is highly associated with some diseases, efficacy and toxicity of drugs, and precisely therapeutic personality. Despite the great effects and fruitful results achieved, to date, the expression and functions of individual UGTs have not been well clarified, the inconsistency of UGTs is often observed in human and experimental animals, and the complex regulation factors affecting UGTs have not been systematically summarized. This article gives an overview of updated reports on UGTs involving the various regulatory factors in terms of the genetic, environmental, pathological, and physiological effects on the functioning of individual UGTs, in turn, the dysfunction of UGTs induced disease risk and endo- or xenobiotic metabolism-related toxicity. The complex cross-talk effect of UGTs with internal homeostasis is systematically summarized and discussed in detail, which would be of great importance for personalized precision medicine.
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Affiliation(s)
- Na Yang
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Runbin Sun
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoying Liao
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Jiye Aa
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
| | - Guangji Wang
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
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19
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Dietrich CG, Rau M, Jahn D, Geier A. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease. Expert Opin Drug Metab Toxicol 2017; 13:625-640. [PMID: 28359183 DOI: 10.1080/17425255.2017.1314461] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.
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Affiliation(s)
- Christoph G Dietrich
- a Bethlehem Center of Health , Department of Medicine , Stolberg/Rhineland , Germany
| | - Monika Rau
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Daniel Jahn
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
| | - Andreas Geier
- b Division of Hepatology, Department of Medicine II , University of Würzburg , Würzburg , Germany
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20
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Both cholestatic and steatotic drugs trigger extensive alterations in the mRNA level of biliary transporters in rat hepatocytes: Application to develop new predictive biomarkers for early drug development. Toxicol Lett 2016; 263:58-67. [DOI: 10.1016/j.toxlet.2016.10.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 10/11/2016] [Accepted: 10/14/2016] [Indexed: 01/29/2023]
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21
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A diet-induced Sprague-Dawley rat model of nonalcoholic steatohepatitis-related cirrhosis. J Nutr Biochem 2016; 40:62-69. [PMID: 27863346 DOI: 10.1016/j.jnutbio.2016.10.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/03/2016] [Accepted: 10/15/2016] [Indexed: 12/12/2022]
Abstract
Certain modified diets containing saturated fatty acids, cholesterol or fructose lead to the development of nonalcoholic steatohepatitis (NASH)-related fibrosis in rodents; however, progression to cirrhosis is rare. Experimental liver cirrhosis models have relied on genetic manipulation or administration of hepatotoxins. This study aimed to establish a reliable dietary model of NASH-related cirrhosis in a relatively short period. Male Sprague-Dawley rats (9 weeks of age) were randomly assigned to normal, high-fat (HF), or two types (1.25% or 2.5% cholesterol) of high-fat and high-cholesterol (HFC) diets for 18 weeks. All HFC diets contained 2% cholic acid by weight. Histopathological analysis revealed that the HFC diets induced obvious hepatic steatosis, inflammation with hepatocyte ballooning and advanced fibrosis (stage 3-4) in all 12 rats at 27 weeks of age. In contrast, all five rats given the HF diet developed mild steatosis and inflammation without fibrosis. The amount of cholesterol in the liver and hepatocellular mitochondrial and microsomal fractions was significantly higher in rats fed the HFC diets than the normal or HF diets. The HFC diets significantly suppressed mRNA levels of microsomal triglyceride transfer protein, adenosine triphosphate binding cassette transporter G5, bile acid CoA: amino acid N-acyltransferase and bile salt export pump, as well as the enzymatic activity of carnitine palmitoyltransferase in the liver. In conclusion, the HFC diets induced liver cirrhosis in conjunction with hepatic features of NASH in Sprague-Dawley rats within 18 weeks, and altered gene expression and enzyme activity to accumulate lipid and bile acid in the liver.
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22
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Nakajima T, Naito H. [Mechanism Analysis and Prevention of Pathogenesis of Nonalcoholic Steatohepatitis]. Nihon Eiseigaku Zasshi 2016; 70:197-204. [PMID: 26411937 DOI: 10.1265/jjh.70.197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common disease in humans having a broad spectrum of liver histology from simple fatty liver to mixed inflammatory cell infiltration and fibrosis (nonalcoholic steatohepatitis, NASH), which is a more severe and progressing form. NASH/NAFLD is significantly associated with lifestyle such as diet and exercise, obesity, insulin resistance, type 2 diabetes, dyslipidemia and hypertension. Age and gender are also associated with the development. On the other hand, NAFLD has been found in a high percentage of nonobese individuals in the Asia-Pacific area. Some characteristic animal models of NAFLD/NASH have been developed to clarify the pathogenesis of human NAFLD/NASH. We have recently developed a novel NASH rat model (stroke-prone spontaneously hypertensive rats, SHRSP5/Dmcr), which showed hepatic steatosis and inflammation at 2 weeks, ballooning, macrovesicular steatosis and fibrosis at 8 weeks, and bridging fibrosis at 14 weeks by feeding of high-fat and -cholesterol (HFC) diet alone. This animal model does not have obesity, insulin resistance or diabetes. Therefore, this may be an excellent animal model of human NASH/NAFLD without obesity and diabetes. Sex and strain differences observed in fibrogenesis by the HFC diet in SHRSP5/Dmcr may be associated with the sensitivity to detoxification enzymes in the liver, because the levels of UGP-glucuronosyltransferase and sulfotransferase and their regulating nuclear receptors only decreased in male SHRSP5/Dmcr rats, but not in female and SHRSP rats. This suggests the importance of phase II reactions of drug-metabolizing enzymes in NASH progression. Importantly, SHRSP5/Dmcr rats are spontaneously hypertensive; therefore, when we use the original strain Wistar Kyoto, which has normal blood pressure, the involvement of blood pressure in the development of human NASH/NAFLD may also be clarified.
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23
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Naito H, Jia X, Yetti H, Yanagiba Y, Tamada H, Kitamori K, Hayashi Y, Wang D, Kato M, Ishii A, Nakajima T. Importance of detoxifying enzymes in differentiating fibrotic development between SHRSP5/Dmcr and SHRSP rats. Environ Health Prev Med 2016; 21:368-381. [PMID: 27209494 DOI: 10.1007/s12199-016-0539-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 05/09/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES High-fat and -cholesterol diet (HFC) induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive rat (SHRSP) 5/Dmcr, the fifth substrain from SHRSP, by dysregulating bile acid (BA) kinetics. This study aimed to clarify the histopathological and BA kinetic differences in HFC-induced fibrosis between SHRSP5/Dmcr and SHRSP. METHODS Ten-week-old male SHRSP5/Dmcr and SHRSP were randomly allocated to groups and fed with either control diet or HFC for 2 and 8 weeks. The liver histopathology, biochemical features, and molecular signaling involved in BA kinetics were measured. RESULTS HFC caused more severe hepatocyte ballooning, macrovesicular steatosis and fibrosis in SHRSP5/Dmcr than in SHRSP. It was noted that fibrosis was disproportionately formed in retroperitoneal side of both strains. As for BA kinetics, HFC greatly increased the level of Cyp7a1 and Cyp7b1 to the same degree in both strains at 8 weeks, while multidrug resistance-associated protein 3 was greater in SHRSP5/Dmcr than SHRSP. The diet decreased the level of bile salt export pump by the same degree in both strains, while constitutive androstane receptor, pregnane X receptor, and UDP-glucuronosyltransferase activity more prominent in SHRSP5/Dmcr than SHRSP at 8 weeks. In the fibrosis-related genes, only expression of collagen, type I, alpha 1 mRNA was greater in SHRSP5/Dmcr than SHRSP. CONCLUSIONS The greater progression of fibrosis in SHRSP5/Dmcr induced by HFC may be due to greater suppression of UDP-glucuronosyltransferase activity detoxifying toxicants, such as hydrophobic BAs.
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Affiliation(s)
- Hisao Naito
- Department of Public Health, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukake-cho, Toyoake, 470-1192, Japan. .,Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Xiaofang Jia
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Husna Yetti
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukie Yanagiba
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hazuki Tamada
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Kazuya Kitamori
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Human Life and Environment, Kinjo Gakuin University, Nagoya, Japan
| | - Yumi Hayashi
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dong Wang
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masashi Kato
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Ishii
- Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tamie Nakajima
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.,College of Life and Health Sciences, Chubu University, Kasugai, Japan
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24
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Dietrich CG, Götze O, Geier A. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance. World J Gastroenterol 2016; 22:72-88. [PMID: 26755861 PMCID: PMC4698509 DOI: 10.3748/wjg.v22.i1.72] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 09/24/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.
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25
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Ferslew BC, Xie G, Johnston CK, Su M, Stewart PW, Jia W, Brouwer KLR, Barritt AS. Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis. Dig Dis Sci 2015; 60:3318-3328. [PMID: 26138654 PMCID: PMC4864493 DOI: 10.1007/s10620-015-3776-8] [Citation(s) in RCA: 266] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 06/17/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. METHODS Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial time points following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. RESULTS Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH 2595-3549 µM and healthy 1171-1458 µM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH 4444-5898 µM and healthy 2634-2829 µM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. CONCLUSIONS Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.
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Affiliation(s)
- Brian C Ferslew
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA.
- Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., 901 Gateway Blvd, South San Francisco, CA, 94080, USA.
| | - Guoxiang Xie
- Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
| | - Curtis K Johnston
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA.
| | - Mingming Su
- Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
| | - Paul W Stewart
- Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 3105G McGavran-Greenberg Hall, Chapel Hill, NC, 27599, USA.
| | - Wei Jia
- Metabolomics Shared Resource, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Kerr Hall, CB #7569, Chapel Hill, NC, 27599, USA.
| | - A Sidney Barritt
- Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina at Chapel Hill, 8004 Burnett Womack, CB #7584, Chapel Hill, NC, 27599-7584, USA.
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26
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Xu JY, Li ZP, Zhang L, Ji G. Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20:13493-13500. [PMID: 25309079 PMCID: PMC4188900 DOI: 10.3748/wjg.v20.i37.13493] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Revised: 05/22/2014] [Accepted: 06/25/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor (FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.
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27
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Oostindjer M, Alexander J, Amdam GV, Andersen G, Bryan NS, Chen D, Corpet DE, De Smet S, Dragsted LO, Haug A, Karlsson AH, Kleter G, de Kok TM, Kulseng B, Milkowski AL, Martin RJ, Pajari AM, Paulsen JE, Pickova J, Rudi K, Sødring M, Weed DL, Egelandsdal B. The role of red and processed meat in colorectal cancer development: a perspective. Meat Sci 2014; 97:583-96. [DOI: 10.1016/j.meatsci.2014.02.011] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/14/2014] [Accepted: 02/17/2014] [Indexed: 02/07/2023]
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28
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Jia X, Suzuki Y, Naito H, Yetti H, Kitamori K, Hayashi Y, Kaneko R, Nomura M, Yamori Y, Zaitsu K, Kato M, Ishii A, Nakajima T. A possible role of chenodeoxycholic acid and glycine-conjugated bile acids in fibrotic steatohepatitis in a dietary rat model. Dig Dis Sci 2014; 59:1490-501. [PMID: 24448653 DOI: 10.1007/s10620-014-3028-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 01/03/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Our previous study indicated that hepatic bile acids (BAs) may have deposited and stimulated the pathogenesis of a high fat-cholesterol (HFC) diet-induced fibrotic steatohepatitis in stroke-prone spontaneously hypertensive 5/Dmcr rats, based on dysregulated BA homeostasis pathways. We aimed to further characterize BA profiles in liver and evaluate their relationships to liver injury using this model. METHODS Hepatic 21 BA levels were determined by ultra-performance liquid chromatography-tandem mass spectrometry, and their correlations with macrovesicular steatosis score, serum alanine aminotransferase (ALT) level and quantified fibrotic area were assessed using Spearman and Pearson correlations. RESULTS Compared to control, BAs highly accumulated in HFC-fed rat liver at 2 weeks: cholic acid (CA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) were major species, thereafter, levels of CA and DCA declined, but CDCA species persistently increased, which induced a decrease in total CA/total CDCA ratio at 8 and 14 weeks. CDCA species positively, while total CA/total CDCA negatively, correlated with macrovesicular steatosis score, serum ALT and quantified fibrotic area. Unlike control, total ursodeoxycholic acid was minor in HFC-fed rat liver, and inversely correlated to aforementioned indicators of liver injury; total glyco-BAs, rather than tauro-BAs, were predominant in HFC-fed rat liver, and positively correlated with macrovesicular steatosis score. Moreover, its ratio to total tauro-BAs positively correlated with each parameter of liver injury, while inverse associations were detected for total tauro-BAs. CONCLUSIONS Hepatic BA accumulation may potentiate liver disease. CDCA and glyco-BAs play a more important role in the pathogenesis of fibrotic steatohepatitis.
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Affiliation(s)
- Xiaofang Jia
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 380] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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