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Capinha F, Carvalhana S, Cortez-Pinto H. Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors. Dig Dis Sci 2025:10.1007/s10620-025-08912-4. [PMID: 40025309 DOI: 10.1007/s10620-025-08912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.
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Affiliation(s)
- Francisco Capinha
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal.
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Wang Z, Gao P, Gao J, Liang B, Ma Q, Sun Q, Hu Y, Wang Y, Peng Y, Liu H, Wu Y, Yi T, Liu J, Qu LN, Guo H, Shi L, Long J. Daphnetin ameliorates hepatic steatosis by suppressing peroxisome proliferator-activated receptor gamma (PPARG) in ob/ob mice. Biochem Pharmacol 2024; 230:116610. [PMID: 39510197 DOI: 10.1016/j.bcp.2024.116610] [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: 07/02/2024] [Revised: 09/29/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.
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Affiliation(s)
- Zhen Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Peipei Gao
- Department of Health Education and Management and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710000, PR China
| | - Jing Gao
- College of Sports and Health Science, Xi'an Physical Education University, Xi'an 710068, PR China
| | - Bing Liang
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, PR China
| | - Qingqing Ma
- Guizhou Aerospace Hospital, Zunyi 563099, PR China
| | - Qiong Sun
- Yulin Hospital, First Affiliated Hospital of Xi'an Jiao Tong University, Yulin 718000, PR China
| | - Yachong Hu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Yan Wang
- Department of Stem Cell and Regenerative Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, PR China
| | - Yunhua Peng
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Huadong Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Yuan Wu
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China
| | - Tao Yi
- Faculty of Health Sciences and Sports, Macao Polytechnic University, Macau 999078, PR China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China; School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, PR China
| | - Li-Na Qu
- Department of Cellular and Molecular Biology, State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, PR China
| | - Hui Guo
- Department of Endocrinology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710000, PR China.
| | - Le Shi
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science, Xi'an Jiaotong University, Xi'an 710049, PR China.
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Sun M, Zhang Y, Guo A, Xia Z, Peng L. Progress in the Correlation Between Inflammasome NLRP3 and Liver Fibrosis. J Clin Transl Hepatol 2024; 12:191-200. [PMID: 38343611 PMCID: PMC10851067 DOI: 10.14218/jcth.2023.00231] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 09/02/2023] [Accepted: 09/13/2023] [Indexed: 01/04/2025] Open
Abstract
Liver fibrosis is a reversible condition that occurs in the early stages of chronic liver disease. To develop effective treatments for liver fibrosis, understanding the underlying mechanism is crucial. The NOD-like receptor protein 3 (NLRP3) inflammasome, which is a part of the innate immune system, plays a crucial role in the progression of various inflammatory diseases. NLRP3 activation is also important in the development of various liver diseases, including viral hepatitis, alcoholic or nonalcoholic liver disease, and autoimmune liver disease. This review discusses the role of NLRP3 and its associated molecules in the development of liver fibrosis. It also highlights the signal pathways involved in NLRP3 activation, their downstream effects on liver disease progression, and potential therapeutic targets in liver fibrosis. Further research is encouraged to develop effective treatments for liver fibrosis.
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Affiliation(s)
- Meihua Sun
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Yanqing Zhang
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Anbing Guo
- Department of Gastroenterology, Linyi People’s Hospital, Linyi, Shandong, China
| | - Zongting Xia
- School of Clinical Medicine, Weifang Medical University, Weifang, Shandong, China
| | - Lijun Peng
- Department of Gastroenterology, Linyi People’s Hospital, Linyi, Shandong, China
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Khan MQ, Hassan S, Lizaola-Mayo BC, Bhat M, Watt KD. Navigating the "specific etiology" steatohepatitis category: Evaluation and management of nonalcoholic/nonmetabolic dysfunction-associated steatohepatitis. Hepatology 2023:01515467-990000000-00637. [PMID: 37939197 DOI: 10.1097/hep.0000000000000674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/26/2023] [Indexed: 11/10/2023]
Affiliation(s)
- Mohammad Qasim Khan
- Department of Internal Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada
| | - Sara Hassan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Blanca C Lizaola-Mayo
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - Mamatha Bhat
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| | - Kymberly D Watt
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Cheng Y, Zhang Q, Li H, Zhou G, Shi P, Zhang X, Guan L, Yan F, Xu C. Remnant cholesterol, stronger than triglycerides, is associated with incident non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1098078. [PMID: 37214248 PMCID: PMC10198261 DOI: 10.3389/fendo.2023.1098078] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/23/2023] [Indexed: 05/24/2023] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals. Methods All subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status. Results In multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p<0.001), high-density lipoprotein cholesterol (HDL-C) (HR, 95% CI: 0.571,0.487-0.670; p<0.001), and remnant-C (HR, 95% CI: 1.143,1.052-1.242; p=0.002), but not total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C), were associated with incident NAFLD. Atherogenic dyslipidemia (triglycerides>1.69 mmol/L, HDL-C<1.03 mmol/L in men or<1.29 mmol/L in women) was also associated with NAFLD (HR, 95% CI: 1.343,1.177-1.533; p<0.001). Remnant-C levels were higher in females than in males and increased with increasing BMI and in participants with diabetes and CVD compared with those without diabetes or CVD. After adjusting for other factors in the Cox regression models, we found that serum levels of TG and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes in women group, non-cardiovascular disease status, non-diabetes status and middle BMI categories (24 to 28 kg/m2). Discussion In the middle aged and elderly subset of the Chinese population, especially those who were women, non-CVD status, non-diabetes status and middle BMI status (24 to 28 kg/m2), levels of triglycerides and remnant-C, but not TC or LDL-C, were associated with NAFLD outcomes independent of other risk factors.
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Affiliation(s)
- Yiping Cheng
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Qiang Zhang
- Department of Critical Care Medicine, Zibo Central Hospital, Zibo, Shandong, China
| | - Haizhen Li
- Department of Endocrinology, Dongying City District People Hospital, Dongying, Shandong, China
| | - Guangshuai Zhou
- Department of Scientific Research and Cooperation, Zibo Central Hospital, Zibo, Shandong, China
| | - Ping Shi
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Xu Zhang
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Liying Guan
- Department of Health Examination Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Fang Yan
- Department of Pain Management, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Chao Xu
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
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Tan LJ, Shin S. Effects of oily fish and its fatty acid intake on non-alcoholic fatty liver disease development among South Korean adults. Front Nutr 2022; 9:876909. [PMID: 35938102 PMCID: PMC9353947 DOI: 10.3389/fnut.2022.876909] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/28/2022] [Indexed: 12/02/2022] Open
Abstract
Background The benefits of fish fatty acid intake for non-alcoholic fatty liver disease (NAFLD) are rarely reported, although a previous study assessed the relationship between oily fish consumption and the prevalence of NAFLD. Aims We investigated whether oily fish and fish-based monounsaturated fatty acids, polyunsaturated fatty acids, and omega-3 fatty acids affect the development of NAFLD in South Korean adults. Methods In this large-scale cohort study, 44,139 participants of the Health Examinees study were selected for analysis after 5 years of follow-up. NAFLD is diagnosed with a non-invasive index, the fatty liver index. Using multivariable Cox proportional hazards models, adjusted for age, body mass index, total energy intake, education, physical activity, smoking status, and drinking (alcohol) status, we calculated the hazard ratios and 95% confidence intervals. Results For men, NAFLD had no statistically significant associations with quartiles of total oily fish or its fatty acid intake. However, among women, an inverse association was observed (all p for trend <0.05). Regarding the standard deviation (SD) increment of total oily fish or its fatty acid intake by one, all fatty acids from oily fish showed inverse associations for NAFLD in both men and women. After stratified analyses, we found that drinking status and menopause status were independent risk factors for NAFLD. Oily fish or its fatty acid intake has the same benefit pattern on metabolic dysfunction-associated fatty liver disease as NAFLD. Conclusion Oily fish and its fatty acid intake showed a preventative benefit for NAFLD and metabolic dysfunction-associated fatty liver disease, especially in South Korean women.
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Chen X, Zhang L, Zheng L, Tuo B. Role of Ca 2+ channels in non-alcoholic fatty liver disease and their implications for therapeutic strategies (Review). Int J Mol Med 2022; 50:113. [PMID: 35796003 PMCID: PMC9282635 DOI: 10.3892/ijmm.2022.5169] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 06/07/2022] [Indexed: 01/10/2023] Open
Affiliation(s)
- Xingyue Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Liming Zheng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
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8
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Yu L, Hong W, Lu S, Li Y, Guan Y, Weng X, Feng Z. The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment. Front Pharmacol 2022; 13:780496. [PMID: 35350750 PMCID: PMC8957978 DOI: 10.3389/fphar.2022.780496] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent primary liver diseases worldwide and can develop into various conditions, ranging from simple steatosis, through non-alcoholic steatohepatitis (NASH), to fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Nevertheless, there is no effective treatment for NAFLD due to the complicated etiology. Recently, activation of the NLPR3 inflammasome has been demonstrated to be a contributing factor in the development of NAFLD, particularly as a modulator of progression from initial hepatic steatosis to NASH. NLRP3 inflammasome, as a caspase-1 activation platform, is critical for processing key pro-inflammatory cytokines and pyroptosis. Various stimuli involved in NAFLD can activate the NLRP3 inflammasome, depending on the diverse cellular stresses that they cause. NLRP3 inflammasome-related inhibitors and agents for NAFLD treatment have been tested and demonstrated positive effects in experimental models. Meanwhile, some drugs have been applied in clinical studies, supporting this therapeutic approach. In this review, we discuss the activation, biological functions, and treatment targeting the NLRP3 inflammasome in the context of NAFLD progression. Specifically, we focus on the different types of therapeutic agents that can inhibit the NLRP3 inflammasome and summarize their pharmacological effectiveness for NAFLD treatment.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China.,The Third Clinical College of Xinxiang Medical University, Xinxiang, China.,Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
| | - Wei Hong
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
| | - Shen Lu
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Yanrong Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
| | - Yaya Guan
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Xiaogang Weng
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China.,Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
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Petrtýl J, Dvořák K, Stříteský J, Leníček M, Jirásková A, Šmíd V, Haluzík M, Brůha R, Vítek L. Association of Serum Bilirubin and Functional Variants of Heme Oxygenase 1 and Bilirubin UDP-Glucuronosyl Transferase Genes in Czech Adult Patients with Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10122000. [PMID: 34943103 PMCID: PMC8698489 DOI: 10.3390/antiox10122000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 12/29/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients.
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Affiliation(s)
- Jaromír Petrtýl
- 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (J.P.); (K.D.); (V.Š.)
| | - Karel Dvořák
- 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (J.P.); (K.D.); (V.Š.)
| | - Jan Stříteský
- Institute of Pathology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic;
| | - Martin Leníček
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (M.L.); (A.J.); (M.H.)
| | - Alena Jirásková
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (M.L.); (A.J.); (M.H.)
| | - Václav Šmíd
- 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (J.P.); (K.D.); (V.Š.)
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (M.L.); (A.J.); (M.H.)
| | - Martin Haluzík
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (M.L.); (A.J.); (M.H.)
- Institute of Clinical and Experimental Medicine, 140 00 Prague, Czech Republic
| | - Radan Brůha
- 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (J.P.); (K.D.); (V.Š.)
- Correspondence: (R.B.); (L.V.); Tel.: +420-224-962-506 (R.B.); +420-224-964-203 (L.V.)
| | - Libor Vítek
- 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (J.P.); (K.D.); (V.Š.)
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic; (M.L.); (A.J.); (M.H.)
- Correspondence: (R.B.); (L.V.); Tel.: +420-224-962-506 (R.B.); +420-224-964-203 (L.V.)
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10
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Gadour E, Hassan Z, Gadour R. A Comprehensive Review of Transaminitis and Irritable Bowel Syndrome. Cureus 2021; 13:e16583. [PMID: 34322359 PMCID: PMC8300593 DOI: 10.7759/cureus.16583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
We observed in the literature that irritable bowel syndrome (IBS) may be linked to irregular parameters of the metabolic system (MS) and liver function. For that reason, we conducted this systematic review to comprehensively analyze the association of transaminitis (elevated alanine transaminase (ALT)) with IBS. This review was designed by following methods described in the Cochrane Handbook for Systematic Reviews of Interventions. Published peer-reviewed journal articles were included. Data were extracted based on study design, age, gender, author, date of publication or availability online, publication type, participants, gender (M/F), and types of IBS. Our electronic multiple databases yielded a total of 519 preliminary studies; we then removed duplicate studies and left with 326 studies. After reviewing the full text of these articles, a total of 83 studies were eliminated and lastly, three studies were selected for this systematic review for quantitative and qualitative analysis. All the enrolled subjects in included studies were diagnosed with IBS by the Rome II and III criteria and among these sub-jects, 50.4% had IBS-D, 13.8% had IBS-C, 30.3% had IBS-M, and 3.5% had IBS-U. The prevalence of elevated ALT with other liver enzymes (γ-GT levels and aspartate aminotransferase (AST)) in patients with irritable bowel syndrome whether their body mass index (BMI) was high or not (16.9% vs. 7.7%; p=0.015) and γ-GT (24.1% vs. 11.5%; p=0.037), Lee et al., 2016. The IBS-D subtype was seen more commonly in patients whose alcohol intake was significantly high however their study data showed no significant change in elevation of ALT. The upper limits normal values for serum liver enzymes were de-fined as 41 international per liter in males and 31 international units per liter in females for ALT. No significant relationships were observed between IBS status and elevated γ-GT (OR, 1.647; 95% CI, 0.784-3.461). The review study proposes a potential relation between elevated ALT levels, MS, and IBS, and this review might be the first review in IBS patients to observe the association of elevated ALT in the IBS population. Although further additional trials with a large sample size will be required to confirm these results. Furthermore, for assessing the efficacy of the manipulation of gut microbiota ran-domized controlled trials in a large population of IBS patients are needed to establish a causal-resultant relationship between IBS, MS, and liver damage.
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Affiliation(s)
- Eyad Gadour
- Gastroenterology and Hepatology, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, GBR
| | - Zeinab Hassan
- Department of Medicine, Stockport Hospital NHS Foundation Trust, Manchester, GBR
| | - Rajaey Gadour
- Responsible Medical Services, The National Ambulance, Abu Dhabi, ARE
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Wei R, Han C, Deng D, Ye F, Gan X, Liu H, Li L, Xu H, Wei S. Research progress into the physiological changes in metabolic pathways in waterfowl with hepatic steatosis. Br Poult Sci 2020; 62:118-124. [DOI: 10.1080/00071668.2020.1812527] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- R. Wei
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - C. Han
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - D. Deng
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - F. Ye
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - X. Gan
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - H. Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - L. Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - H. Xu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, P.R. China
| | - S. Wei
- College of Life Science, Sichuan Agricultural University, Ya’an, Sichuan, P.R. China
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12
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Huang Y, Qu H, Liu D, Wa Y, Sang J, Yin B, Chen D, Chen X, Gu R. The effect of Lactobacillus fermentum DALI02 in reducing the oxidative stress and inflammatory response induced by high-fat diet of rats. RSC Adv 2020; 10:34396-34402. [PMID: 35514407 PMCID: PMC9056810 DOI: 10.1039/d0ra05694d] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/21/2020] [Indexed: 11/21/2022] Open
Abstract
A long-term high-fat diet (HFD) leads to significant oxidative stress in the body and induces inflammation. A preliminary evidence suggests a potential therapeutic utility of probiotics for this condition. To evaluate the potential effect of Lactobacillus fermentum DALI02 on the oxidative stress and inflammatory damage induced by HFD, we used a hyperlipidemic rat as a model fed with HFD. Results revealed that HFD induced a significant oxidative stress and inflammation. However, results reveal that L. fermentum DALI02, manifested a significant decrease in levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and resistin, while the catalase (CAT), total antioxidant capability (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and adiponectin (ADPN) levels significantly increased. And it was dose-dependent that the effect of high dose groups with high viable count was particularly notable. The results suggest that L. fermentum DALI02 could alleviate oxidative stress and inflammation as it appeared to reduce lipid peroxidation and improved the lipid metabolism in vivo. A long-term high-fat diet (HFD) leads to significant oxidative stress in the body and induces inflammation.![]()
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Affiliation(s)
- Yujun Huang
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Hengxian Qu
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Dong Liu
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Yunchao Wa
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Jian Sang
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Boxin Yin
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Dawei Chen
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Xia Chen
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
| | - Ruixia Gu
- College of Food Science and Technology, Yangzhou University Yangzhou Jiangsu 225127 China .,Key Laboratory of Dairy Biotechnology and Safety Control Yangzhou Jiangsu 225127 China
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13
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Yang G, Jang JH, Kim SW, Han SH, Ma KH, Jang JK, Kang HC, Cho YY, Lee HS, Lee JY. Sweroside Prevents Non-Alcoholic Steatohepatitis by Suppressing Activation of the NLRP3 Inflammasome. Int J Mol Sci 2020; 21:ijms21082790. [PMID: 32316419 PMCID: PMC7216241 DOI: 10.3390/ijms21082790] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 04/15/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH), a type of non-alcoholic fatty liver disease, is characterized as steatosis and inflammation in the liver. NLRP3 inflammasome activation is associated with NASH pathology. We hypothesized that suppressing the NLRP3 inflammasome could be effective in preventing NASH. We searched substances that could inhibit the activation of the NLRP3 inflammasome and identified sweroside as an NLRP3 inhibitor. We investigated whether sweroside can be applied to prevent the pathological symptoms associated with NASH in a methionine–choline-deficient (MCD) diet-induced NASH mouse model. The activation of the NLRP3 inflammasome was determined by detecting the production of caspase-1 and IL-1β from pro-caspase-1 and pro-IL-1β in primary mouse macrophages and mouse liver. In a NASH model, mice were fed an MCD diet for two weeks with daily intraperitoneal injections of sweroside. Sweroside effectively inhibited NLRP3 inflammasome activation in primary macrophages as shown by a decrease in IL-1β and caspase-1 production. In a MCD diet-induced NASH mouse model, intraperitoneal injection of sweroside significantly reduced serum aspartate transaminase and alanine transaminase levels, hepatic immune cell infiltration, hepatic triglyceride accumulation, and liver fibrosis. The improvement of NASH symptoms by sweroside was accompanied with its inhibitory effects on the hepatic NLRP3 inflammasome as hepatic IL-1β and caspase-1 were decreased. Furthermore, sweroside blocked de novo synthesis of mitochondrial DNA in the liver, contributing to suppression of the NLRP3 inflammasome. These results suggest that targeting the NLRP3 inflammasome with sweroside could be beneficially employed to improve NASH symptoms.
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Affiliation(s)
- Gabsik Yang
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
- Department of Pharmacology, College of Korean Medicine, Woosuk University, Jeonbuk 55338, Korea
| | - Joo Hyeon Jang
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
| | - Sung Wook Kim
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
| | - Sin-Hee Han
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration, Eumsung 27709, Korea; (S.-H.H.); (K.-H.M.); (J.-K.J.)
| | - Kyung-Ho Ma
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration, Eumsung 27709, Korea; (S.-H.H.); (K.-H.M.); (J.-K.J.)
| | - Jae-Ki Jang
- Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Rural Development Administration, Eumsung 27709, Korea; (S.-H.H.); (K.-H.M.); (J.-K.J.)
| | - Han Chang Kang
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
| | - Yong-Yeon Cho
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
| | - Hye Suk Lee
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
| | - Joo Young Lee
- BK21plus Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; (G.Y.); (J.H.J.); (S.W.K.); (H.C.K.); (Y.-Y.C.); (H.S.L.)
- Correspondence: ; Tel.: +82-2-2164-4095; Fax: +82-2-2164-4059
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PTUPB ameliorates high-fat diet-induced non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in mice. Biochem Biophys Res Commun 2020; 523:1020-1026. [PMID: 31973813 DOI: 10.1016/j.bbrc.2019.12.131] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 12/31/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global adult population, and no effective pharmacological treatment has been found. Products of arachidonic acid metabolism have been developed into a novel therapy for metabolic syndrome and diabetes. It has been demonstrated that protective actions of a novel dual cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) inhibitor, PTUPB, on the metabolic abnormalities. Here, we investigated the effects of PTUPB on hepatic steatosis in high-fat diet (HFD)-induced obese mice, as well as in hepatocytes in vitro. We found that PTUPB treatment reduced body weight, liver weight, liver triglyceride and cholesterol content, and the expression of lipolytic/lipogenic and lipid uptake related genes (Acc, Cd36, and Cidec) in HFD mice. In addition, PTUPB treatment arrested fibrotic progression with a decrease of collagen deposition and expression of Col1a1, Col1a3, and α-SMA. In vitro, PTUPB decreased palmitic acid-induced lipid deposition and downregulation of lipolytic/lipogenic genes (Acc and Cd36) in hepatocytes. Additionally, we found that PTUPB reduced the production of pro-inflammatory cytokines and suppressed the NLRP3 inflammasome activation in HFD mice and hepatocytes. In conclusion, dual inhibition of COX-2/sEH attenuates hepatic steatosis by inhibiting the NLRP3 inflammasome activation. PTUPB might be a promising potential therapy for liver steatosis associated with obesity.
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15
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Liu T, Luo X, Li ZH, Wu JC, Luo SZ, Xu MY. Zinc-α2-glycoprotein 1 attenuates non-alcoholic fatty liver disease by negatively regulating tumour necrosis factor-α. World J Gastroenterol 2019; 25:5451-5468. [PMID: 31576092 PMCID: PMC6767980 DOI: 10.3748/wjg.v25.i36.5451] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/26/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Zinc-α2-glycoprotein 1 (AZGP1) plays important roles in metabolism-related diseases. The underlying molecular mechanisms and therapeutic effects of AZGP1 remain unknown in non-alcoholic fatty liver disease (NAFLD).
AIM To explore the effects and potential mechanism of AZGP1 on NAFLD in vivo and in vitro.
METHODS The expression of AZGP1 and its effects on hepatocytes were examined in NAFLD patients, CCl4-treated mice fed a high fat diet (HFD), and human LO2 cells.
RESULTS AZGP1 levels were significantly decreased in liver tissues of NAFLD patients and mice. AZGP1 knockdown was found to activate inflammation; enhance steatogenesis, including promoting lipogenesis [sterol regulatory element-binding protein (SREBP)-1c, liver X receptor (LXR), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl CoA desaturase 1 (SCD)-1], increasing lipid transport and accumulation [fatty acid transport protein (FATP), carnitine palmitoyl transferase (CPT)-1A, and adiponectin], and reducing fatty acid β-oxidation [farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR)-α]; accelerate proliferation; and reverse apoptosis in LO2 cells. AZGP1 overexpression (OV-AZGP1) had the opposite effects. Furthermore, AZGP1 alleviated NAFLD by blocking TNF-α-mediated inflammation and intracellular lipid deposition, promoting proliferation, and inhibiting apoptosis in LO2 cells. Finally, treatment with OV-AZGP1 plasmid dramatically improved liver injury and eliminated liver fat in NAFLD mice.
CONCLUSION AZGP1 attenuates NAFLD with regard to ameliorating inflammation, accelerating lipolysis, promoting proliferation, and reducing apoptosis by negatively regulating TNF-α. AZGP1 is suggested to be a novel promising therapeutic target for NAFLD.
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Affiliation(s)
- Ting Liu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Xin Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Zheng-Hong Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jun-Cheng Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Sheng-Zheng Luo
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Ming-Yi Xu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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16
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Metin NO, Karaosmanoğlu AD, Metin Y, Karçaaltıncaba M. Focal hypersteatosis: a pseudolesion in patients with liver steatosis. ACTA ACUST UNITED AC 2019; 25:14-20. [PMID: 30582571 DOI: 10.5152/dir.2018.17519] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We aimed to describe ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) findings of focal hypersteatosis (FHS). METHODS We retrospectively reviewed our database for patients with hypersteatosis. Over a 5-year period (February 2005 to September 2010) a total of 17 321 patients underwent abdominal CT scan and 28 patients were determined to have FHS. All patients had US, CT, and MRI studies. Size, area, and density measurements were performed on CT images. Fat signal percentage (FSP) was measured on T1-weighted in- and out-of-phase gradient-echo images. FHS was defined based on MRI findings, as an area of greater signal drop on out-of phase images compared with the rest of the fatty liver. RESULTS The period prevelance of focal hypersteatosis was measured as 0.16% over the 5-year period. Cancer was the most common diagnosis (22 of 28 patients, 78.5%), with the breast (32.1%) and colorectal (25%) cancers predominating. FHS was seen in segment 4 (n=26, 92.8%), segment 8 (n=1, 3.6%), and segment 3 (n=1, 3.6%). Shape was nodular in 21 patients (75%), while triangular or amorphous in the remaining 7 patients (25%). FHS was hyperechoic and isoechoic in 5 (17.9%) and 23 (82.1%) patients, respectively. FHS was hypodense on CT of all patients relative to fatty liver. On MRI, the FHS was hyperintense on T1-weighted in-phase images in 17 patients (60.7%). Median liver parenchymal FSP was 21.5% (range, 10%-41.4%) and median FSP of hypersteatotic area was 32.5% (range, 19%-45%). CONCLUSION Focal hypersteatosis is a pseudolesion that can be observed in patients with liver steatosis. It appears hypodense on CT and mostly isoechoic on US relative to fatty liver. It may mimic metastasis in cancer patients with steatosis, due to nodular shape and atypical location. MRI should be used for correct diagnosis in patients with equivocal findings on CT to avoid biopsy.
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Affiliation(s)
- Nurgül Orhan Metin
- Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey
| | | | - Yavuz Metin
- Department of Radiology, Hacettepe University School of Medicine, Ankara, Turkey
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17
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Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019; 76:99-128. [PMID: 30343320 PMCID: PMC11105781 DOI: 10.1007/s00018-018-2947-0] [Citation(s) in RCA: 400] [Impact Index Per Article: 66.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a main hepatic manifestation of metabolic syndrome. It represents a wide spectrum of histopathological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis and, eventually, cirrhosis and hepatocellular carcinoma. While hepatic simple steatosis seems to be a rather benign manifestation of hepatic triglyceride accumulation, the buildup of highly toxic free fatty acids associated with insulin resistance-induced massive free fatty acid mobilization from adipose tissue and the increased de novo hepatic fatty acid synthesis from glucose acts as the "first hit" for NAFLD development. NAFLD progression seems to involve the occurrence of "parallel, multiple-hit" injuries, such as oxidative stress-induced mitochondrial dysfunction, endoplasmic reticulum stress, endotoxin-induced, TLR4-dependent release of inflammatory cytokines, and iron overload, among many others. These deleterious factors are responsible for the triggering of a number of signaling cascades leading to inflammation, cell death, and fibrosis, the hallmarks of NASH. This review is aimed at integrating the overwhelming progress made in the characterization of the physiopathological mechanisms of NAFLD at a molecular level, to better understand the factor influencing the initiation and progression of the disease.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - María Valeria Razori
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 570, 2000, Rosario, Argentina.
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18
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Schwenger KJP, Bolzon CM, Li C, Allard JP. Non-alcoholic fatty liver disease and obesity: the role of the gut bacteria. Eur J Nutr 2018; 58:1771-1784. [PMID: 30306296 DOI: 10.1007/s00394-018-1844-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty-liver disease (NAFLD) is now considered one of the leading causes of liver disease worldwide and is associated with metabolic syndrome and obesity. There are several factors contributing to the disease state. Recent research suggests that the intestinal microbiota (IM) and bacterial products may play a role through several mechanisms which include increased energy uptake, intestinal permeability and chronic inflammation. In addition to diet and exercise, treatment options targeting the IM are being investigated and include the use of pre-, pro- and synbiotics as well as the possibility of fecal microbial transfers. This literature review explores the relationship between NAFLD and the IM as well as highlight new IM treatment options that may become available in the near future.
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Affiliation(s)
- Katherine J P Schwenger
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada.,Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Colin M Bolzon
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Carrie Li
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada
| | - Johane P Allard
- Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada. .,Department of Medicine, University of Toronto, Toronto, Canada. .,Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
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19
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Kačarević ŽP, Grgić A, Šnajder D, Bijelić N, Belovari T, Cvijanović O, Blažičević V, Radić R. Different combinations of maternal and postnatal diet are reflected in changes of hepatic parenchyma and hepatic TNF-alpha expression in male rat offspring. Acta Histochem 2017; 119:719-726. [PMID: 28923316 DOI: 10.1016/j.acthis.2017.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 09/06/2017] [Accepted: 09/06/2017] [Indexed: 01/22/2023]
Abstract
Obesity is related to increased TNF-alpha production in different tissues. TNF-alpha is connected to mitochondrial dysfunction in the liver and also development of fatty infiltration of the liver. Also, postnatal change from normal to high-fat diet causes a significant increase in TNF-alpha serum levels. The aim of this research was to determine how maternal diet and switching male offspring to a different dietary regime after lactation influences rat liver. Ten female Sprague Dawley rats at nine weeks of age were randomly divided in two groups and fed either standard laboratory chow or high-fat diet during six weeks, and then mated with the same male subject. After birth and lactation male offspring from both groups were further divided into four subgroups depending on their subsequent diet. At 22 weeks of age, the animals were weighted, sacrificed and major organs were collected and weighted. Immunohistochemistry for TNF-alpha was performed on liver, and liver samples were analyzed for pathohistological changes. The group in which mothers were fed standard chow and offspring high-fat diet had the most pronounced changes: heaviest liver, poorest histopathological findings and strongest TNF-alpha immunohistochemical staining of liver parenchyma. High-fat diet during pregnancy and lactation and switching to high-fat diet postnatally affects liver weight, histological structure and TNF-alpha expression in male offspring.
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Affiliation(s)
- Željka Perić Kačarević
- Department of Anatomy and Neuroscience, Faculty of Medicine, University of Osijek, J. Huttlera 4, 3100 Osijek, Croatia.
| | - Anđela Grgić
- Department of Anatomy and Neuroscience, Faculty of Medicine, University of Osijek, J. Huttlera 4, 3100 Osijek, Croatia; Department of Physical Medicine and Rehabilitation, University Hospital Centre Osijek, Osijek, Croatia.
| | - Darija Šnajder
- Department of Anatomy and Neuroscience, Faculty of Medicine, University of Osijek, J. Huttlera 4, 3100 Osijek, Croatia; Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Centre Osijek, Osijek, Croatia.
| | - Nikola Bijelić
- Department of Histology and Embryology, Faculty of Medicine, University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia.
| | - Tatjana Belovari
- Department of Histology and Embryology, Faculty of Medicine, University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia.
| | - Olga Cvijanović
- Department of Anatomy, Rijeka Medical Faculty, Brace Branchetta 20/1, 51000 Rijeka, Croatia.
| | - Valerija Blažičević
- Department of Pathology, Faculty of Medicine, University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia.
| | - Radivoje Radić
- Department of Anatomy and Neuroscience, Faculty of Medicine, University of Osijek, J. Huttlera 4, 3100 Osijek, Croatia.
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20
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Matsushita N, Hassanein MT, Martinez-Clemente M, Lazaro R, French SW, Xie W, Lai K, Karin M, Tsukamoto H. Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1. PLoS One 2017; 12:e0181052. [PMID: 28797077 PMCID: PMC5552280 DOI: 10.1371/journal.pone.0181052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 06/26/2017] [Indexed: 12/22/2022] Open
Abstract
Myeloid cell and hepatocyte IKKβ may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of non-alcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKKβ deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKKβ deficiency (IkbkbΔhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male IkbkbΔhep mice having worst NASH and lowest plasma estradiol levels. LXRα is enriched to LXRE on Sult1e1 promoter in male WT and IkbkbΔhep mice with NASH, and a Sult1e1 promoter activity is increased by LXRα and its ligand and augmented by expression of a S32A mutant of IκBα. These results demonstrate striking gender differences in regulation by IKKβ of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKKβ is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.
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Affiliation(s)
- Noriko Matsushita
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Mohamed T. Hassanein
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Marcos Martinez-Clemente
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Raul Lazaro
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Samuel W. French
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Harbor-UCLA Medical Center, Torrance, California, United States of America
| | - Wen Xie
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States of America
| | - Keane Lai
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
| | - Michael Karin
- Departments of Pharmacology and Pathology, University of California San Diego, La Jolla, California, United States of America
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis of the University of Southern California, Los Angeles, California, United States of America
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
- * E-mail:
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HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res 2017; 66:477-486. [PMID: 28285394 DOI: 10.1007/s00011-017-1029-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/15/2017] [Accepted: 02/17/2017] [Indexed: 12/13/2022] Open
Abstract
Over the course of time, Hepatitis C has become a universal health menace. Its deleterious effects on human liver encompass a lot of physiological, genetic as well as epigenetic alterations. Fatty liver (Hepatic steatosis) is an inflammation having multifactorial ancestries; one of them is HCV (steatohepatitis). HCV boosts several cellular pathways involving up-regulation of a number of cytokines. Current study reviews the regulation of some selective key cytokines during HCV infection, to help generate an improved understanding of their role. These cytokines, IL-1β, IL-6, TNF-α, and IFN-ϒ, are inflammatory markers of the body. These particular markers along with others help hepatocytes against viral infestation. However, recently, their association has been found in degradation of liver on the trail heading to non-alcoholic steatohepatitis (NASH). Consequently, the disturbance in their equilibrium has been repeatedly reported during HCV infection. Quite a number of findings are affirming their up-regulation. Although these cell markers are stimulated by hepatocytes as their standard protection mechanism, but modern studies have testified the paradoxical nature of this defense line. Nevertheless, direct molecular or epigenetic research is needed to question the actual molecular progressions and directions commanding liver to steatosis, cirrhosis, or eventually HCC (Hepatocellular Carcinoma).
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Ito K, Yoshida K, Maruyama H, Mamou J, Yamaguchi T. Acoustic Impedance Analysis with High-Frequency Ultrasound for Identification of Fatty Acid Species in the Liver. ULTRASOUND IN MEDICINE & BIOLOGY 2017; 43:700-711. [PMID: 28040242 DOI: 10.1016/j.ultrasmedbio.2016.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 10/21/2016] [Accepted: 11/14/2016] [Indexed: 06/06/2023]
Abstract
Acoustic properties of free fatty acids present in the liver were studied as a possible basis for non-invasive ultrasonic diagnosis of non-alcoholic steatohepatitis. Acoustic impedance was measured for the following types of tissue samples: Four pathologic types of mouse liver, five kinds of FFAs in solvent and five kinds of FFAs in cultured Huh-7 cells. A transducer with an 80-MHz center frequency was incorporated into a scanning acoustic microscopy system. Acoustic impedance was calculated from the amplitude of the signal reflected from the specimen surface. The Kruskal-Wallis test revealed statistically significant differences (p < 0.01) in acoustic impedance not only among pathologic types, but also among the FFAs in solvent and in cultured Huh-7 cells. These results suggest that each of the FFAs, especially palmitate, oleate and palmitoleate acid, can be distinguished from each other, regardless of whether they were in solution or absorbed by cells.
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Affiliation(s)
- Kazuyo Ito
- Graduate School of Engineering, Chiba University, Inage, Chiba, Chiba, Japan.
| | - Kenji Yoshida
- Center for Frontier Medical Engineering, Chiba University, Inage, Chiba, Chiba, Japan
| | - Hitoshi Maruyama
- Graduate School of Medicine, Chiba University, Chuou, Chiba, Chiba, Japan
| | - Jonathan Mamou
- F. L. Lizzi Center for Biomedical Engineering, Riverside Research Institute, New York, New York, USA
| | - Tadashi Yamaguchi
- Center for Frontier Medical Engineering, Chiba University, Inage, Chiba, Chiba, Japan
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Fraunberger P, Gröne E, Gröne HJ, Drexel H, Walli AK. Ezetimibe reduces cholesterol content and NF-kappaB activation in liver but not in intestinal tissue in guinea pigs. JOURNAL OF INFLAMMATION-LONDON 2017; 14:3. [PMID: 28167864 PMCID: PMC5288872 DOI: 10.1186/s12950-017-0150-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/04/2017] [Indexed: 02/06/2023]
Abstract
Background Statins (HMG CoA reductase inhibitors), in addition to reducing circulating cholesterol and incidence of coronary heart disease, also have pleiotropic, anti-inflammatory effects. Patients with chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) or hepatitis C are often excluded from statin therapy because of adverse effects in a small cohort of patients despite increased cardiovascular risk cholesterol. Ezetimibe, which inhibits cholesterol absorption by inhibition of Niemann-Pick C1 like 1 (NPC1L1) protein in the brush border of intestinal cells, has been suggested as a new therapeutic option in these patients. Methods Effects of ezetimibe on lipoprotein metabolism, hepatic and intestinal lipid content in guinea pigs, an animal model with a lipoprotein profile and pattern similar to humans were investigated. In order to investigate a possible effect of ezetimibe on cholesterol induced inflammation NF-kappaB activation as an indicator for inflammatory processes in liver and gut tissue was measured. Results Lipid enriched diet led to accumulation of lipids in hepatic tissue which caused strong hepatic NF-kappaB activation. Ezetimibe reduced lipid diet induced increase of circulating cholesterol by about 77% and prevent hepatic NF-kappaB activation almost completely. In contrast in intestinal cells Ezetimibe, though lowering diet induced cholesterol accumulation, increased triglyceride content and subsequent NF-kappaB activation. Conclusion In summary these data show, that ezetimibe effectively reduced diet induced circulating cholesterol levels, hepatic lipid accumulation and inflammatory response in our guinea pig model. However this drug elicited a local inflammatory response in intestinal tissue. Whether these diverse effects of ezetimibe on inflammatory parameters such as NF-kappaB have clinical relevance remains to be determined.
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Affiliation(s)
- Peter Fraunberger
- Medical Central Laboratories, Carinagasse 41, A-6800 Feldkirch, Austria.,Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany
| | - Elisabeth Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Hermann-Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
| | - Heinz Drexel
- Vorarlberger Institute of Vascular Investigation and Treatment (VIVIT), Dornbirn, Austria
| | - Autar K Walli
- Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany
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Liu L, Zhao X, Wang Q, Sun X, Xia L, Wang Q, Yang B, Zhang Y, Montgomery S, Meng H, Geng T, Gong D. Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System. Sci Rep 2016; 6:31763. [PMID: 27550859 PMCID: PMC4994046 DOI: 10.1038/srep31763] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 07/27/2016] [Indexed: 01/07/2023] Open
Abstract
Goose can develop severe hepatic steatosis without overt injury, thus it may serve as a unique model for uncovering how steatosis-related injury is prevented. To identify the markedly prosteatotic and protective mechanisms, we performed an integrated analysis of liver transcriptomes and gut microbial metagenomes using samples collected from overfed and normally-fed geese at different time points. The results indicated that the fatty liver transcriptome, initially featuring a 'metabolism' pathway, was later joined by 'cell growth and death' and 'immune diseases' pathways. Gut microbiota played a synergistic role in the liver response as microbial and hepatic genes affected by overfeeding shared multiple pathways. Remarkably, the complement system, an inflammatory component, was comprehensively suppressed in fatty liver, which was partially due to increased blood lactic acid from enriched Lactobacillus. Data from in vitro studies suggested that lactic acid suppressed TNFα via the HNF1α/C5 pathway. In conclusion, gut microbes and their hosts respond to excess energy influx as an organic whole, severe steatosis and related tolerance of goose liver may be partially attributable to gut microbiotic products and suppressed complement system, and lactic acid from gut microbiota participates in the suppression of hepatic TNFα/inflammation through the HNF1α/C5 pathway.
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Affiliation(s)
- Long Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xing Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiaoxian Sun
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Lili Xia
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Qianqian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Biao Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yihui Zhang
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Sean Montgomery
- Department of Botany, University of British Columbia, 6270 University Boulevard, British Columbia, V6T 1Z4, Canada
| | - He Meng
- School of Agriculture and Biology, Shanghai Jiaotong University; Shanghai Key Laboratory of Veterinary Biotechnology, 800 Dongchuan Road, Shanghai 200240, China
| | - Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
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Bozaykut P, Sahin A, Karademir B, Ozer NK. Endoplasmic reticulum stress related molecular mechanisms in nonalcoholic steatohepatitis. Mech Ageing Dev 2016; 157:17-29. [PMID: 27393639 DOI: 10.1016/j.mad.2016.07.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 06/23/2016] [Accepted: 07/02/2016] [Indexed: 12/18/2022]
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Chon YE, Kim KJ, Jung KS, Kim SU, Park JY, Kim DY, Ahn SH, Chon CY, Chung JB, Park KH, Bae JC, Han KH. The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter. Yonsei Med J 2016; 57:885-892. [PMID: 27189281 PMCID: PMC4951464 DOI: 10.3349/ymj.2016.57.4.885] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 09/21/2015] [Accepted: 10/17/2015] [Indexed: 01/02/2023] Open
Abstract
PURPOSE The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). MATERIALS AND METHODS Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). RESULTS Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. CONCLUSION Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.
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Affiliation(s)
- Young Eun Chon
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Kwang Joon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
| | - Kyu Sik Jung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Seung Up Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Jun Yong Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Do Young Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Sang Hoon Ahn
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Chae Yoon Chon
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
| | - Jae Bock Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
- Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
| | - Kyeong Hye Park
- Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
| | - Ji Cheol Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Hyub Han
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea.
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Alam S, Mustafa G, Alam M, Ahmad N. Insulin resistance in development and progression of nonalcoholic fatty liver disease. World J Gastrointest Pathophysiol 2016; 7:211-217. [PMID: 27190693 PMCID: PMC4867400 DOI: 10.4291/wjgp.v7.i2.211] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 01/03/2016] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Although insulin resistance (IR) is strongly associated with nonalcoholic fatty liver disease (NAFLD), the association of IR and NAFLD is not universal and correlation between IR and severity of NAFLD is still controversial. In this review, we summarize recent evidence that partially dissociates insulin resistance from NAFLD. It has also been reported that single-nucleotide polymorphisms in the diacylglycerol acyltransferase gene, rather than IR, account for the variability in liver fat content. Polymorphisms of the patatin-like phospholipase 3 gene have also been reported to be associated with NAFLD without metabolic syndrome, which suggests that genetic conditions that promote the development of fatty changes in the liver may occur independently of IR. Moreover, environmental factors such as nutrition and physical activity as well as small intestinal bacterial overgrowth have been linked to the pathogenesis of NAFLD, although some of the data are conflicting. Therefore, findings from both genetically engineered animal models and humans with genetic conditions, as well as recent studies that have explored the role of environmental factors, have confirmed the view that NAFLD is a polygenic disease process caused by both genetic and environmental factors. Therefore, IR is not the sole predictor of the pathogenesis of NAFLD.
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Nawata A, Noguchi H, Mazaki Y, Kurahashi T, Izumi H, Wang KY, Guo X, Uramoto H, Kohno K, Taniguchi H, Tanaka Y, Fujii J, Sasaguri Y, Tanimoto A, Nakayama T, Yamada S. Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease. PLoS One 2016; 11:e0152549. [PMID: 27035833 PMCID: PMC4818088 DOI: 10.1371/journal.pone.0152549] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 03/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. METHODS & RESULTS Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. CONCLUSION Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.
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Affiliation(s)
- Aya Nawata
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Hirotsugu Noguchi
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Yuichi Mazaki
- Department of Cellular Pharmacology, Graduate School of Medicine, Hokkaido University, Sapporo, 060–8638, Japan
| | - Toshihiro Kurahashi
- Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, Yamagata, 990–9585, Japan
| | - Hiroto Izumi
- Department of Occupational Pneumology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Ke-Yong Wang
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- Shared-Use Research Center, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Xin Guo
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Hidetaka Uramoto
- Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei, Medical University, Jiankang Road 12, Shijiazhuang, 050011, Hebei, China
- Department of Thoracic Surgery, Saitama Cancer Center, Saitama, 362–0806, Japan
| | - Kimitoshi Kohno
- The President Laboratory, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- Asahi-Matsumoto Hospital, Kitakyushu, 800–0242, Japan
| | - Hatsumi Taniguchi
- Department of Microbiology, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Junichi Fujii
- Department of Biomolecular Function, Graduate School of Medical Science, Yamagata University, Yamagata, 990–9585, Japan
| | - Yasuyuki Sasaguri
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- Laboratory of Pathology, Fukuoka Wajiro Hospital, Fukuoka, 811–0213, Japan
| | - Akihide Tanimoto
- Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890–8544, Japan
| | - Toshiyuki Nakayama
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
| | - Sohsuke Yamada
- Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8555, Japan
- Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890–8544, Japan
- Institute of Pathology, Medical University of Graz, Graz, 8010, Austria
- Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria
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Geng T, Yang B, Li F, Xia L, Wang Q, Zhao X, Gong D. Identification of protective components that prevent the exacerbation of goose fatty liver: Characterization, expression and regulation of adiponectin receptors. Comp Biochem Physiol B Biochem Mol Biol 2016; 194-195:32-38. [PMID: 26804769 DOI: 10.1016/j.cbpb.2016.01.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 12/26/2015] [Accepted: 01/19/2016] [Indexed: 12/15/2022]
Abstract
Fat accumulation in the liver is a natural process in goose, which prepares goose for long-distance migration. In contrast to mammalian fatty liver that usually progresses into an irreversible status, steatohepatitis, goose fatty liver can return to normal without obvious pathological damage, suggesting a protective system exists in goose liver. This study was to identify the components of this system. We first focused on goose adiponectin receptor 1 and 2 (Adipor1/2) as they have ceramidase activity, and can cleave ceramide, a group of proinflammatory signaling lipid species. Quantitative analysis indicated that tumor necrosis factor alpha (Tnfα), a key proinflammatory cytokine, was down-regulated in goose fatty liver by overfeeding. This inhibition of Tnfα was accompanied with reduced adiponectin and increased Adipor1/2 in the adipose tissues and in the livers of the overfed geese, respectively. To investigate the regulation of goose Adipor2 in the context of fatty liver, we treated goose primary hepatocytes with fatty liver associated factors. Data indicated that Adipor2 was upregulated by glucose and oleate but not palmitate. Its expression was even suppressed by high level of insulin. The regulation of Adipor1 by these factors was quite similar to that of Adipor2 except that glucose did not induce Adipor1. Together, these findings suggest the upregulation of Adipor1/2 may, at least partially, contribute to the inhibition of inflammation in goose fatty liver, and the expression of Adipor1/2 can be regulated by fatty liver-associated factors.
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Affiliation(s)
- Tuoyu Geng
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
| | - Biao Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Fuyuan Li
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Lili Xia
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Qianqian Wang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Xing Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China
| | - Daoqing Gong
- College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu 225009, China.
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Azeemuddin M, Rafiq M, Anturlikar SD, Sharath Kumar LM, Patki PS, Babu UV, Shyam R. Extract of a polyherbal formulation ameliorates experimental nonalcoholic steatohepatitis. J Tradit Complement Med 2016; 6:160-7. [PMID: 27114939 PMCID: PMC4833463 DOI: 10.1016/j.jtcme.2014.12.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/24/2014] [Accepted: 12/04/2014] [Indexed: 12/16/2022] Open
Abstract
The objective of the present study is to evaluate the effect of the extract of a well-known hepatospecific polyherbal formulation, Liv.52, in an experimental model of high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) in rats. Feeding a HFD for 15 weeks resulted in significant impairment of the lipid profile, elevation of hepatic enzyme markers, and insulin resistance in rats. The histological examination of the liver furthermore indicated fibrotic changes and fat deposition in hepatic tissues. The treatment with Liv.52 extract [125 mg/kg body weight per os (b.wt. p.o.)], which was administered from week 9 onward, reversed the HFD-induced changes to a statistically significant extent, compared to the untreated positive control animals. The effect observed with Liv.52 extract was comparable to that of pioglitazone (4 mg/kg b.wt.), a standard drug that is useful in the management of NASH. The treatment with Liv.52 extract significantly reduced steatosis, collagen deposition, and necrosis in hepatic tissues, which indicates its antifibrotic and antinecrotic properties. The results obtained in the present set of experiments indicate that Liv.52 extract effectively reverses metabolic and histological changes associated with HFD-induced NASH.
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Affiliation(s)
- Mohammed Azeemuddin
- Department of Pharmacology, R&D Center, The Himalaya Drug Company, Bangalore, India
| | - Mohamed Rafiq
- Department of Pharmacology, R&D Center, The Himalaya Drug Company, Bangalore, India
| | | | | | | | | | - Ramakrishnan Shyam
- Chief Scientific Officer, R&D Center, The Himalaya Drug Company, Bangalore, India
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Lee SH, Kim KN, Kim KM, Joo NS. Irritable Bowel Syndrome May Be Associated with Elevated Alanine Aminotransferase and Metabolic Syndrome. Yonsei Med J 2016; 57:146-52. [PMID: 26632395 PMCID: PMC4696946 DOI: 10.3349/ymj.2016.57.1.146] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 02/13/2015] [Accepted: 02/27/2015] [Indexed: 02/07/2023] Open
Abstract
PURPOSE Recent studies have revealed close relationships between hepatic injury, metabolic pathways, and gut microbiota. The microorganisms in the intestine also cause irritable bowel syndrome (IBS). The aim of this study was to examine whether IBS was associated with elevated hepatic enzyme [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], gamma-glutamyl transferase (γ-GT) levels, and metabolic syndrome (MS). MATERIALS AND METHODS This was a retrospective, cross-sectional, case-control study. The case and control groups comprised subjects who visited our health promotion center for general check-ups from June 2010 to December 2010. Of the 1127 initially screened subjects, 83 had IBS according to the Rome III criteria. The control group consisted of 260 age- and sex-matched subjects without IBS who visited our health promotion center during the same period. RESULTS Compared to control subjects, patients with IBS showed significantly higher values of anthropometric parameters (body mass index, waist circumference), liver enzymes, γ-GT, and lipid levels. The prevalences of elevated ALT (16.9% vs. 7.7%; p=0.015) and γ-GT (24.1% vs. 11.5%; p=0.037) levels were significantly higher in patients with IBS than in control subjects. A statistically significant difference was observed in the prevalence of MS between controls and IBS patients (12.7% vs. 32.5%; p<0.001). The relationships between elevated ALT levels, MS, and IBS remained statistically significant after controlling for potential confounding factors. CONCLUSION On the basis of our study results, IBS may be an important condition in certain patients with elevated ALT levels and MS.
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Affiliation(s)
- Seung Hwa Lee
- Department of Family Medicine, Seo-Hae Hospital, Seocheon, Korea
| | - Kyu Nam Kim
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea.
| | - Kwang Min Kim
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
| | - Nam Seok Joo
- Department of Family Practice and Community Health, Ajou University School of Medicine, Suwon, Korea
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Maruyama H, Kiyono S, Kondo T, Sekimoto T, Yokosuka O. Palmitate-induced Regulation of PPARγ via PGC1α: a Mechanism for Lipid Accumulation in the Liver in Nonalcoholic Fatty Liver Disease. Int J Med Sci 2016; 13:169-78. [PMID: 26941577 PMCID: PMC4773281 DOI: 10.7150/ijms.13581] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023] Open
Abstract
The aim was to examine the effect of free fatty acids on the regulation of PPARγ-PGC1α pathway, and the effect of PPARγ/PGC1α in NAFLD. The mRNA and protein expression of PGC1α and phospho/total PPARγ were examined in Huh7 cells after the palmitate/oleate treatment with/without the transfection with siRNA against PGC1a. The palmitate content, mRNA and protein expression of PGC1α and PPARγ in the liver were examined in the control and NAFLD mice. Palmitate (500 μM), but not oleate, increased protein expression of PGC1α and phospho PPARγ (PGC1α, 1.42-fold, P=0.038; phospho PPARγ, 1.56-fold, P=0.022). The palmitate-induced PPARγ mRNA expression was reduced after the transfection (0.46‑fold), and the protein expressions of PGC1α (0.52-fold, P=0.019) and phospho PPARγ (0.43-fold, P=0.011) were suppressed in siRNA-transfected cells. The palmitate (12325.8 ± 1758.9 μg/g vs. 6245.6 ± 1182.7 μg/g, p=0.002), and mRNA expression of PGC1α (11.0 vs. 5.5, p=0.03) and PPARγ (4.3 vs. 2.2, p=0.0001) in the liver were higher in high-triglyceride liver mice (>15.2 mg/g) than in low-triglyceride liver mice (<15.2 mg/g). The protein expressions of both PGC1α and PPARγ were higher in the NAFLD group than in the controls (PGC1α, 1.41-fold, P=0.035; PPARγ, 1.39-fold, P=0.042), and were higher in the high-triglyceride liver group (PGC1α, 1.52-fold, p=0.03; PPARγ, 1.22-fold, p=0.05) than in the low-triglyceride liver group. In conclusion, palmitate appear to up-regulate PPARγ via PGC1α in Huh7 cells, and both PGC1α and PPARγ are up-regulated in the NAFLD mice liver, suggesting an effect on lipid metabolism leading to intrahepatic triglyceride accumulation.
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Affiliation(s)
- Hitoshi Maruyama
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Tadashi Sekimoto
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku, Chiba, 260-8670, Japan
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de Castro Barra PM, Sabarense CM, Alvarenga MB, de Sousa RA, de Oliveira MAL. Selenium Content in the Liver of Wistar Rats Fed Diets of Different Fatty Acid Quality. Biol Trace Elem Res 2015; 168:441-6. [PMID: 25957597 DOI: 10.1007/s12011-015-0359-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/28/2015] [Indexed: 11/24/2022]
Abstract
The purpose of this work was to measure the amounts of selected mineral elements (sodium, calcium, iron, selenium, magnesium, zinc, copper, and manganese) in the liver of Wistar rats and evaluate possible correlations between the levels of these minerals and the lipid metabolism in the studied animals. Three experimental groups each containing six Wistar rats were designed. Each group was fed a different diet. The control group was fed a diet prepared with fresh soybean oil and named control group--CG. The second group (named experimental group B--EGB) and third group (named experimental group C--EGC) were fed a diet containing soybean oil that had been used to fry different foods for four or ten cycles, respectively. The mineral elements in Wistar rat livers were measured by inductively coupled plasma optical emission spectrometry (ICP OES). Only the elements calcium and selenium differed significantly between the control and experimental groups. There was a significant reduction of 33% for Ca and 41% for Se in the EGB in comparison to the control group. The reduction in mineral concentration, especially Se, is the result of interactions with fatty acid metabolism. The animals in the EGC exhibited more intracytoplasmic accumulation of fat and more intense vasodilatation, in relation to the other groups. Collectively, evidence hereby collected suggests that impaired dietary lipid quality in otherwise balanced diets can reduce hepatic Se levels and potentially harm liver function.
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Affiliation(s)
| | | | | | - Rafael Arromba de Sousa
- Chemistry Department, Institute of Exact Sciences, Federal University of Juiz de Fora, Juiz de Fora, MG, Brazil
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Willebrords J, Pereira IVA, Maes M, Crespo Yanguas S, Colle I, Van Den Bossche B, Da Silva TC, de Oliveira CPMS, Andraus W, Alves VA, Cogliati B, Vinken M. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research. Prog Lipid Res 2015; 59:106-125. [PMID: 26073454 PMCID: PMC4596006 DOI: 10.1016/j.plipres.2015.05.002] [Citation(s) in RCA: 131] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 05/13/2015] [Accepted: 05/13/2015] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.
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Affiliation(s)
- Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabelle Colle
- Department of Hepatology and Gastroenterology, Algemeen Stedelijk Ziekenhuis Campus Aalst, Merestraat 80, 9300 Aalst, Belgium.
| | - Bert Van Den Bossche
- Department of Abdominal Surgery and Hepato-Pancreatico-Biliary Surgery, Algemeen Stedelijk Ziekenhuis Campus Aalst, Merestraat 80, 9300 Aalst, Belgium.
| | - Tereza Cristina Da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | | | - Wellington Andraus
- Department of Gastroenterology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, São Paulo, Brazil.
| | - Venâncio Avancini Alves
- Laboratory of Medical Investigation, Department of Pathology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, São Paulo, Brazil.
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, São Paulo, Brazil.
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
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Deciphering non-alcoholic fatty liver disease through metabolomics. Biochem Soc Trans 2015; 42:1447-52. [PMID: 25233430 DOI: 10.1042/bst20140138] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders in industrialized countries. NAFLD develops in the absence of alcohol abuse and encompasses a wide spectrum of disorders ranging from benign fatty liver to non-alcoholic steatohepatitis (NASH). NASH often leads to fibrosis, cirrhosis and, finally, hepatocellular carcinoma (HCC). Therefore the earlier NAFLD is diagnosed, the better the patient's outlook. A tightly connected basic and applied research is essential to find the molecular mechanisms that accompany illness and to translate them into the clinic. From the simple starting point for triacylglycerol (TG) accumulation in the liver to the more complex implications of phospholipids in membrane biophysics, the influence of lipids may be the clue to understand NAFLD pathophysiology. Nowadays, it is achievable to diagnose non-invasively the initial symptoms to stop, revert or even prevent disease development. In this context, merging metabolomics with other techniques and the interpretation of the huge information obtained resembles the 'Rosetta stone' to decipher the pathological metabolic fluxes that must be targeted to find a cure. In the present review, we have tackled the application of metabolomics to find out the metabolic fluxes that underlie membrane integrity in NAFLD.
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New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro. Cell Signal 2015; 27:1831-9. [PMID: 25917316 DOI: 10.1016/j.cellsig.2015.04.010] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 04/17/2015] [Accepted: 04/20/2015] [Indexed: 01/09/2023]
Abstract
Irisin is a newly identified myokine related to exercise and the browning of white fat. Recently, it was reported that irisin serum levels are associated with intrahepatic triglyceride content, suggesting that it might have an important role in the liver. The aim of this study was to determine the role of irisin in hepatocytes. Specifically, the effect of recombinant irisin on palmitic acid (PA)-induced lipogenesis and its related signal pathways were examined in AML12 cells and mouse primary hepatocytes. In the present study, we observed the presence of irisin inside the cells in response to the treatment of recombinant irisin by flow cytometry and cell imaging technique. Recombinant irisin significantly inhibited the PA-induced increase in lipogenic markers ACC and FAS at the mRNA and protein levels, and prevented the PA-induced lipid accumulation in hepatocytes. Additionally, irisin inhibited the PA-induced increase in the expression, nuclear localization, and transcriptional activities of the master regulators of lipogenesis (LXRα and SREBP-1c). Moreover, irisin attenuated PA-induced oxidative stress, which was confirmed by measuring the expression of inflammatory markers (NFκB, COX-2, p38 MAPK, TNF, IL-6) and superoxide indicator (dihydroethidium). The preventive effects of irisin against lipogenesis and oxidative stress were mediated by the inhibition of protein arginine methyltransferase-3 (PRMT3). These findings suggested that irisin might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress in a PRMT3 dependent manner.
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Ledder O, Haller W, Couper RT, Lewindon P, Oliver M. Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations. J Gastroenterol Hepatol 2014; 29:1954-62. [PMID: 25238538 DOI: 10.1111/jgh.12785] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/20/2014] [Indexed: 12/14/2022]
Abstract
This paper, the second in the series, will build on the first and explore the importance of liver and pancreatic manifestations of cystic fibrosis (CF) and the effect on morbidity and mortality of this multifaceted genetic condition. It will also further develop the critical role of the gastroenterologist as part of the multidisciplinary group of clinicians and allied health staff in the effective management of patients with CF.
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Affiliation(s)
- Oren Ledder
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital Parkville, Melbourne, Victoria
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Liu Y, Song H, Wang L, Xu H, Shu X, Zhang L, Li Y, Li D, Ji G. Hepatoprotective and antioxidant activities of extracts from Salvia-Nelumbinis naturalis against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet in mice. J Transl Med 2014; 12:315. [PMID: 25406833 PMCID: PMC4239328 DOI: 10.1186/s12967-014-0315-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 10/28/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH), the advanced stage of nonalcoholic fatty liver disease that is characterized by both steatosis and severe injury in liver, still lacks efficient treatment. The traditional Chinese formula Salvia-Nelumbinis naturalis (SNN) is effectively applied to improve the symptoms of nonalcoholic simple fatty liver (NAFL) patients. Previous studies have confirmed that SNN could reduce the liver lipid deposition and serum transaminases of NAFL experimental models. This study aims to determine whether SNN is effective for murine NASH model and investigate the underlying pharmacological mechanisms. METHODS C57BL/6 J mice were fed with methionine- and choline-deficient (MCD) diet for six weeks to induce NASH. Simultaneously, SNN or saline was intragastrically administered daily to the mice in the SNN or model group, respectively. A standard diet was given to the control mice. Serum biochemical indices and tumor necrosis factor-α were measured. Liver histopathology was observed, and the contents of triglycerides and lipid peroxide malondialdehyde (MDA) in liver homogenates were evaluated. The hepatic expression and/or activation of genes associated with inflammation, apoptosis, and oxidative stress were determined by quantitative RT-PCR or Western blot analysis. RESULTS The prominent liver steatosis displayed in the NASH model was prevented by SNN. The liver injury of NASH mice was obviously manifested by the increased levels of serum transaminases and bilirubin, as well as the lobular inflammation, elevated pro-inflammatory cytokines, and upregulated apoptosis in liver tissues. SNN administration improved the aforementioned pathological changes. The increased hepatic levels of MDA and cytochrome P450 2E1 of the model confirmed the unregulated balance of oxidative stress. The hepatic expression of nuclear factor erythroid 2-related factor 2 and its target genes decreased, whereas c-Jun N-terminal kinase activation in the model mice increased. Treating the mice with SNN significantly improved oxidative stress-related harmful factors. CONCLUSIONS This study shows that SNN can protect the liver from severe steatosis and damage induced by MCD diet, which suggests the potential use of SNN on the treatment of NASH patient. The results also indicate that improving the hepatic antioxidant capability of the liver may contribute to the underlying hepatoprotective mechanism.
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Affiliation(s)
- Yang Liu
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Haiyan Song
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Lei Wang
- />Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Hanchen Xu
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Xiangbing Shu
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Li Zhang
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Ying Li
- />Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
| | - Dongfei Li
- />Department of Traditional Chinese Medicine, East Hospital, Tongji University, Shanghai, 200120 China
| | - Guang Ji
- />Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032 China
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Al-Rasadi K, Rizzo M, Montalto G, Berg G. Nonalcoholic Fatty Liver Disease, Cardiovascular Risk, and Carotid Inflammation. Angiology 2014; 66:601-3. [DOI: 10.1177/0003319714557353] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Khalid Al-Rasadi
- Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
| | - Manfredi Rizzo
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Gabriela Berg
- Department of Clinical Biochemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:637027. [PMID: 25371775 PMCID: PMC4211163 DOI: 10.1155/2014/637027] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.
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Lee HS, Son WC, Ryu JE, Koo BA, Kim YS. Standardized Salvia miltiorrhiza extract suppresses hepatic stellate cell activation and attenuates steatohepatitis induced by a methionine-choline deficient diet in mice. Molecules 2014; 19:8189-211. [PMID: 24941342 PMCID: PMC6271030 DOI: 10.3390/molecules19068189] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/05/2014] [Accepted: 06/11/2014] [Indexed: 01/07/2023] Open
Abstract
The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor β-1 (TGF-β1) or TGF-β1 plus SME (0.1–10 μg/mL). To investigate the effect of SME on reactive oxygen species (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2plus SME (0.1–100 μg/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-α), TGF-β1, interleukin-1β (IL-1β), C-reactive protein (CRP), α-smooth muscle actin (α-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-β1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.
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Affiliation(s)
- Hak Sung Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
| | - Woo-Chan Son
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
| | - Jae-Eun Ryu
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
| | - Bon Am Koo
- Research Center, Samil Pharmaceutical Co. Ltd., 216 Sandan-ro, Danwon-gu, Ansan 425-852, Korea.
| | - Yeong Shik Kim
- Natural Products Research Institute, College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
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Herbal medicines for the treatment of nonalcoholic steatohepatitis: current scenario and future prospects. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:648308. [PMID: 24987431 PMCID: PMC4060323 DOI: 10.1155/2014/648308] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 04/30/2014] [Indexed: 12/11/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is a multifactorial disease and has close correlations with other metabolic disorders. This makes its treatment difficult using a single pharmacological drug. Use of plant extract/decoction or polyherbal formulation to treat various liver diseases is very well mentioned in various traditional systems of medicine (Ayurveda, Japanese or traditional Chinese Medicine, and Kampo medicine). Medicinal herbs are known for their multifaceted implications and thus can form an effective treatment schedule against NASH. Till date, several plant extracts, polyherbal formulations, and phytochemicals have been evaluated for their possible therapeutic potential in preventing onset and progression of NASH in experimental models, but clinical studies using the same are sparse. Herbal extracts with antioxidants, antidiabetic, and antihyperlipidemic properties have been shown to ameliorate symptoms of NASH. This review article is a meticulous compilation of our current knowledge on the role of natural products in alleviating NASH and possible lacunae in research that needs to be addressed.
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Maruyama H, Takahashi M, Sekimoto T, Shimada T, Yokosuka O. Linoleate appears to protect against palmitate-induced inflammation in Huh7 cells. Lipids Health Dis 2014; 13:78. [PMID: 24885871 PMCID: PMC4038110 DOI: 10.1186/1476-511x-13-78] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 05/01/2014] [Indexed: 02/07/2023] Open
Abstract
Background Polyunsaturated fatty acids (PUFAs) may protect against metabolic diseases. Although the benefits of the n-3 family of PUFA have been well investigated in nonalcoholic steatohepatitis (NASH), little is known about the effect of the n-6 family. This study examined the effect of linoleate, a member of the n-6 family, on regulation of the palmitate-induced inflammatory cytokine interleukin-8 (IL8) in hepatocytes. Methods Huh7 cells and HepG2 cells were cultured with and without free fatty acid treatment (palmitate and linoleate, alone or in combination, 100–1000 μM). Inflammatory pathways, lipid accumulation, apoptosis and cell viability were monitored. Results Dose- and time-related changes of IL8 mRNA expression were examined and 9 h treatment with 500 μM palmitate showed the greatest elevation of IL8. Co-treatment with 500 μM palmitate and 400 μM linoleate significantly suppressed IL8 production below that with palmitate alone in both cells (both mRNA and protein). A quantitative measurement for lipid accumulation showed no significant difference between palmitate-treated cells (1.69 ± 0.21), linoleate-treated cells (1.61 ± 0.16) and palmitate and linoleate-treated cells (1.73 ± 0.22, NS, n = 7). The co-treatment with 400 μM linoleate inhibited phospho-c-Jun N-terminal kinase (pJNK) activation and IkBα reduction caused by 500 μM palmitate treatment. Treatment with 400 μM linoleate alone led to IL8 production (5.48 fold change), similar to co-treatment, with no influence on the expression of pJNK/IkBα. The cell viability was similar between treatment with 500 μM palmitate and with both 500 μM palmitate and 400 μM linoleate, showing no significant changes in the expression of cleaved caspase-3. Conclusions Linoleate is a potent regulator of the proinflammatory cytokine IL8 via the JNK and nuclear factor kappa B pathways that are involved in the pathophysiology of NASH, suggesting a future recommendation of dietary management.
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Affiliation(s)
- Hitoshi Maruyama
- Department of Gastroenterology, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuou-ku 260-8670, Chiba, Japan.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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Affiliation(s)
- Katherine J P Schwenger
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
| | - Johane P Allard
- Katherine JP Schwenger, Institute of Medical Science, University of Toronto, 1 King's Circle, Toronto M5S 1A8, Canada
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Schwenger KJP, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20:1712-1723. [PMID: 24587650 PMCID: PMC3930971 DOI: 10.3748/wjg.v20.i7.1712] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/05/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients.
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Lai YC, Cheng BC, Hwang JC, Lee YT, Chiu CH, Kuo LC, Chen JB. Association of fatty liver disease with nonfatal cardiovascular events in patients undergoing maintenance hemodialysis. Nephron Clin Pract 2014; 124:218-23. [PMID: 24503573 DOI: 10.1159/000357952] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Accepted: 11/29/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIMS The prevalence of cardiovascular (CV) disease in patients undergoing maintenance hemodialysis (HD) is reportedly higher than that in healthy individuals. In the present study, we aimed to investigate whether ultrasonographically documented fatty liver disease (FLD) is an independent risk factor for nonfatal CV events in patients undergoing HD. METHODS A retrospective cohort study was conducted in a medical center in southern Taiwan. The medical records of 490 patients undergoing HD who were enrolled between July 1998 and October 2012 were screened. Finally, 278 patients who had undergone hepatic ultrasonography and had available data were recruited in the present study. The patients included 130 men and 148 women; their mean age was 59.9 years. The primary endpoint was nonfatal CV events in the observation period. The comparable data included epidemiological, hematological, and biochemical profiles. A time-dependent statistical method was used to analyze the associated factors. RESULTS The prevalence of nonfatal CV events was significantly increased in the patients with FLD compared with those without FLD (CV events: 32 vs. 18%, respectively; p = 0.008). After adjusting for associated risk factors (sex, age, body mass index, smoking, diabetes, hypertension, dyslipidemia, and Kt/V), multivariate analyses identified FLD (CV events: hazard ratio 2.84, 95% confidence interval 1.52-5.28, p = 0.001), advanced age, and diabetes to be independently associated with nonfatal CV events. CONCLUSION The study suggests that FLD was an independent risk factor for nonfatal CV events in patients undergoing maintenance HD.
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Affiliation(s)
- Yu-Cheng Lai
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
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Ritze Y, Bárdos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One 2014; 9:e80169. [PMID: 24475018 PMCID: PMC3903470 DOI: 10.1371/journal.pone.0080169] [Citation(s) in RCA: 219] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 10/08/2013] [Indexed: 11/29/2022] Open
Abstract
Objective Experimental evidence revealed that obesity-associated non-alcoholic fatty liver disease (NAFLD) is linked to changes in intestinal permeability and translocation of bacterial products to the liver. Hitherto, no reliable therapy is available except for weight reduction. Within this study, we examined the possible effect of the probiotic bacterial strain Lactobacillus rhamnosus GG (LGG) as protective agent against experimental NAFLD in a mouse model. Methods Experimental NAFLD was induced by a high-fructose diet over eight weeks in C57BL/J6 mice. Fructose was administered via the drinking water containing 30% fructose with or without LGG at a concentration resulting in approximately 5×107 colony forming units/g body weight. Mice were examined for changes in small intestinal microbiota, gut barrier function, lipopolysaccharide (LPS) concentrations in the portal vein, liver inflammation and fat accumulation in the liver. Results LGG increased beneficial bacteria in the distal small intestine. Moreover, LGG reduced duodenal IκB protein levels and restored the duodenal tight junction protein concentration. Portal LPS (P≤0.05) was reduced and tended to attenuate TNF-α, IL-8R and IL-1β mRNA expression in the liver feeding a high-fructose diet supplemented with LGG. Furthermore liver fat accumulation and portal alanine-aminotransferase concentrations (P≤0.05) were attenuated in mice fed the high-fructose diet and LGG. Conclusions We show for the first time that LGG protects mice from NAFLD induced by a high-fructose diet. The underlying mechanisms of protection likely involve an increase of beneficial bacteria, restoration of gut barrier function and subsequent attenuation of liver inflammation and steatosis.
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Affiliation(s)
- Yvonne Ritze
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Gyöngyi Bárdos
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Anke Claus
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Veronika Ehrmann
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - Ina Bergheim
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
- Department of Nutritional Science, Friedrich-Schiller-University, Jena, Germany
| | | | - Stephan C. Bischoff
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
- * E-mail:
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Ritze Y, Böhle M, Haub S, Hubert A, Enck P, Zipfel S, Bischoff SC. Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice. BMC Gastroenterol 2013; 13:169. [PMID: 24321090 PMCID: PMC4029732 DOI: 10.1186/1471-230x-13-169] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Accepted: 11/28/2013] [Indexed: 01/14/2023] Open
Abstract
Background Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system. Methods C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used. Results Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease. Conclusion In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier.
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Affiliation(s)
| | | | | | | | | | | | - Stephan C Bischoff
- Department of Nutritional Medicine, University of Hohenheim, Fruwirthstr, 12, 70599, Stuttgart, Germany.
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Pimenta NM, Santa-Clara H, Cortez-Pinto H, Silva-Nunes J, da Lapa Rosado M, Sousa PJ, Calé R, Melo X, Sardinha LB, Fernhall B. Body composition and body fat distribution are related to cardiac autonomic control in non-alcoholic fatty liver disease patients. Eur J Clin Nutr 2013; 68:241-6. [PMID: 24300906 DOI: 10.1038/ejcn.2013.249] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Revised: 10/24/2013] [Accepted: 10/25/2013] [Indexed: 01/23/2023]
Abstract
BACKGROUND/OBJECTIVES Heart rate recovery (HRR), a cardiac autonomic control marker, was shown to be related to body composition (BC), yet this was not tested in non-alcoholic fatty liver disease (NAFLD) patients. The aim of this study was to determine if, and to what extent, markers of BC and body fat (BF) distribution are related to cardiac autonomic control in NAFLD patients. SUBJECTS/METHODS BC was assessed with dual-energy X-ray absorptiometry in 28 NAFLD patients (19 men, 51±13 years, and 9 women, 47±13 years). BF depots ratios were calculated to assess BF distribution. Subjects' HRR was recorded 1 (HRR1) and 2 min (HRR2) immediately after a maximum graded exercise test. RESULTS BC and BF distribution were related to HRR; particularly weight, trunk BF and trunk BF-to-appendicular BF ratio showed a negative relation with HRR1 (r=-0.613, r=-0.597 and r=-0.547, respectively, P<0.01) and HRR2 (r=-0.484, r=-0.446, P<0.05, and r=-0.590, P<0.01, respectively). Age seems to be related to both HRR1 and HRR2 except when controlled for BF distribution. The preferred model in multiple regression should include trunk BF-to-appendicular BF ratio and BF to predict HRR1 (r2=0.549; P<0.05), and trunk BF-to-appendicular BF ratio alone to predict HRR2 (r2=0.430; P<0.001). CONCLUSIONS BC and BF distribution were related to HRR in NAFLD patients. Trunk BF-to-appendicular BF ratio was the best independent predictor of HRR and therefore may be best related to cardiovascular increased risk, and possibly act as a mediator in age-related cardiac autonomic control variation.
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Affiliation(s)
- N M Pimenta
- 1] Exercise and Health Laboratory, Interdisciplinary Centre for the Study of Human Performance, Faculty of Human Kinetics, Technical University of Lisbon, Cruz-Quebrada, Portugal [2] Physical Activity and Health MS, Sport Sciences School of Rio Maior, Polytechnic Institute of Santarém, Rio Maior, Portugal
| | - H Santa-Clara
- Exercise and Health Laboratory, Interdisciplinary Centre for the Study of Human Performance, Faculty of Human Kinetics, Technical University of Lisbon, Cruz-Quebrada, Portugal
| | - H Cortez-Pinto
- Unidade de Nutrição e Metabolismo, Departamento de Gastrenterologia, IMM, FML, Hospital Universitário de Santa Maria, Lisbon, Portugal
| | - J Silva-Nunes
- Endocrinology Department, Curry Cabral Hospital, Lisbon, Portugal
| | - M da Lapa Rosado
- Exercise and Health Laboratory, Interdisciplinary Centre for the Study of Human Performance, Faculty of Human Kinetics, Technical University of Lisbon, Cruz-Quebrada, Portugal
| | - P J Sousa
- Cardiology Department, Santa Cruz Hospital, Carnaxide, Portugal
| | - R Calé
- Cardiology Department, Garcia de Orta Hospital, Almada, Portugal
| | - X Melo
- Exercise and Health Laboratory, Interdisciplinary Centre for the Study of Human Performance, Faculty of Human Kinetics, Technical University of Lisbon, Cruz-Quebrada, Portugal
| | - L B Sardinha
- Exercise and Health Laboratory, Interdisciplinary Centre for the Study of Human Performance, Faculty of Human Kinetics, Technical University of Lisbon, Cruz-Quebrada, Portugal
| | - B Fernhall
- Dean of the College of Applied Health Sciences, University of Illinois, Chicago, IL, USA
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Park HJ, Han JM, Kim HG, Choi MK, Lee JS, Lee HW, Son CG. Chunggan extract (CGX), methionine-and choline-deficient (MCD) diet-induced hepatosteatosis and oxidative stress in C57BL/6 mice. Hum Exp Toxicol 2013; 32:1258-1269. [PMID: 23970447 DOI: 10.1177/0960327113485253] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In the present study, we aimed to evaluate the hepatoprotective and antioxidant effects of Chunggan extract (CGX) in an animal model of hepatosteatosis. The C57BL/6N mice were fed either methionine- and choline-sufficient (MCS) diet (n = 10) or a methionine- and choline-deficient (MCD) diet (n = 50) for 4 weeks, and then they were treated orally with CGX (100 or 200 mg/kg), ursodeoxycholic acid (80 mg/kg, as a positive control), or distilled water (DW, MCS diet group, and MCD diet group) for the final 2 weeks (once per day). The MCD diet induced severe hepatic injury with the typical features of hepatosteatosis in both serum and hepatic tissues. CGX treatment significantly attenuated these alterations in the serum levels including triglyceride (TG), aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin. Moreover, CGX also efficiently prevented from the hepatic TG accumulation in the hepatic tissue, evidenced by histopathological findings, compared with the MCD diet. In addition, CGX treatment significantly ameliorated the excessive oxidative stress and antioxidant markers in the serum as well as the hepatic levels of reactive oxygen species, the levels of malondialdehyde, the protein carbonyl, and total antioxidant capacity, and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. In conclusion, our results indicate the experimental relevance of CGX for potential clinical application in patients with hepatosteatotic disorders and a possible mechanism related to its antioxidant properties.
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Affiliation(s)
- H-J Park
- 1Department of Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, Republic of Korea
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