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Lupu A, Mihai CM, Dragan F, Tarnita I, Alecsa M, Chisnoiu T, Morariu ID, Cuciureanu M, Nedelcu AH, Salaru DL, Anton E, Danielescu C, Fotea S, Stoleriu G, Beser OF, Lupu VV. Antioxidant Supplementation in Childhood Obesity: A Path to Improved Metabolic Health? Antioxidants (Basel) 2025; 14:466. [PMID: 40298814 PMCID: PMC12024302 DOI: 10.3390/antiox14040466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 04/30/2025] Open
Abstract
Childhood obesity is linked to heightened oxidative stress, a key driver of endothelial dysfunction, inflammation, and metabolic complications. Antioxidants, including Vitamins C and E, are vital in neutralizing free radicals and mitigating oxidative damage. This non-systematic review examines the potential advantages of antioxidant supplementation in pediatric obesity, focusing on its effects on vascular health, insulin sensitivity, and inflammatory processes. Emerging data suggest that antioxidants may improve endothelial function, reduce blood pressure, and enhance metabolic homeostasis in obese children. However, the long-term efficacy and safety of antioxidant supplementation remain uncertain, necessitating further rigorous randomized controlled trials. A deeper understanding of antioxidants' role in pediatric obesity could unlock novel therapeutic approaches for managing obesity-related complications and improving children's overall health outcomes.
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Affiliation(s)
- Ancuta Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.L.); (M.A.); (V.V.L.)
| | - Cristina Maria Mihai
- Pediatrics, Faculty of Medicine, “Ovidius” University, 900470 Constanta, Romania; (C.M.M.); (T.C.)
| | - Felicia Dragan
- Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Irina Tarnita
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.L.); (M.A.); (V.V.L.)
| | - Mirabela Alecsa
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.L.); (M.A.); (V.V.L.)
| | - Tatiana Chisnoiu
- Pediatrics, Faculty of Medicine, “Ovidius” University, 900470 Constanta, Romania; (C.M.M.); (T.C.)
| | - Ionela Daniela Morariu
- Faculty of Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Magdalena Cuciureanu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (A.H.N.); (D.L.S.); (E.A.); (C.D.)
| | - Alin Horatiu Nedelcu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (A.H.N.); (D.L.S.); (E.A.); (C.D.)
| | - Delia Lidia Salaru
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (A.H.N.); (D.L.S.); (E.A.); (C.D.)
| | - Emil Anton
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (A.H.N.); (D.L.S.); (E.A.); (C.D.)
| | - Ciprian Danielescu
- Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (M.C.); (A.H.N.); (D.L.S.); (E.A.); (C.D.)
| | - Silvia Fotea
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunarea de Jos” University of Galati, 800008 Galati, Romania; (S.F.); (G.S.)
| | - Gabriela Stoleriu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunarea de Jos” University of Galati, 800008 Galati, Romania; (S.F.); (G.S.)
| | - Omer Faruk Beser
- Department of Pediatric Gastroenterology, Hepatology & Nutrition, Cerrahpasa Medical Faculty, Istanbul University Cerrahpasa, 34776 Istanbul, Turkey;
| | - Vasile Valeriu Lupu
- Pediatrics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.L.); (M.A.); (V.V.L.)
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Guo Y, Tian W, Wang D, Yang L, Wang Z, Wu X, Zhi Y, Zhang K, Wang Y, Li Z, Jiang R, Sun G, Li G, Tian Y, Wang H, Kang X, Liu X, Li H. LncHLEF promotes hepatic lipid synthesis through miR-2188-3p/GATA6 axis and encoding peptides and enhances intramuscular fat deposition via exosome. Int J Biol Macromol 2023; 253:127061. [PMID: 37751822 DOI: 10.1016/j.ijbiomac.2023.127061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 08/29/2023] [Accepted: 09/20/2023] [Indexed: 09/28/2023]
Abstract
Long noncoding RNAs (lncRNAs) have emergingly been implicated in mammalian lipid metabolism. However, their biological functions and regulatory mechanisms underlying adipogenesis remain largely elusive in chicken. Here, we systematically characterized the genome-wide full-length lncRNAs in the livers of pre- and peak-laying hens, and identified a novel intergenic lncRNA, lncHLEF, an RNA macromolecule with a calculated molecular weight of 433 kDa. lncHLEF was primarily distributed in cytoplasm of chicken hepatocyte and significantly up-regulated in livers of peak-laying hens. Functionally, lncHLEF could promote hepatocyte lipid droplet formation, triglycerides and total cholesterol contents. Mechanistically, lncHLEF could not only serve as a competitive endogenous RNA to modulate miR-2188-3p/GATA6 axis, but also encode three small functional polypeptides that directly interact with ACLY protein to enable its stabilization. Importantly, adeno-associated virus-mediated liver-specific lncHLEF overexpression resulted in increased hepatic lipid synthesis and intramuscular fat (IMF) deposition, but did not alter abdominal fat (AbF) deposition. Furthermore, hepatocyte lncHLEF could be delivered into intramuscular and abdominal preadipocytes via hepatocyte-secreted exosome to enhance intramuscular preadipocytes differentiation without altering abdominal preadipocytes differentiation. In conclusion, this study revealed that the lncHLEF could promote hepatic lipid synthesis through two independent regulatory mechanisms, and could enhance IMF deposition via hepatocyte-adipocyte communications mediated by exosome.
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Affiliation(s)
- Yulong Guo
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Weihua Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Dandan Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Liyu Yang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Zhang Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Xing Wu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Yihao Zhi
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Ke Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Yangyang Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China
| | - Zhuanjian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Ruirui Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Guirong Sun
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Hongjun Wang
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China.
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China.
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China.
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Cui Z, Jin N, Amevor FK, Shu G, Du X, Kang X, Ning Z, Deng X, Tian Y, Zhu Q, Wang Y, Li D, Zhang Y, Wang X, Han X, Feng J, Zhao X. Dietary Supplementation of Salidroside Alleviates Liver Lipid Metabolism Disorder and Inflammatory Response to Promote Hepatocyte Regeneration via PI3K/AKT/Gsk3-β Pathway. Poult Sci 2022; 101:102034. [PMID: 35926351 PMCID: PMC9356167 DOI: 10.1016/j.psj.2022.102034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 01/07/2023] Open
Abstract
Fatty liver hemorrhagic syndrome (FLHS) is a chronic hepatic disease which occurs when there is a disorder in lipid metabolism. FLHS is often observed in caged laying hens and characterized by a decrease in egg production and dramatic increase of mortality. Salidroside (SDS) is an herbal drug which has shown numerous pharmacological activities, such as protecting mitochondrial function, attenuating cell apoptosis and inflammation, and promoting antioxidant defense system. We aimed to determine the therapeutic effects of SDS on FLHS in laying hens and investigate the underlying mechanisms through which SDS operates these functions. We constructed oleic acid (OA)-induced fatty liver model in vitro and high-fat diet-induced FLHS of laying hens in vivo. The results indicated that SDS inhibited OA-induced lipid accumulation in chicken primary hepatocytes, increased hepatocyte activity, elevated the mRNA expression of proliferation related genes PCNA, CDK2, and cyclinD1 and increased the protein levels of PCNA and CDK2 (P < 0.05), as well as decreased the cleavage levels of Caspase-9, Caspase-8, and Caspase-3 and apoptosis in hepatocytes (P < 0.05). Moreover, SDS promoted the phosphorylation levels of PDK1, AKT, and Gsk3-β, while inhibited the PI3K inhibitor (P < 0.05). Additionally, we found that high-fat diet-induced FLHS hens had heavier body weight, liver weight, and abdominal fat weight, and severe steatosis in histology, compared with the control group (Con). However, hens fed with SDS maintained lighter body weight, liver weight, and abdominal fat weight, as well as normal liver without hepatic steatosis. In addition, high-fat diet-induced FLHS hens had high levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate aminotransferase (AST) compared to the Con group, however, in the Model+SDS group, the levels of TC, TG, ALT, and AST decreased significantly, whereas the level of superoxide dismutase (SOD) increased significantly (P < 0.05). We also found that SDS significantly decreased the mRNA expression abundance of PPARγ, SCD, and FAS in the liver, as well as increased levels of PPARα and MTTP, and decreased the mRNA expression of TNF-α, IL-1β, IL-6, and IL-8 in the Model+SDS group (P < 0.05). In summary, this study showed that 0.3 mg/mL SDS attenuated ROS generation, inhibited lipid accumulation and hepatocyte apoptosis, and promoted hepatocyte proliferation by targeting the PI3K/AKT/Gsk3-β pathway in OA-induced fatty liver model in vitro, and 20 mg/kg SDS alleviated high-fat-diet-induced hepatic steatosis, oxidative stress, and inflammatory response in laying hens in vivo.
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Affiliation(s)
- Zhifu Cui
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China; College of Animal Science and Technology, Southwest University, Chongqing, P. R. China
| | - Ningning Jin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Gang Shu
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan Province, P. R. China
| | - Xiaxia Du
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Xincheng Kang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Zifan Ning
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Xun Deng
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Yaofu Tian
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Qing Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Yan Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Diyan Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Yao Zhang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China
| | - Xiaoqi Wang
- Agriculture and Animal Husbandry Comprehensive Service Center of Razi County, Tibet Autonomous Region, P. R. China
| | - Xue Han
- Guizhou Institute of Animal Husbandry and Veterinary Medicine, Guizhou province, P. R. China
| | - Jing Feng
- Institute of Animal Husbandry and Veterinary Medicine, College of Agriculture and Animal Husbandry, Tibet Autonomous Region, P. R. China
| | - Xiaoling Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China.
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Rodríguez-Antonio I, López-Sánchez GN, Garrido-Camacho VY, Uribe M, Chávez-Tapia NC, Nuño-Lámbarri N. Cholecystectomy as a risk factor for non-alcoholic fatty liver disease development. HPB (Oxford) 2020; 22:1513-1520. [PMID: 32773176 DOI: 10.1016/j.hpb.2020.07.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/12/2019] [Accepted: 07/07/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic steatosis and gallstone disease are highly prevalent in the general population; the shared risk factors are age, ethnicity, obesity, insulin resistance, metabolic syndrome, atherosclerosis, risk of cardiovascular disease, and mortality. The presence of insulin resistance is the critical element in this association because it represents a crucial link between metabolic syndrome and non-alcoholic fatty liver disease, as well as a higher susceptibility to gallstone formation. METHODS An exhaustive search engine investigation of gallstone disease, cholecystectomy, and liver steatosis latest literature was made. RESULTS Clinical studies and systematic reviews suggest an association between gallstone disease, cholecystectomy, and hepatic steatosis. CONCLUSION The bidirectional relationship between liver steatosis and gallstone disease and cholecystectomy is summarized in the role of insulin resistance, lipid metabolism, bile acids signaling pathways regulated by transcription factors expression, and to the gallbladder physiological role; however, more epidemiological and experimental studies should be complemented.
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Affiliation(s)
- Itzayana Rodríguez-Antonio
- Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico; School of Medicine, Benemérita Universidad Autónoma de Puebla, 13 Sur 2702, Los Volcanes, Z.C. 72420, Puebla, Mexico
| | - Guillermo N López-Sánchez
- Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico
| | - Victor Y Garrido-Camacho
- Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico
| | - Norberto C Chávez-Tapia
- Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico; Obesity and Digestive Diseases Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico
| | - Natalia Nuño-Lámbarri
- Translational Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra Tlalpan, Z.C. 14050, Mexico City, Mexico.
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Wang HH, Lee DK, Liu M, Portincasa P, Wang DQH. Novel Insights into the Pathogenesis and Management of the Metabolic Syndrome. Pediatr Gastroenterol Hepatol Nutr 2020; 23:189-230. [PMID: 32483543 PMCID: PMC7231748 DOI: 10.5223/pghn.2020.23.3.189] [Citation(s) in RCA: 148] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/17/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
The metabolic syndrome, by definition, is not a disease but is a clustering of individual metabolic risk factors including abdominal obesity, hyperglycemia, hypertriglyceridemia, hypertension, and low high-density lipoprotein cholesterol levels. These risk factors could dramatically increase the prevalence of type 2 diabetes and cardiovascular disease. The reported prevalence of the metabolic syndrome varies, greatly depending on the definition used, gender, age, socioeconomic status, and the ethnic background of study cohorts. Clinical and epidemiological studies have clearly demonstrated that the metabolic syndrome starts with central obesity. Because the prevalence of obesity has doubly increased worldwide over the past 30 years, the prevalence of the metabolic syndrome has markedly boosted in parallel. Therefore, obesity has been recognized as the leading cause for the metabolic syndrome since it is strongly associated with all metabolic risk factors. High prevalence of the metabolic syndrome is not unique to the USA and Europe and it is also increasing in most Asian countries. Insulin resistance has elucidated most, if not all, of the pathophysiology of the metabolic syndrome because it contributes to hyperglycemia. Furthermore, a major contributor to the development of insulin resistance is an overabundance of circulating fatty acids. Plasma fatty acids are derived mainly from the triglycerides stored in adipose tissues, which are released through the action of the cyclic AMP-dependent enzyme, hormone sensitive lipase. This review summarizes the latest concepts in the definition, pathogenesis, pathophysiology, and diagnosis of the metabolic syndrome, as well as its preventive measures and therapeutic strategies in children and adolescents.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Bari, Italy
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Tommasi S, Yoon JI, Besaratinia A. Secondhand Smoke Induces Liver Steatosis through Deregulation of Genes Involved in Hepatic Lipid Metabolism. Int J Mol Sci 2020; 21:E1296. [PMID: 32075112 PMCID: PMC7072934 DOI: 10.3390/ijms21041296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/05/2020] [Accepted: 02/13/2020] [Indexed: 12/24/2022] Open
Abstract
We investigated the role of secondhand smoke (SHS) exposure, independently of diet, in the development of chronic liver disease. Standard diet-fed mice were exposed to SHS (5 h/day, 5 days/week for 4 months). Genome-wide gene expression analysis, together with molecular pathways and gene network analyses, and histological examination for lipid accumulation, inflammation, fibrosis, and glycogen deposition were performed on the liver of SHS-exposed mice and controls, upon termination of exposure and after one-month recovery in clean air. Aberrantly expressed transcripts were found in the liver of SHS-exposed mice both pre- and post-recovery in clean air (n = 473 vs. 222). The persistent deregulated transcripts (n = 210) predominantly affected genes and functional networks involved in lipid metabolism as well as in the regulation of the endoplasmic reticulum where manufacturing of lipids occurs. Significant hepatic fat accumulation (steatosis) was observed in the SHS-exposed mice, which progressively increased as the animals underwent recovery in clean air. Moderate increases in lobular inflammation infiltrates and collagen deposition as well as loss of glycogen were also detectable in the liver of SHS-exposed mice. A more pronounced phenotype, manifested as a disrupted cord-like architecture with foci of necrosis, apoptosis, inflammation, and macrovesicular steatosis, was observed in the liver of SHS-exposed mice post-recovery. The progressive accumulation of hepatic fat and other adverse histological changes in the SHS-exposed mice are highly consistent with the perturbation of key lipid genes and associated pathways in the corresponding animals. Our data support a role for SHS in the genesis and progression of metabolic liver disease through deregulation of genes and molecular pathways and functional networks involved in lipid homeostasis.
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Affiliation(s)
- Stella Tommasi
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
| | - Jae-In Yoon
- Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA;
| | - Ahmad Besaratinia
- Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
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Wang X, Xing C, Yang F, Zhou S, Li G, Zhang C, Cao H, Hu G. Abnormal expression of liver autophagy and apoptosis-related mRNA in fatty liver haemorrhagic syndrome and improvement function of resveratrol in laying hens. Avian Pathol 2020; 49:171-178. [PMID: 31774299 DOI: 10.1080/03079457.2019.1698712] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Fatty liver haemorrhagic syndrome (FLHS) is characterized by hepatic rupture and haemorrhage leading to sudden death in laying hens. Resveratrol (Res) is a natural polyphenol with antioxidant and anti-inflammatory effects that can ameliorate chronic liver disease. The aim of this study was to investigate the improved effect of Res on the altered expression of autophagy and apoptosis-related genes in laying hens with FLHS. A total of 144 healthy 150-day-old laying hens were randomly divided into four groups: control group (standard diet), HELP group (high-energy-low-protein (HELP) diet), HELP + Res group (HELP diet with 400 mg/kg Res) and Res group (standard diet with 400 mg/kg Res). Histopathological lesions of the liver and the mRNA levels of Beclin-1, Atg5, Atg7, p62, Bcl-2, Bax and Caspase-3 on days 40, 80, and 120 were measured. The results showed that lipid accumulation and hepatocyte damage in the HELP group were more serious than those in the HELP + Res group. The mRNA levels of Beclin-1, Atg5, Atg7, and Bcl-2 in the HELP and HELP + Res groups were strikingly declined (P < 0.01) compared to the control group, and their mRNA levels were markedly higher in HELP group than those in the HELP + Res group (P < 0.05). Additionally, the mRNA levels of p62, Bax and Caspase-3 were significantly increased in the HELP and HELP + Res groups (P < 0.01 or P < 0.05), but their mRNA levels in the HELP group were higher than those in the HELP + Res group (P < 0.05). Collectively, FLHS could induce severe lipid accumulation, abnormal mRNA levels of liver autophagy and apoptosis-related genes. Res as a dietary supplement could attenuate these abnormal changes.
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Affiliation(s)
- Xiaoyu Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Chenghong Xing
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Fan Yang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Sihui Zhou
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Guyue Li
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China
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Zhao L, Rao S, Zhu X, Liu S, Tao Q, Yang X, Zhu Y, Hu J. Coicis Semen formula treating monosodium glutamate-induced obesity in mice by alleviating hypothalamic injury. FOOD AGR IMMUNOL 2019. [DOI: 10.1080/09540105.2019.1703911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Lijun Zhao
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Shiyu Rao
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Xiaoqiang Zhu
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Shuo Liu
- Joint Laboratory for the Research of Pharmaceutics, Huazhong University of Science and Technology and Infinitus, Wuhan, People’s Republic of China
| | - Qian Tao
- Joint Laboratory for the Research of Pharmaceutics, Huazhong University of Science and Technology and Infinitus, Wuhan, People’s Republic of China
| | - Xiangliang Yang
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yanhong Zhu
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jun Hu
- College of Life Science and Technology, National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
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DNA Hydroxymethylation at the Interface of the Environment and Nonalcoholic Fatty Liver Disease. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16152791. [PMID: 31387232 PMCID: PMC6695744 DOI: 10.3390/ijerph16152791] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 08/02/2019] [Accepted: 08/03/2019] [Indexed: 12/25/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disorders among adults, children, and adolescents, and a growing epidemic, worldwide. Notwithstanding the known susceptibility factors for NAFLD, i.e., obesity and metabolic syndrome, the exact cause(s) of this disease and the underlying mechanisms of its initiation and progression are not fully elucidated. NAFLD is a multi-faceted disease with metabolic, genetic, epigenetic, and environmental determinants. Accumulating evidence shows that exposure to environmental toxicants contributes to the development of NAFLD by promoting mitochondrial dysfunction and generating reactive oxygen species in the liver. Imbalances in the redox state of the cells are known to cause alterations in the patterns of 5-hydroxymethylcytosine (5hmC), the oxidative product of 5-methylcytosine (5mC), thereby influencing gene regulation. The 5hmC-mediated deregulation of genes involved in hepatic metabolism is an emerging area of research in NAFLD. This review summarizes our current knowledge on the interactive role of xenobiotic exposure and DNA hydroxymethylation in the pathogenesis of fatty liver disease. Increasing the mechanistic knowledge of NAFLD initiation and progression is crucial for the development of new and effective strategies for prevention and treatment of this disease.
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10
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Guo L, Guo YY, Li BY, Peng WQ, Chang XX, Gao X, Tang QQ. Enhanced acetylation of ATP-citrate lyase promotes the progression of nonalcoholic fatty liver disease. J Biol Chem 2019; 294:11805-11816. [PMID: 31197036 DOI: 10.1074/jbc.ra119.008708] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/11/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatic steatosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and is promoted by dysregulated de novo lipogenesis. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is up-regulated in individuals with NAFLD. A previous study has shown that acetylation of ACLY at Lys-540, Lys-546, and Lys-554 (ACLY-3K) increases ACLY protein stability by antagonizing its ubiquitylation, thereby promoting lipid synthesis and cell proliferation in lung cancer cells. But the functional importance of this regulatory mechanism in other cellular or tissue contexts or under other pathophysiological conditions awaits further investigation. Here, we show that ACLY-3K acetylation also promotes ACLY protein stability in AML12 cells, a mouse hepatocyte cell line, and found that the deacetylase sirtuin 2 (SIRT2) deacetylates ACLY-3K and destabilizes ACLY in these cells. Of note, the livers of mice and humans with NAFLD had increased ACLY protein and ACLY-3K acetylation levels and decreased SIRT2 protein levels. Mimicking ACLY-3K acetylation by replacing the three lysines with three glutamines (ACLY-3KQ variant) promoted lipid accumulation both in high glucose-treated AML12 cells and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, overexpressing SIRT2 in AML12 cells inhibited lipid accumulation, which was more efficiently reversed by overexpressing the ACLY-3KQ variant than by overexpressing WT ACLY. Additionally, hepatic SIRT2 overexpression decreased ACLY-3K acetylation and its protein level and alleviated hepatic steatosis in HF/HS diet-fed mice. Our findings reveal a posttranscriptional mechanism underlying the up-regulation of hepatic ACLY in NAFLD and suggest that the SIRT2/ACLY axis is involved in NAFLD progression.
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Affiliation(s)
- Liang Guo
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ying-Ying Guo
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Bai-Yu Li
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wan-Qiu Peng
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xin-Xia Chang
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xin Gao
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qi-Qun Tang
- Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of the School of Basic Medical Sciences and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai 200032, China
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11
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Coupling of COPII vesicle trafficking to nutrient availability by the IRE1α-XBP1s axis. Proc Natl Acad Sci U S A 2019; 116:11776-11785. [PMID: 31123148 DOI: 10.1073/pnas.1814480116] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The cytoplasmic coat protein complex-II (COPII) is evolutionarily conserved machinery that is essential for efficient trafficking of protein and lipid cargos. How the COPII machinery is regulated to meet the metabolic demand in response to alterations of the nutritional state remains largely unexplored, however. Here, we show that dynamic changes of COPII vesicle trafficking parallel the activation of transcription factor X-box binding protein 1 (XBP1s), a critical transcription factor in handling cellular endoplasmic reticulum (ER) stress in both live cells and mouse livers upon physiological fluctuations of nutrient availability. Using live-cell imaging approaches, we demonstrate that XBP1s is sufficient to promote COPII-dependent trafficking, mediating the nutrient stimulatory effects. Chromatin immunoprecipitation (ChIP) coupled with high-throughput DNA sequencing (ChIP-seq) and RNA-sequencing analyses reveal that nutritional signals induce dynamic XBP1s occupancy of promoters of COPII traffic-related genes, thereby driving the COPII-mediated trafficking process. Liver-specific disruption of the inositol-requiring enzyme 1α (IRE1α)-XBP1s signaling branch results in diminished COPII vesicle trafficking. Reactivation of XBP1s in mice lacking hepatic IRE1α restores COPII-mediated lipoprotein secretion and reverses the fatty liver and hypolipidemia phenotypes. Thus, our results demonstrate a previously unappreciated mechanism in the metabolic control of liver protein and lipid trafficking: The IRE1α-XBP1s axis functions as a nutrient-sensing regulatory nexus that integrates nutritional states and the COPII vesicle trafficking.
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Gao X, Liu P, Wu C, Wang T, Liu G, Cao H, Zhang C, Hu G, Guo X. Effects of fatty liver hemorrhagic syndrome on the AMP-activated protein kinase signaling pathway in laying hens. Poult Sci 2019; 98:2201-2210. [DOI: 10.3382/ps/pey586] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 12/12/2018] [Indexed: 12/21/2022] Open
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13
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Cekdemir D. Correlation of Liver Enzyme Levels and Insulin Resistance in Patients with Non-Alcoholic Steatosis. ANKARA MEDICAL JOURNAL 2019. [DOI: 10.17098/amj.542200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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14
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Lee SH, Kim MJ, Kim YS, Chun H, Won BY, Lee JH, Han K, Rim KS, Park KC. Low hair copper concentration is related to a high risk of nonalcoholic fatty liver disease in adults. J Trace Elem Med Biol 2018; 50:28-33. [PMID: 30262292 DOI: 10.1016/j.jtemb.2018.06.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 06/01/2018] [Accepted: 06/01/2018] [Indexed: 12/19/2022]
Abstract
Copper, an essential micronutrient, is required for lipid metabolism, mitochondrial function, iron metabolism, and antioxidant defense. Copper deficiency has been linked to alterations in lipid metabolism and various metabolic processes of the liver, including nonalcoholic fatty liver disease (NAFLD); however, most of these studies relied on copper measurements in the blood or tissues. In this study, we investigated the association between hair copper concentration and NAFLD in Korean adults, independent of metabolic syndrome status. Clinical and laboratory parameters, including factors of metabolic syndrome, were analyzed in 751 Korean adults divided into quintiles, according to hair copper concentration. Lower hair copper concentration was significantly correlated with higher body mass index, waist circumference, blood pressure, and lower levels of high-density lipoprotein cholesterol. Subjects with NAFLD showed significantly lower hair copper concentrations, and the risk of NAFLD was significantly higher for the lower hair copper quintile groups even after adjusting for metabolic syndrome-related factors. Overall, this study suggests that lower hair copper concentration could be associated with NAFLD, independent of metabolic syndrome factors.
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Affiliation(s)
- Soo-Hyun Lee
- Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Moon-Jong Kim
- Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Young-Sang Kim
- Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Hyejin Chun
- Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Bo Youn Won
- Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Joo-Ho Lee
- Department of Internal Medicine, Division of Hepatology, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Kunhee Han
- Department of Family Medicine, Seoul Metropolitan Seonam Hospital, Seoul 08049, Republic of Korea
| | - Kyu-Sung Rim
- Health Promotion Center, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea
| | - Kyung-Chae Park
- Health Promotion Center, CHA Bundang Medical Center, CHA University, Seongnam 13496, Republic of Korea.
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Tung YT, Huang CZ, Lin JH, Yen GC. Effect of Phyllanthus emblica L. fruit on methionine and choline-deficiency diet-induced nonalcoholic steatohepatitis. J Food Drug Anal 2018; 26:1245-1252. [PMID: 30249323 PMCID: PMC9298569 DOI: 10.1016/j.jfda.2017.12.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/04/2017] [Accepted: 12/17/2017] [Indexed: 11/18/2022] Open
Abstract
Phyllanthus emblica L. fruit contains abundant bioactive components and exhibits a variety of biological activities. In this study, the hepatoprotective effect of water extract of P. emblica (WEPE) on nonalcoholic steatohepatitis (NASH) was evaluated. C57BL/6 mice were fed methionine and choline-deficiency diet (MCD diet) for 4 or 8 weeks to induce NASH. Results showed that administration of WEPE could significantly reduce serum AST and ALT as compared to MCD diet-alone group. Administration of WEPE could significantly decrease lipid peroxidation and CYP2E1 mRNA expression, and elevate the antioxidant activities in mice livers. In addition, administration of WEPE after 8 weeks could significantly decrease the mRNA expressions of TNF-α and IL-1β in mice livers, but have less improving effect of hepatic steatosis and mononuclear cell infiltration. Taken together, MCD diet might cause serious hepatic steatosis and mild inflammation in mice livers, but administration of WEPE could ameliorate the rapid progression of NASH.
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Affiliation(s)
- Yu-Tang Tung
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 110, Taiwan, ROC
| | - Cheng-Ze Huang
- Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung, 40227, Taiwan, ROC
| | - Jia-Hong Lin
- Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung, 40227, Taiwan, ROC
| | - Gow-Chin Yen
- Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung, 40227, Taiwan, ROC.
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16
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Abdel Monem SM. Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals. Euroasian J Hepatogastroenterol 2017; 7:101-106. [PMID: 29201787 PMCID: PMC5663789 DOI: 10.5005/jp-journals-10018-1226] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/23/2016] [Indexed: 12/11/2022] Open
Abstract
Aim: Nonalcoholic fatty liver disease (NAFLD) is probably the most common liver disorder in the world. A subgroup of NAFLD patients is characterized by injury to the hepatocytes and inflammation in addition to excessive fat (steatohepatitis), the latter condition is nominated nonalcoholic steatohepatitis (NASH). This work aimed to evaluate the role of probiotics on the outcome of NASH in patients admitted to the Tropical Medicine Department, Faculty of Medicine, Zagazig University (inpatients and outpatients). Materials and methods: This study was performed on 30 patients (17 males and 13 females), with body mass index from 30 to 35 and average age of 44 years with bright fatty liver in ultrasonography and raised alanine transaminase (ALT) and aspartate transaminase (AST) and positive liver biopsy findings. The patients were divided into group I (case group) that included 15 patients who received probiotics and group II of 15 patients as control group who did not receive probiotics; the study was conducted between November 2014 and April 2016. Clinical assessment, laboratory evaluation, pelvic-abdominal ultrasound, and liver biopsy of all cases were carried out. Results: In this study, there was significant decrease in liver enzymes (ALT and AST) and no statistically significant other laboratory findings. Also there was relief for dyspepsia in some patients. Conclusion: Probiotics treatment is effective, safe, well-tolerated, inexpensive, appropriate for long-term use, and optimally, works at multiple levels to downregulate inflammatory mediators, and therefore, probiotics could be an option in the treatment of NASH. How to cite this article: Monem SMA. Probiotic Therapy in Patients with Nonalcoholic Steatohepatitis in Zagazig University Hospitals. Euroasian J Hepato-Gastroenterol 2017;7(1):101-106.
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Affiliation(s)
- Sameh M Abdel Monem
- Department of Tropical Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Nishiyama K, Fujimoto Y, Takeuchi T, Azuma YT. Aggressive Crosstalk Between Fatty Acids and Inflammation in Macrophages and Their Influence on Metabolic Homeostasis. Neurochem Res 2017; 43:19-26. [PMID: 28424949 DOI: 10.1007/s11064-017-2269-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/09/2017] [Accepted: 04/12/2017] [Indexed: 02/08/2023]
Abstract
From the immunological point of view, macrophages are required to maintain metabolic homeostasis. Recently, there has been an increased focus on the influence of macrophage phenotypes in adipose tissue on the maintenance of metabolic homeostasis in healthy conditions because dysregulated metabolic homeostasis causes metabolic syndrome. This review notes several types of inflammatory and anti-inflammatory mediators in metabolic homeostasis. M1 macrophage polarization mediates inflammation, whereas M2 macrophage polarization mediates anti-inflammation. Fatty acids and their related factors mediate both inflammatory and anti-inflammatory responses. Saturated fatty acids and polyunsaturated fatty acids mediate inflammation, whereas marine-derived n-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, mediate anti-inflammation. In this review, we discuss the current understanding of the crosstalk between fatty acids and inflammation in macrophages and their influence on metabolic homeostasis.
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Affiliation(s)
- Kazuhiro Nishiyama
- Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, 1-58 Rinku-ohraikita, Izumisano, Osaka, 598-8531, Japan
| | - Yasuyuki Fujimoto
- Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, 1-58 Rinku-ohraikita, Izumisano, Osaka, 598-8531, Japan
| | - Tadayoshi Takeuchi
- Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, 1-58 Rinku-ohraikita, Izumisano, Osaka, 598-8531, Japan
| | - Yasu-Taka Azuma
- Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, 1-58 Rinku-ohraikita, Izumisano, Osaka, 598-8531, Japan.
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Activation of Insulin-PI3K/Akt-p70S6K Pathway in Hepatic Stellate Cells Contributes to Fibrosis in Nonalcoholic Steatohepatitis. Dig Dis Sci 2017; 62:968-978. [PMID: 28194671 DOI: 10.1007/s10620-017-4470-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 01/20/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIMS Hyperinsulinemia and insulin resistance are hallmark features of nonalcoholic fatty liver disease and steatohepatitis (NASH). It remains unclear whether and how insulin contributes to the development of fibrosis in NASH. In this study, we explored insulin signaling in the regulation of hepatic stellate cell (HSC) activation and the progression of NASH-fibrosis. METHODS Phosphorylation of Akt and p70S6K were examined in primary HSC and in a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet for 24 weeks. HSC activation was analyzed for the changes in cell morphology, intracellular lipid droplets, expression of α-SMA and cell proliferation. The serum markers and histology for NASH-fibrosis were also characterized in animals. RESULTS Insulin enhanced the expression of smooth muscle actin-α in quiescent but not in activated HSC in culture. Insulin-mediated activation of the PI3K/Akt-p70S6K pathway was involved in the regulation of profibrogenic effects of insulin. Although insulin did not stimulate HSC proliferation directly, the insulin-PI3K/Akt-p70S6K pathway was necessary for serum-enhanced cell proliferation during initial HSC activation. In a rat model of NASH-fibrosis induced by high-fat and high-cholesterol diet, hyperinsulinemia is associated with the activation of p70S6K and enhanced fibrosis. CONCLUSION The insulin-PI3K/Akt-p70S6K pathway plays an important role in the early activation of HSC. The profibrogenic effect of insulin is dependent on the activation stage of HSC. Dysregulation of the insulin pathway likely correlates with the development of fibrosis in NASH, suggesting a potentially novel antifibrotic target of inhibiting insulin signaling in HSC.
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Influence of Roux-en-Y Gastric Bypass on the Hepatocellular Function and Bile Flow of Obese Patients Assessed by Scintigraphy with DISIDA. Obes Surg 2016; 26:2718-2723. [DOI: 10.1007/s11695-016-2176-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Abstract
Hepatitis is damage and inflammation of the liver. It is triggered by both environmental and endogenous insults and is a platform for developing liver cirrhosis and cancer. Both innate and adaptive immune activation contribute to hepatic inflammation and disease. Viral hepatitis is the most common form of hepatitis and is typically associated with chronic viral infection. Alcohol-induced and non-alcoholic steatohepatitis are two rising hepatic problems. The innate immune inflammasome signaling cascade mediates the production of essential proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. These cytokines regulate hepatic cell interaction and crosstalk of the various inflammatory pathways and influence disease outcome.
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Affiliation(s)
- Amina A Negash
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA
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Pardina E, Ferrer R, Rossell J, Baena-Fustegueras JA, Lecube A, Fort JM, Caubet E, González Ó, Vilallonga R, Vargas V, Balibrea JM, Peinado-Onsurbe J. Diabetic and dyslipidaemic morbidly obese exhibit more liver alterations compared with healthy morbidly obese. BBA CLINICAL 2016; 5:54-65. [PMID: 27051590 PMCID: PMC4802404 DOI: 10.1016/j.bbacli.2015.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/17/2015] [Accepted: 12/22/2015] [Indexed: 12/14/2022]
Abstract
Background & aims To study the origin of fat excess in the livers of morbidly obese (MO) individuals, we analysed lipids and lipases in both plasma and liver and genes involved in lipid transport, or related with, in that organ. Methods Thirty-two MO patients were grouped according to the absence (healthy: DM − DL −) or presence of comorbidities (dyslipidemic: DM − DL +; or dyslipidemic with type 2 diabetes: DM + DL +) before and one year after gastric bypass. Results The livers of healthy, DL and DM patients contained more lipids (9.8, 9.5 and 13.7 times, respectively) than those of control subjects. The genes implicated in liver lipid uptake, including HL, LPL, VLDLr, and FAT/CD36, showed increased expression compared with the controls. The expression of genes involved in lipid-related processes outside of the liver, such as apoB, PPARα and PGC1α, CYP7a1 and HMGCR, was reduced in these patients compared with the controls. PAI1 and TNFα gene expression in the diabetic livers was increased compared with the other obese groups and control group. Increased steatosis and fibrosis were also noted in the MO individuals. Conclusions Hepatic lipid parameters in MO patients change based on their comorbidities. The gene expression and lipid levels after bariatric surgery were less prominent in the diabetic patients. Lipid receptor overexpression could enable the liver to capture circulating lipids, thus favouring the steatosis typically observed in diabetic and dyslipidaemic MO individuals.
The criteria used to define the “metabolically healthy” obese is not applicable to morbidly obese patients. Virtually no studies of how bariatric surgery affects depending on comorbidities and less how affect to the liver. Anthropometrics, fat, lipid profile and inflammation parameters are different depending of comorbidities, not only in plasma but also in liver. The extent of lipases and lipids in the liver biopsies could help not only the diagnosis but also to follow the course of recovery after surgery. The morbidly obese individuals with diabetes and dyslipidemia have more altered metabolic profiles than the other two groups.
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Key Words
- ALT, Alanine transaminase
- AST, Aspartate transaminase
- ATGL, Adipose Tissue Glycerol Lipase
- ApoA1, Apolipoprotein A1
- BMI, Body Mass Index
- CPT1a, Carnitine Palmitoyltransferase 1a
- CRP, C-reactive protein
- CYP7a1, Cholesterol 7 Alpha-Hydroxylase
- DL, Dyslipidaemia
- DM, Type 2 diabetes mellitus
- DM + DL +, Obese patients with type 2 diabetes and dyslipidaemia
- DM − DL +, Dyslipidemic obese patients
- DM − DL −, “Healthy” obese patients, or patients without type 2 diabetes or dyslipidaemia
- Diabetes
- FAT/CD36, Fatty Acid Translocase or Cluster of Differentiation 36
- GGT, gamma-glutaryl transferase
- HL, Hepatic lipase
- HMGCR, 3-Hydroxy-3-Methylglutaryl-CoA Reductase
- HOMA-IR, Homeostasis Model Assessment of Insulin Resistance
- HSL, Hormone-sensitive lipase
- HTA, Hypertension
- IL6, Interleukin-6
- IR, Insulin resistance
- KBs, Ketone bodies
- LDLr, Low-Density Lipoprotein receptor
- Lipases
- Lipids
- Liver
- MO, Morbidly obese
- NAFLD
- NAFLD, Non-alcoholic fatty liver disease
- NASH, Non-alcoholic liver steatohepatitis
- NEFA, Non-esterified fatty acid
- PAI1, Plasminogen Activator Inhibitor of Type 1
- PLs, Phospholipids
- PPARα, Peroxisome Proliferator-Activated Receptor alpha
- PPARα, Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha
- QMs, Chylomicrons
- RYGBP, Roux-en-Y gastric bypass
- SAT, Subcutaneous adipose tissue
- SCARB1, Scavenger Receptor Class B, Member 1
- Steatosis
- TAGs, Triacylglycerides
- TC, Total cholesterol
- TNFα, Tumour Necrosis Factor-alpha
- UCP2, Uncoupling Protein 2
- VAT, Visceral adipose tissue
- VLDLr, Very-Low-Density Lipoprotein receptor
- apoB, Apolipoprotein B
- cHDL, High-Density Lipoprotein Cholesterol
- cLDL, Low-Density Lipoprotein Cholesterol
- eNOS3, Endothelial Nitric Oxide Synthase 3
- iNOS2, Inducible Nitric Oxide Synthase 2
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Affiliation(s)
- Eva Pardina
- Biochemistry and Molecular Biology Department, Biology Faculty, Barcelona University, Spain
| | - Roser Ferrer
- Biochemistry Department, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Joana Rossell
- Biochemistry and Molecular Biology Department, Biology Faculty, Barcelona University, Spain
| | | | - Albert Lecube
- Endocrinology and Nutrition Department, Arnau de Vilanova University Hospital (UdL), Diabetes and Metabolism Research Unit (VHIR, UAB), CIBER de Diabetes y Enfermedades Metabólicas (CIBERDEM) del Instituto de Salud Carlos III, Spain
| | - Jose Manuel Fort
- Endocrinology Surgery Unit, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Enric Caubet
- Endocrinology Surgery Unit, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Óscar González
- Endocrinology Surgery Unit, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Ramón Vilallonga
- Endocrinology Surgery Unit, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Víctor Vargas
- CIBER de Enfermedades Hepáticas y Digestivas (CIBEREHD) del Instituto de Salud Carlos III (ISCIII), Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - José María Balibrea
- Endocrinology Surgery Unit, Hospital Universitari Vall D'Hebron, Universitat Autònoma de Barcelona, Spain
| | - Julia Peinado-Onsurbe
- Biochemistry and Molecular Biology Department, Biology Faculty, Barcelona University, Spain
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Hepatic scavenger receptor BI is associated with type 2 diabetes but unrelated to human and murine non-alcoholic fatty liver disease. Biochem Biophys Res Commun 2015; 467:377-82. [PMID: 26431876 DOI: 10.1016/j.bbrc.2015.09.149] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 09/27/2015] [Indexed: 02/07/2023]
Abstract
Scavenger receptor, class B type I (SR-BI) is a physiologically relevant regulator of high density lipoprotein (HDL) metabolism. Low HDL is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). Here, hepatic SR-BI expression was analyzed in human and murine NAFLD. In primary human hepatocytes NAFLD relevant factors like inflammatory cytokines, lipopolysaccharide and TGF-β did not affect SR-BI protein. Similarly, oleate and palmitate had no effect. The adipokines chemerin, adiponectin, leptin and omentin did not regulate SR-BI expression. Accordingly, hepatic SR-BI was not changed in human and murine fatty liver and non-alcoholic steatohepatits. SR-BI was higher in type 2 diabetes patients but not in those with hypercholesterolemia. The current study indicates a minor if any role of SR-BI in human and murine NAFLD.
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Miranda-Henriques MSD, Diniz MDFFDM, Araújo MSTD. Ginseng, green tea or fibrate: valid options for nonalcoholic steatohepatitis prevention? ARQUIVOS DE GASTROENTEROLOGIA 2015; 51:255-60. [PMID: 25296088 DOI: 10.1590/s0004-28032014000300016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/20/2014] [Indexed: 01/14/2023]
Abstract
OBJECTIVES Panax ginseng, Camellia sinensis and bezafibrate were compared for their lipid-lowering, antioxidant and anti-inflammatory properties as potential agents to prevent nonalcoholic fatty liver disease and its progression to nonalcoholic steatohepatitis. METHODS Fifty Wistar rats were randomized into five groups: G1 (feed with standard diet); G2 (feed with high-fat diet with 58% of energy from fat); G3 (high-fat diet + standardized Panax ginseng extract at 100 mg/kg/day); G4 (high-fat diet + standardized Camellia sinensis extract at 100 mg/kg/day); and G5 (high-fat diet + bezafibrate at 100 mg/kg/day), given by gavage. The animals were sacrificed eight weeks later and blood was collected for glucose, insulin, cholesterol, triglycerides, AST, ALT, alkaline phosphatase and gamma-glutamyl transferase determinations. The score system for nonalcoholic fatty liver disease was used to analyse the liver samples. RESULTS AND CONCLUSIONS High-fat diet resulted in a significant increase in animal body weight, biochemical changes and enzymatic elevations. Steatosis, inflammation and hepatocellular ballooning scores were significant high in this group. The biochemical and histological variables were statistically similar in the bezafibrate group and control group. Treatment with Panax ginseng extract prevented obesity and histological features of nonalcoholic steatohepatitis (steatosis and inflammation) compared to high-fat diet. Camellia sinensis showed a less effective biochemical response, with small reduction in steatosis and inflammation but lower ballooning scores.
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Nonalcoholic fatty liver disease: different classifications concordance and relationship between degrees of morphological features and spectrum of the disease. Anal Cell Pathol (Amst) 2014; 2014:526979. [PMID: 25763333 PMCID: PMC4333905 DOI: 10.1155/2014/526979] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 10/16/2014] [Indexed: 12/27/2022] Open
Abstract
The morphological features of nonalcoholic fatty liver disease (NAFLD) range from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Liver biopsy remains the main tool for NASH diagnosis and many histological systems to diagnose and grade NAFLD were proposed. We evaluated the relationship among NAFLD activity score (NAS), histological diagnoses (non-NASH, possible NASH, and definite NASH), and histological algorithm proposed by Bedossa et al.; additionally the degrees of morphological features were semiquantified and correlated with non-NASH and NASH. Seventy-one liver biopsies were studied. The agreement among the three systems considering NASH and non-NASH was excellent (Κ = 0.96). Among the 22 biopsies with NAS 3-4, 72.7% showed to be NASH according to Bedossa's algorithm. The degree of steatosis, ballooning, lobular inflammation, and fibrosis stage were correlated with NASH (P < 0.001). Fibrosis stage 1 was also found in non-NASH. Over the spectrum of NAFLD, no association was observed between intensity of steatosis and fibrosis grade. The degrees of lobular inflammation showed association with fibrosis stage (P < 0.0001). In conclusion, there is agreement among different NAFLD classifications and NAS > 4 may be a better cutoff from which to consider NASH diagnosis; besides the highest degrees of steatosis, ballooning, inflammation, and fibrosis are associated with NASH.
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Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20:15539-15548. [PMID: 25400438 PMCID: PMC4229519 DOI: 10.3748/wjg.v20.i42.15539] [Citation(s) in RCA: 317] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 03/05/2014] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.
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Renaud HJ, Cui YJ, Lu H, Zhong XB, Klaassen CD. Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing. PLoS One 2014; 9:e104560. [PMID: 25102070 PMCID: PMC4125194 DOI: 10.1371/journal.pone.0104560] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 07/14/2014] [Indexed: 12/18/2022] Open
Abstract
The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age). The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5–Day 5 (perinatal-enriched), Day 10–Day 20 (pre-weaning-enriched), and Day 25–Day 60 (adolescence/adulthood-enriched). Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty acids-like 3. These data shed new light on the ontogeny of homeostatic regulation of hepatic energy metabolism, which could ultimately provide new therapeutic targets for metabolic diseases.
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Affiliation(s)
- Helen J. Renaud
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Yue Julia Cui
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York, United States of America
| | - Xiao-bo Zhong
- Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut, United States of America
| | - Curtis D. Klaassen
- College of Medicine, University of Kansas, Kansas City, Kansas, United States of America
- * E-mail:
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Leite NC, Villela-Nogueira CA, Cardoso CRL, Salles GF. Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosis and treatment. World J Gastroenterol 2014; 20:8377-8392. [PMID: 25024596 PMCID: PMC4093691 DOI: 10.3748/wjg.v20.i26.8377] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 12/01/2013] [Accepted: 01/19/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with diabetes mellitus and increasing evidence suggests that patients with type 2 diabetes are at a particularly high risk for developing the progressive forms of NAFLD, non-alcoholic steatohepatitis and associated advanced liver fibrosis. Moreover, diabetes is an independent risk factor for NAFLD progression, and for hepatocellular carcinoma development and liver-related mortality in prospective studies. Notwithstanding, patients with NAFLD have an elevated prevalence of prediabetes. Recent studies have shown that NAFLD presence predicts the development of type 2 diabetes. Diabetes and NAFLD have mutual pathogenetic mechanisms and it is possible that genetic and environmental factors interact with metabolic derangements to accelerate NAFLD progression in diabetic patients. The diagnosis of the more advanced stages of NAFLD in diabetic patients shares the same challenges as in non-diabetic patients and it includes imaging and serological methods, although histopathological evaluation is still considered the gold standard diagnostic method. An effective established treatment is not yet available for patients with steatohepatitis and fibrosis and randomized clinical trials including only diabetic patients are lacking. We sought to outline the published data including epidemiology, pathogenesis, diagnosis and treatment of NAFLD in diabetic patients, in order to better understand the interplay between these two prevalent diseases and identify the gaps that still need to be fulfilled in the management of NAFLD in patients with diabetes mellitus.
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Bendezú García RÁ, Casado Martín M, Lázaro Sáez M, Patrón Román GÓ, Gálvez Miras A, Rodríguez Laiz GP, González Sánchez M, Vega Sáenz JL. Elevación de las enzimas de función hepática en nuestro medio: estudio etiológico y de la eficacia de una consulta de acto único. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:450-6. [DOI: 10.1016/j.gastrohep.2013.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/04/2013] [Accepted: 05/06/2013] [Indexed: 10/26/2022]
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Bouglé D, Brouard J. Iron in child obesity. Relationships with inflammation and metabolic risk factors. Nutrients 2013; 5:2222-30. [PMID: 23783556 PMCID: PMC3725502 DOI: 10.3390/nu5062222] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 05/27/2013] [Accepted: 06/02/2013] [Indexed: 12/15/2022] Open
Abstract
Iron (Fe) sequestration is described in overweight and in its associated metabolic complications, i.e., metabolic syndrome (MetS) and non-alcoholic liver fatty disease (NAFLD); however, the interactions between Fe, obesity and inflammation make it difficult to recognize the specific role of each of them in the risk of obesity-induced metabolic diseases. Even the usual surrogate marker of Fe stores, ferritin, is influenced by inflammation; therefore, in obese subjects inflammation parameters must be measured together with those of Fe metabolism. This cross-sectional study in obese youth (502 patients; 57% girls): 11.4 ± 3.0 years old (x ± SD); BMI z score 5.5 ± 2.3), multivariate regression analysis showed associations between Fe storage assessed by serum ferritin with risk factors for MetS and NAFLD, assessed by transaminase levels, which were independent of overweight and the acute phase protein fibrinogen. Further studies incorporating the measurement of complementary parameters of Fe metabolism could improve the comprehension of mechanisms involved.
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Hepatic injury due to combined choline-deprivation and thioacetamide administration: an experimental approach to liver diseases. Dig Dis Sci 2012; 57:3168-77. [PMID: 22777615 DOI: 10.1007/s10620-012-2299-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Accepted: 06/14/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND The induction of prolonged choline-deprivation (CD) in rats receiving thioacetamide (TAA) is an experimental approach of mild hepatotoxicity that could resemble commonly presented cases in clinical practice (in which states of malnutrition and/or alcoholism are complicated by the development of other liver-associated diseases). AIM The present study aimed to investigate the time-dependent effects of a 30-, a 60- and a 90-day dietary CD and/or TAA administration on the adult rat liver histopathology and the serum markers of hepatic functional integrity. METHODS Rats were divided into four main groups: (a) control, (b) CD, (c) TAA and (d) CD + TAA. Dietary CD was provoked through the administration of choline-deficient diet, while TAA administration was performed ad libitum through the drinking water (300 mg/l of drinking water). RESULTS Histological examination of the CD + TAA liver sections revealed micro- and macro-vesicular steatosis with degeneration and primary fibrosis at day 30, to extensive steatosis and fibrosis at day 90. Steatosis was mostly of the macrovesicular type, involving all zones of the lobule, while inflammatory infiltrate consisted of foci of acute and chronic inflammatory cells randomly distributed in the lobule. These changes were accompanied by gradually increasing mitotic activity, as well as by a constantly high alpha-smooth muscle actin immunohistochemical staining. The determination of hepatocellular injury markers such as the serum enzyme levels' of alanine aminotransferase and aspartate aminotransferase demonstrated a decrease at day 30 (they returned to control levels at days 60 and 90). However, the determination of those serum enzymes used for the assessment of cholestatic liver injury (gamma-glutamyltransferase, alkaline phosphatase) revealed a constant (time-independent) statistically-significant increase versus control values. CONCLUSIONS Long-term combined dietary CD and TAA administration could be a more realistic experimental approach to human liver diseases involving severe steatosis, fibrosis, stellate cell activation and significant regenerative hepatocellular response.
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Tomita K, Teratani T, Suzuki T, Oshikawa T, Yokoyama H, Shimamura K, Nishiyama K, Mataki N, Irie R, Minamino T, Okada Y, Kurihara C, Ebinuma H, Saito H, Shimizu I, Yoshida Y, Hokari R, Sugiyama K, Hatsuse K, Yamamoto J, Kanai T, Miura S, Hibi T. p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol 2012; 57:837-43. [PMID: 22641095 DOI: 10.1016/j.jhep.2012.05.013] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 05/14/2012] [Accepted: 05/21/2012] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH). METHODS Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated. RESULTS Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed. CONCLUSIONS p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.
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Affiliation(s)
- Kengo Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa-shi, Saitama 359-8513, Japan.
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Arienti V, Aluigi L, Pretolani S, Accogli E, Polimeni L, Domanico A, Violi F. Ultrasonography (US) and non-invasive diagnostic methods for non-alcoholic fatty liver disease (NAFLD) and early vascular damage. Possible application in a population study on the metabolic syndrome (MS). Intern Emerg Med 2012; 7 Suppl 3:S283-90. [PMID: 23073869 DOI: 10.1007/s11739-012-0824-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Abdominal ultrasonography (US) represents the first-line imaging examination in chronic liver diseases; in most cases, US, laboratory findings and the clinical context are generally sufficient to guide the diagnosis. Thanks to the considerable diffusion of US, we have seen an increased diagnosis of NAFLD in recent years, although this condition is generally silent from a clinical point of view. We have to identify the metabolic syndrome in the general population and to promptly recognize NAFLD to prevent its development into non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. Among the non-invasive diagnostic techniques for NAFLD and for early vascular damage, ultrasonography represents the method of choice. In fact, besides the traditional semiotics of fundamental US of the liver, new US techniques have recently been proposed (contrast enhancement US, acoustic structure characterization), with respect to serum biomarkers and Fibroscan, for the study of liver fibrosis. Similarly, also as concerns the US measurement of carotid intima-media thickness, new automated methods with sophisticated software and radio-frequency signal have recently been introduced. Finally, we report the preliminary results of a personal experience on liver and carotid US in the epidemiology of the metabolic syndrome.
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Affiliation(s)
- Vincenzo Arienti
- Ultrasound Center, Internal Medicine A, Maggiore Hospital, Bologna, Italy.
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MRI Steatosis Grading: Development and Initial Validation of a Color Mapping System. AJR Am J Roentgenol 2012; 198:582-8. [DOI: 10.2214/ajr.11.6729] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major causative agent of chronic liver disease worldwide, but the actual mechanisms responsible for liver injury remain unclear. NAFLD includes a spectrum of clinical entities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with possible evolution to cirrhosis and hepatocellular carcinoma. Iron is considered a putative element that interacts with oxygen radicals in inducing liver damage/fibrosis and insulin resistance. The role of hepatic iron in the progression of NASH remains controversial, but in some patients, iron may have a role in the pathogenesis of NASH. Though genetic factors, insulin resistance, dysregulation of iron-regulatory molecules, erythrophagocytosis by Kupffer cells may be responsible for hepatic iron accumulation in NASH, exact mechanisms involved in iron overload remain to be clarified. Iron reduction therapy such as phlebotomy or iron-restricted diet may be promising in patients with NAFLD/NASH to reduce hepatic injury as well as insulin resistance. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of phlebotomy and/or iron-restricted diet in NAFLD/NASH.
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Serum immunoglobulin a concentration is an independent predictor of liver fibrosis in nonalcoholic steatohepatitis before the cirrhotic stage. Dig Dis Sci 2011; 56:3648-54. [PMID: 21674175 DOI: 10.1007/s10620-011-1771-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 05/28/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS The similarity of alcoholic liver disease and nonalcoholic steatohepatitis (NASH) in terms of pathogenic mechanisms suggests that immunoglobulin A (IgA) may play an important role in the pathogenesis of NASH. We aimed to determine whether serum IgA concentrations allow a diagnosis of liver fibrosis in NASH. METHODS We compared serum IgA concentrations between 108 patients with stages 0-2 NASH and 19 patients with stage 3 NASH. RESULTS In a univariate analysis, age (P < 0.0001), gender (P = 0.0039), serum albumin level (P = 0.0192), AST (P < 0.0001), AST/ALT ratio (P < 0.0001), platelet count (P = 0.0027), hyaluronic acid level (P < 0.0001), fasting blood sugar (FBS) (P = 0.0013), IRI (P = 0.0001), prothrombin time (%) (P = 0.0287), IgA (P < 0.0001), total sum of IgG, IgA, and IgM (P = 0.0049), and IgA/(IgG + IgA + IgM) (P = 0.0105) were significantly elevated in severe-stage NASH patients compared with the early-stage NASH group. Multiple logistic regression analysis showed that in severe-stage NASH patients, only serum IgA concentrations were significantly elevated (P = 0.0225) relative to early-stage NASH patients. The area under the curve (AUC) of serum IgA concentrations was 0.758 for detecting severe-stage NASH compared with early-stage NASH. CONCLUSIONS Serum IgA concentration could be a useful independent predictor for assessing the pre-cirrhotic progression of NASH.
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Min AK, Kim MK, Kim HS, Seo HY, Lee KU, Kim JG, Park KG, Lee IK. Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6 mice. Life Sci 2011; 90:200-5. [PMID: 22154902 DOI: 10.1016/j.lfs.2011.11.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 11/06/2011] [Accepted: 11/08/2011] [Indexed: 02/04/2023]
Abstract
AIMS Non-alcoholic steatohepatitis (NASH) is a liver disease that causes fat accumulation, inflammation and fibrosis. Increased oxidative stress contributes to hepatic inflammation and fibrosis by upregulation of Cytochrome P450 2E1 (CYP2E1), endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) activity. This study examined whether alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents steatohepatitis through the inhibition of several pathways involved in hepatic inflammation and fibrosis. MAIN METHODS C57BL/6 mice were fed an MCD diet with or without ALA for 4weeks. Liver sections from mice on control or MCD diets with or without ALA were stained with hematoxylin-eosin, oil red O, and anti-4-HNE antibody. The effects of ALA on methionine-choline deficient MCD-diet induced plasma AST and ALT as well as tissue TBARS were measured. The effects of ALA on CYP2E1 expression, ER stress, MAPK levels, and NF-κB activity in MCD diet-fed mice liver were measured by northern and western blot analysis. KEY FINDINGS Dietary supplementation with ALA reduced MCD diet-induced hepatic lipid accumulation, hepatic inflammation, TBARS, 4-HNE, and plasma ALT and AST levels. These effects were associated with a reduced expression of CYP2E1 and reduced ER stress and MAPK and NF-κB activity. SIGNIFICANCE Taken together, the results of the present study indicate that ALA attenuates steatohepatitis through inhibition of several pathways, and provide the possibility that ALA can be used to prevent the development and progression of non-alcoholic fatty liver disease in patients who have strong risk factors for NASH.
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Affiliation(s)
- Ae-Kyung Min
- World Class University Program, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 700-721, South Korea
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Plasma free myristic acid proportion is a predictor of nonalcoholic steatohepatitis. Dig Dis Sci 2011; 56:3045-52. [PMID: 21516322 DOI: 10.1007/s10620-011-1712-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 04/05/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS Serum free fatty acid (FFA) composition and abnormal fatty acid metabolism have been implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we determined if the serum FFA composition can provide accurate diagnosis of NASH. METHODS We compared fasting serum FFA compositions in 20 patients with simple steatosis to those in 77 patients with NASH, including 65 patients with early-stage NASH. RESULTS By univariate analysis, the proportions of serum free myristic acid (P = 0.002) and palmitoleic acid (P = 0.033) and the stearoyl CoA desaturase (SCD)-1 index (P = 0.047) were significantly elevated in NASH patients in comparison to patients with simple steatosis. Only the serum free myristic acid proportion was significantly elevated in the early-stage NASH group in comparison to the simple steatosis group (P = 0.003). Multiple logistic regression analysis demonstrated that the serum free myristic acid proportion was significantly elevated in all patients with NASH (P = 0.011) and the subset of patients with early-stage NASH (P = 0.012) in comparison to those with simple steatosis. The area under the curve (AUC) for the serum free myristic acid proportion was 0.734 to detect NASH and 0.719 to detect early-stage NASH in comparison to simple steatosis. CONCLUSIONS Serum free myristic acid proportion could be a useful independent predictor to differentiate NASH from simple steatosis.
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common and ubiquitous disorder (Bedogni et al. in Hepatology 42:44-52, 2005; Bellentani et al. in Ann Intern Med 132:112-117, 2000) which in a proportion of subjects leads to non-alcoholic steatohepatitis (NASH), advanced liver disease and hepatocellular carcinoma. Although the factors responsible for progression of disease are still uncertain, there is evidence that insulin resistance (IR) is a key operative mechanism (Angulo et al. in Hepatology 30:1356-1362, 1999) and that two stages are involved. The first is the accumulation of triglycerides in hepatocytes followed by a "second hit" which promotes cellular oxidative stress. Several factors may be responsible for the induction of oxidative stress but hepatic iron has been implicated in various studies. The topic is controversial, however, with early studies showing an association between hepatic iron (with or without hemochromatosis gene mutations) and the progression to hepatic fibrosis. Subsequent studies, however, could not confirm an association between the presence of hepatic iron and any of the histological determinants of NAFLD or NASH. Recent studies have reactivated interest in this subject firstly, with the demonstration that hepatic iron loading increases liver cholesterol synthesis with increased lipid deposition in the liver increasing the cellular lipid burden and secondly, a large clinical study has concluded that hepatocellular iron deposition is associated with an increased risk of hepatic fibrosis, thus, strongly supporting the original observation made over a decade ago. An improvement in insulin sensitivity has been demonstrated following phlebotomy therapy but a suitably powered controlled clinical trial is required before this treatment can be implemented.
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Tabuchi M, Tomioka K, Kawakami T, Murakami Y, Hiramatsu M, Itoshima T, Sugawara S, Kawashima A, Okita M, Tsukamoto I. Serum cytokeratin 18 M30 antigen level and its correlation with nutritional parameters in middle-aged Japanese males with nonalcoholic fatty liver disease (NAFLD). J Nutr Sci Vitaminol (Tokyo) 2011; 56:271-8. [PMID: 21228496 DOI: 10.3177/jnsv.56.271] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Cytokeratin (CK) 18 M30 antigen has been proposed as a diagnostic marker of nonalcoholic fatty liver disease (NAFLD). We studied serum CK18 M30 antigen level and examined the correlations among CK18 and biological data, dietary intake, and plasma fatty acid composition in middle-aged Japanese males with (NAFLD; n=42) and without NAFLD (control; n=35). NAFLD was diagnosed if subjects showed fatty liver on abdominal ultrasonography and their alcohol consumption was <20 g/d. They were also confirmed to have negative serological results for tests of autoimmune liver disease and hepatitis B and C. In the NAFLD group, body mass index, waist circumference, serum M30 antigen, alanine transaminase (ALT), cholinesterase, triacylglycerol, LDL-cholesterol, and HbA1c were significantly higher than in the control group. In the fatty acid analysis of plasma phospholipids, significantly higher dihomo-γ-linolenic acid (DGLA), total saturated fatty acids (SFA), and palmitic/linoleic acid ratio as well as lower arachidonic acid/DGLA ratio were observed in the NAFLD group compared with the control group. In the NAFLD group, M30 antigen was correlated positively with serum ALT, plasma DGLA, dietary SFA, and serum TNF-α as determined by partial correlation analysis controlled for BMI. On the basis of multivariate regression analysis using a stepwise method, M30 antigen was significantly associated with ALT and plasma DGLA. Regarding the determinants of NAFLD as revealed by logistic regression analysis, a high odds ratio was observed for plasma DGLA. In conclusion, members of the NAFLD group showed higher levels of serum CK18 M30 antigen and M30 antigen was strongly associated with serum ALT and plasma DGLA. Abnormal fatty acid metabolism may be a factor that causes aggravation of NAFLD.
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Affiliation(s)
- Mayumi Tabuchi
- Department of Food Science and Nutrition, Nara Women's University, Japan
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40
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Wanninger J, Neumeier M, Bauer S, Weiss TS, Eisinger K, Walter R, Dorn C, Hellerbrand C, Schäffler A, Buechler C. Adiponectin induces the transforming growth factor decoy receptor BAMBI in human hepatocytes. FEBS Lett 2011; 585:1338-44. [PMID: 21496456 DOI: 10.1016/j.febslet.2011.04.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 04/01/2011] [Accepted: 04/01/2011] [Indexed: 02/07/2023]
Abstract
Transforming growth factor (TGF) β is the central cytokine in fibrotic liver diseases. We analyzed whether hepatoprotective adiponectin directly interferes with TGFβ1 signaling in primary human hepatocytes (PHH). Adiponectin induces the TGFβ decoy receptor BMP-and activin-membrane-bound inhibitor (BAMBI) in PHH. Overexpression of BAMBI in hepatoma cells impairs TGFβ-mediated phosphorylation of SMAD2 and induction of connective tissue growth factor. BAMBI is lower in human fatty liver with a higher susceptibility to liver fibrosis and negatively correlates with BMI of the donors. Hepatic BAMBI is reduced in rodent models of liver inflammation and fibrosis. In summary, the current data show that hepatoprotective effects of adiponectin include induction of BAMBI which is reduced in human fatty liver and rodent models of metabolic liver injury.
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Affiliation(s)
- Josef Wanninger
- Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, Germany
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Chen SH, He F, Zhou HL, Wu HR, Xia C, Li YM. Relationship between nonalcoholic fatty liver disease and metabolic syndrome. J Dig Dis 2011; 12:125-30. [PMID: 21401898 DOI: 10.1111/j.1751-2980.2011.00487.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in subjects who underwent a routine health checkup. We intended to establish a clinical association between NAFLD and MS as well as to compare the diagnostic criteria of MS based on the definitions set forth by the International Diabetes Federation (IDF), the US National Cholesterol Education Program Adult Treatment Panel III (2001) (NCEP/ATP-III) and the Metabolic Syndrome Study Group of Chinese Diabetes Society (CDS). METHODS Weight, height, waist circumference, hip circumference, percentage of body fat, blood pressure and ultrasound of liver were performed on subjects undergoing routine health checkup. Serum triglyceride, total cholesterol, high density lipoprotein cholesterol and fasting plasma glucose level were measured. RESULTS A total of 2394 subjects were included in this analysis and 437 had NAFLD. The prevalence of MS in the whole sample according to IDF, NCEP/ATP-III and CDS definitions was 11.11%, 8.48% and 5.30%, respectively. The total degree of agreement between IDF, NCEP/ATP-III and CDS definition was 87.76%. The prevalence of MS in NAFLD subjects is much higher than that in non-NAFLD subjects. The prevalence of NAFLD in MS subjects is also much higher than that in non-MS subjects. CONCLUSION The prevalence of MS varied depending on the diagnostic criteria used. NAFLD was strongly associated with the MS, although it remains unknown whether NAFLD is a cause or effect of MS.
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Affiliation(s)
- Shao Hua Chen
- Department of Gastroenterology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Abstract
As the incidence of obesity continues to rise, increasing numbers of patients are undergoing bariatric surgery to address morbid obesity and weight related health issues. Bariatric procedures aim to reduce dietary intake and/or interfere with food absorption and are now in widespread use but with a huge capacity shortfall leading to a degree of rationing of the resource. Such treatment should be regarded as palliative in that it does not cure the underlying disorder, and guidelines have been produced to define which patients should be considered for this type of surgery, which must be undertaken in a multidisciplinary setting. Long term results show this to be a cost-effective intervention with a durable positive impact on cardiac risk factors and in particular type 2 diabetes and obstructive sleep apnoea, together with a reduction in all cause mortality and malignancy and an improvement in quality of life. Systematic data collection has now started in the UK and will assist in defining the best application of the resource.
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Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011; 53:810-20. [PMID: 21319198 PMCID: PMC3079483 DOI: 10.1002/hep.24127] [Citation(s) in RCA: 938] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2010] [Accepted: 12/06/2010] [Indexed: 02/06/2023]
Abstract
UNLABELLED The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and "not SH" in 22%. The NAS was ≥5 in 50% and ≤4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS ≥5, whereas 28% of borderline SH and 7% of "not SH" biopsies had NAS ≥5. Of biopsies with an NAS ≥5, 86% had SH and 3% "not SH". NAS ≤4 did not indicate benign histology; 29% had SH and only 42% had "not SH." Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome. CONCLUSION The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account.
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Affiliation(s)
- Elizabeth M. Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - David E. Kleiner
- Department of Laboratory Medicine, National Cancer Institute, Washington, DC
| | - Laura A. Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Patricia Belt
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
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Banasik K, Justesen JM, Hornbak M, Krarup NT, Gjesing AP, Sandholt CH, Jensen TS, Grarup N, Andersson A, Jørgensen T, Witte DR, Sandbæk A, Lauritzen T, Thorens B, Brunak S, Sørensen TIA, Pedersen O, Hansen T. Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease. PLoS One 2011; 6:e16542. [PMID: 21339799 PMCID: PMC3029374 DOI: 10.1371/journal.pone.0016542] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 01/04/2011] [Indexed: 02/07/2023] Open
Abstract
Objective Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. Research Design and Methods By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS). Results 273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. Conclusions Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.
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Calderaro J, Zafrani ES. [Non-alcoholic fatty liver disease]. Ann Pathol 2010; 30:413-20. [PMID: 21167426 DOI: 10.1016/j.annpat.2010.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2010] [Revised: 09/16/2010] [Accepted: 10/20/2010] [Indexed: 01/14/2023]
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van Meijl LEC, Popeijus HE, Mensink RP. Amino acids stimulate Akt phosphorylation, and reduce IL-8 production and NF-κB activity in HepG2 liver cells. Mol Nutr Food Res 2010; 54:1568-73. [DOI: 10.1002/mnfr.200900438] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Aigner E, Strasser M, Haufe H, Sonnweber T, Hohla F, Stadlmayr A, Solioz M, Tilg H, Patsch W, Weiss G, Stickel F, Datz C. A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease. Am J Gastroenterol 2010; 105:1978-85. [PMID: 20407430 DOI: 10.1038/ajg.2010.170] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Copper has a role in antioxidant defense, lipid peroxidation, and mitochondrial function, and copper deficiency has been linked to atherogenic dyslipidemia. We aimed to investigate the potential role of copper availability in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). METHODS Patients with NAFLD (n=124) were compared to patients with chronic hepatitis C (n=50), hemochromatosis (n=35), alcoholic liver disease (n=13), autoimmune hepatitis (n=11), and control subjects (n=27). We determined liver and serum copper concentrations with correlation to clinical, histological, and biochemical parameters in humans. The effect of dietary copper restriction on liver histology and intermediary metabolism in rats was investigated. RESULTS Hepatic copper concentrations in patients with NAFLD were lower than in control subjects (17.9+/-8.4 vs. 31.4+/-8.2 microg/g; P<0.001) and in patients with other liver diseases (P<0.05 for all liver diseases). In patients with NAFLD, lower liver copper was correlated with more pronounced hepatic steatosis (R=-0.248; P=0.010), fasting glucose (R=-0.245; P=0.008), and components of the metabolic syndrome (MetS; R=0.363; P<0.001). Patients with nonalcoholic steatohepatitis (NASH; n=31) had lower hepatic copper concentrations than those with simple steatosis (n=93; P=0.038). Restriction of dietary copper in rats induced hepatic steatosis and insulin resistance (IR). CONCLUSIONS Reduced hepatic copper concentrations are found in human NAFLD and are associated with more pronounced hepatic steatosis, NASH, and components of the MetS. The development of hepatic steatosis and IR in response to dietary copper restriction in rats suggests that copper availability may be involved in the development of NAFLD.
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Affiliation(s)
- Elmar Aigner
- Department of Internal Medicine, General Hospital Oberndorf, Oberndorf, Austria
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Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E, Pelckmans P, Michielsen P, Van Gaal L. Visceral adiposity and insulin resistance are independent predictors of the presence of non-cirrhotic NAFLD-related portal hypertension. Int J Obes (Lond) 2010; 35:270-8. [PMID: 20661251 DOI: 10.1038/ijo.2010.134] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION We previously demonstrated in an animal model that steatosis, in the absence of fibrosis, induces a significant rise in portal pressure, indicating substantial changes in liver hemodynamics. As assessment of portal pressure is an invasive procedure, non-invasive parameters are needed to identify patients at risk. AIMS To study the portal pressure in nonalcoholic fatty liver disease patients and to identify factors that are possibly related to steatosis-induced changes in liver hemodynamics. MATERIALS AND METHODS Patients presenting with a problem of overweight or obesity, and in whom non-invasive investigations showed signs of liver involvement, were proposed for transjugular hepatic vein catheterization and liver biopsy. The biopsy was scored according to the Nonalcoholic Steatohepatitis Clinical Research Network Scoring System. RESULTS A total of 50 consecutive patients were studied. Their mean age was 47.9 ± 1.8 years; 31 (62%) were female. Hepatic venous pressure gradient was normal in 36 (72%) and elevated in 14 (28%) patients. The degree of steatosis was the only histological parameter that differed significantly between the two groups (P=0.016), and was a predictor of the presence of portal hypertension (PHT) in regression analysis (P=0.010). Comparing normal versus portal hypertensive patients, waist circumference (117 ± 2 versus 128 ± 4 cm, P=0.005), waist-hip ratio (0.96 ± 0.06 versus 1.04 ± 0.03, P=0.003), visceral fat (229 ± 15 versus 292 ± 35 cm(2), P=0.022), fasting insulin (15.4 ± 1.7 versus 21.8 ± 2.4 μU ml(-1), P=0.032), fasting c-peptide (1.22 ± 0.06 versus 1.49 ± 0.09 nmol l(-1), P=0.035) and homeostasis model assessment-insulin resistance (HOMA IR) (3.28 ± 0.29 versus 4.81 ± 0.57, P=0.019) were significantly higher. Age, gender, liver enzymes, ferritin and high-sensitive C-reactive protein were not significantly different. In regression analysis, waist circumference (P=0.008) and HOMA IR (P=0.043) were independent predictors of PHT. CONCLUSIONS Estimates of both visceral adiposity and IR are predictors for the presence of PHT, related to the degree of steatosis, and may help in identifying patients who are at risk of developing steatosis-related complications.
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Affiliation(s)
- S Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
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Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis: histological diagnostic criteria and scoring systems. Eur J Gastroenterol Hepatol 2010; 22:643-50. [PMID: 19478676 DOI: 10.1097/meg.0b013e32832ca0cb] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease in western countries. NAFLD is etiologically associated with systemic and hepatic insulin resistance and is considered by many as the hepatic manifestation of the metabolic syndrome. NAFLD has a wide histological spectrum ranging from 'simple' steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis. Hepatocellular carcinoma may occur in NASH-related cirrhosis. The diagnosis of NAFLD/NASH is based on clinico-pathological criteria. Currently available noninvasive tests for the diagnosis of NASH lack specificity and sensitivity, so liver biopsy, despite its limitations, still remains the 'golden standard' for confirming or excluding NASH in a patient with chronically-elevated liver enzymes and image-detected steatosis. This review examines the currently used criteria for the histopathological diagnosis of NAFLD/NASH in adults and children and the relevant histological scoring systems.
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Kaser S, Ebenbichler CF, Tilg H. Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease. Int J Clin Pract 2010; 64:968-83. [PMID: 20584230 DOI: 10.1111/j.1742-1241.2009.02327.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a disease spectrum ranging from simple steatosis and steatohepatitis to cirrhosis. Based on its strongest risk factors namely visceral obesity and insulin resistance, NAFLD is thought to be the hepatic manifestation of the metabolic syndrome and is considered to be the most common liver disorder in Western countries. Pathophysiological mechanisms include an enlarged pool of fatty acids, subclinical inflammation, oxidative stress and imbalances of various adipocytokines such as adiponectin. Accordingly, targets for therapeutic interventions are miscellaneous: amelioration of obesity by pharmacological, surgical or lifestyle intervention has been evaluated with success in numerous, but not all studies. Some efficacy was reported for metformin and short-term glitazone treatment. In a large recently reported trial, vitamin E supplementation improved biochemical and histological markers in subjects with non-alcoholic steatohepatitis. Blockade of the endocannabinoid system has been proposed to be a promising target in NAFLD; however, very recently the cannabinoid receptor blocker rimonabant has been withdrawn because of central nervous system toxicity. Cytoprotective therapies and statins have been mainly ineffective in NAFLD. New but so far insufficiently studied therapeutic approaches include inhibitors of the renin-angiotensin system as well as incretin mimetics respectively.
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Affiliation(s)
- S Kaser
- Department of Medicine I, Medical University Innsbruck, Innsbruck, Austria
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