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Teng T, Qiu S, Zhao Y, Zhao S, Sun D, Hou L, Li Y, Zhou K, Yu X, Yang C, Li Y. Pathogenesis and Therapeutic Strategies Related to Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23147841. [PMID: 35887189 PMCID: PMC9322253 DOI: 10.3390/ijms23147841] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/12/2022] [Accepted: 07/14/2022] [Indexed: 12/10/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver cirrhosis, is characterized by a broad spectrum of clinical phenotypes. Although patients with mild NAFL are considered to show no obvious clinical symptoms, patients with long-term NAFL may culminate in NASH and further liver fibrosis. Even though various drugs are able to improve NAFLD, there are no FDA-approved medications that directly treat NAFLD. In this paper, the pathogenesis of NAFLD, the potential therapeutic targets, and their underlying mechanisms of action were reviewed.
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Affiliation(s)
- Tieshan Teng
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
- School of Nursing and Health, Henan University, Kaifeng 475004, China
| | - Shuai Qiu
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
- School of Nursing and Health, Henan University, Kaifeng 475004, China
| | - Yiming Zhao
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Siyuan Zhao
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Dequan Sun
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Lingzhu Hou
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Yihang Li
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Ke Zhou
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Xixi Yu
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
| | - Changyong Yang
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
- School of Nursing and Health, Henan University, Kaifeng 475004, China
- Correspondence: or (C.Y.); (Y.L.)
| | - Yanzhang Li
- Institute of Biomedical Informatics, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (T.T.); (S.Q.); (Y.Z.); (S.Z.); (D.S.); (L.H.); (Y.L.); (K.Z.); (X.Y.)
- Correspondence: or (C.Y.); (Y.L.)
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Traber MG, Head B. Vitamin E: How much is enough, too much and why! Free Radic Biol Med 2021; 177:212-225. [PMID: 34699937 DOI: 10.1016/j.freeradbiomed.2021.10.028] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022]
Abstract
α-Tocopherol (α-T) is a required dietary nutrient for humans and thus is a vitamin. This narrative review focuses on vitamin E structures, functions, biological determinants and its deficiency symptoms in humans. The mechanisms for the preferential α-T tissue enrichment in the human body include the α-T transfer protein (TTPA) and the preferential metabolism of non-α-T forms. Potential new α-T biomarkers, pharmacokinetic data, and whether there are better approaches to evaluate and set the α-T dietary requirement are discussed. Finally, the possible role of α-T supplements in delay of chronic diseases and the evaluation of vitamin E safety are considered.
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Affiliation(s)
- Maret G Traber
- Linus Pauling Institute, USA; School of Biological and Population Health Sciences, College of Public Health and Human Sciences, USA.
| | - Brian Head
- Linus Pauling Institute, USA; Molecular and Cell Biology Program, Oregon State University, Corvallis, OR, USA
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Palmieri B, Corazzari V, Panariello Brasile DG, Sangiovanni V, VadalÀ M. Hepatic steatosis integrated approach: nutritional guidelines and joined nutraceutical administration. MINERVA GASTROENTERO 2021; 66:307-320. [PMID: 33443240 DOI: 10.23736/s1121-421x.20.02738-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The nonalcoholic fat liver disease (NAFLD) progresses in 30% of the patients to not alcoholic steatohepatitis (NASH) and subsequently in liver fibrosis and even primary cancer and death. Due to the complex physiopathology of the liver steatosis, NASH is an area orphan of specific drugs, but many authors suggest an integrated treatment based upon diet, lifestyle change, and pharmacology. METHODS Our clinical study selected from a wider patient cohort, 13 subjects, appealing to the Second Opinion Medical Consulting Network, for liver and nutritional problems. The diet was integrated with regular prescription of an herbal derivative based on Chrysanthellum americanum and Pistacia lentiscus L. extracts. Clinical data of the recruited patients including body weight, Body Mass Index, were recorded before and after treatment. Each patient underwent pre-post accurate clinical examination and lab exams. The liver stiffness and liver steatosis were evaluated by a trained hepatologist with FibroScan®. RESULTS A significant reduction of anthropometric parameters was detected in all the patients at the end of the study; liver fibrosis and steatosis were instrumentally decreased in 8 subjects, but not significant changes in lab exams and no adverse effects were reported. CONCLUSIONS Chrysanthellum americanum and Pistacia lentiscus L. extracts were absolutely safe and effective and gave a substantial contribution to the life quality benefit, metabolic balance and gut function in patients with hepatic steatosis.
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Affiliation(s)
- Beniamino Palmieri
- Second Opinion Medical Network, Modena, Italy.,Medico Cura Te Stesso Onlus, Modena, Italy
| | - Veronica Corazzari
- Second Opinion Medical Network, Modena, Italy - .,Medico Cura Te Stesso Onlus, Modena, Italy
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Tun S, Spainhower CJ, Cottrill CL, Lakhani HV, Pillai SS, Dilip A, Chaudhry H, Shapiro JI, Sodhi K. Therapeutic Efficacy of Antioxidants in Ameliorating Obesity Phenotype and Associated Comorbidities. Front Pharmacol 2020; 11:1234. [PMID: 32903449 PMCID: PMC7438597 DOI: 10.3389/fphar.2020.01234] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been a worldwide epidemic for decades. Despite the abundant increase in knowledge regarding the etiology and pathogenesis of obesity, the prevalence continues to rise with estimates predicting considerably higher numbers by the year 2030. Obesity is characterized by an abnormal lipid accumulation, however, the physiological consequences of obesity are far more concerning. The development of the obesity phenotype constitutes dramatic alterations in adipocytes, along with several other cellular mechanisms which causes substantial increase in systemic oxidative stress mediated by reactive oxygen species (ROS). These alterations promote a chronic state of inflammation in the body caused by the redox imbalance. Together, the systemic oxidative stress and chronic inflammation plays a vital role in maintaining the obese state and exacerbating onset of cardiovascular complications, Type II diabetes mellitus, dyslipidemia, non-alcoholic steatohepatitis, and other conditions where obesity has been linked as a significant risk factor. Because of the apparent role of oxidative stress in the pathogenesis of obesity, there has been a growing interest in attenuating the pro-oxidant state in obesity. Hence, this review aims to highlight the therapeutic role of antioxidants, agents that negate pro-oxidant state of cells, in ameliorating obesity and associated comorbidities. More specifically, this review will explore how various antioxidants target unique and diverse pathways to exhibit an antioxidant defense mechanism.
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Affiliation(s)
- Steven Tun
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Caleb James Spainhower
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Cameron Lee Cottrill
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Hari Vishal Lakhani
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Sneha S Pillai
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Anum Dilip
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Hibba Chaudhry
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Joseph I Shapiro
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
| | - Komal Sodhi
- Departments of Medicine, Surgery and Biomedical Sciences, Marshall University Joan C. Edwards School of Medicine, Huntington, WV, United States
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Violet PC, Ebenuwa IC, Wang Y, Niyyati M, Padayatty SJ, Head B, Wilkins K, Chung S, Thakur V, Ulatowski L, Atkinson J, Ghelfi M, Smith S, Tu H, Bobe G, Liu CY, Herion DW, Shamburek RD, Manor D, Traber MG, Levine M. Vitamin E sequestration by liver fat in humans. JCI Insight 2020; 5:133309. [PMID: 31821172 PMCID: PMC7030816 DOI: 10.1172/jci.insight.133309] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/26/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.
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Affiliation(s)
- Pierre-Christian Violet
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Ifechukwude C. Ebenuwa
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Yu Wang
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Mahtab Niyyati
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Sebastian J. Padayatty
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Brian Head
- Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA
| | - Kenneth Wilkins
- Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Stacey Chung
- Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Varsha Thakur
- Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Lynn Ulatowski
- Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Jeffrey Atkinson
- Department of Chemistry, Brock University, Saint Catharines, Ontario, Canada
| | - Mikel Ghelfi
- Department of Chemistry, Brock University, Saint Catharines, Ontario, Canada
| | - Sheila Smith
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Hongbin Tu
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Gerd Bobe
- Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA
| | | | - David W. Herion
- Clinical Research Informatics, Clinical Center, NIH, Bethesda, Maryland, USA
| | - Robert D. Shamburek
- Cardiovascular Branch, Intramural Research Program, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Danny Manor
- Department of Pharmacology and Department of Nutrition, School of Medicine, Case Western Reserve University and the Case Comprehensive Cancer Center, Cleveland, Ohio, USA
| | - Maret G. Traber
- Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA
| | - Mark Levine
- Molecular and Clinical Nutrition Section, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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The Role of Vitamin E in the Treatment of NAFLD. Diseases 2018; 6:diseases6040086. [PMID: 30249972 PMCID: PMC6313719 DOI: 10.3390/diseases6040086] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 09/17/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023] Open
Abstract
There has been a growing interest in the role of vitamin E supplementation in the treatment and/or prevention of nonalcoholic fatty liver (NAFLD). We performed a systematic review of the medical literature from inception through 15 June 2018 by utilizing PubMed and searching for key terms such as NAFLD, vitamin E, alpha-tocopherol, and nonalcoholic steatohepatitis (NASH). Data from studies and medical literature focusing on the role of vitamin E therapy in patients with NAFLD and nonalcoholic steatohepatitis (NASH) were reviewed. Most studies assessing the impact of vitamin E in NAFLD were designed to evaluate patients with NASH with documented biochemical and histological abnormalities. These studies demonstrated improvement in biochemical profiles, with a decline in or normalization of liver enzymes. Furthermore, histological assessment showed favorable outcomes in lobular inflammation and hepatic steatosis following treatment with vitamin E. Current guidelines regarding the use of vitamin E in the setting of NAFLD recommend that vitamin E-based treatment be restricted to biopsy-proven nondiabetic patients with NASH only. However, some concerns have been raised regarding the use of vitamin E in patients with NASH due to its adverse effects profile and lack of significant improvement in hepatic fibrosis. In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic properties of vitamin E accompanied by ease-of-use and exceptional tolerability have made vitamin E a pragmatic therapeutic choice in non-diabetic patients with histologic evidence of NASH. Future clinical trials with study design to assess vitamin E in combination with other anti-fibrotic agents may yield an additive or synergistic therapeutic effect.
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de Oliveira DG, de Faria Ghetti F, Moreira APB, Hermsdorff HHM, de Oliveira JM, de Castro Ferreira LEVV. Association between dietary total antioxidant capacity and hepatocellular ballooning in nonalcoholic steatohepatitis: a cross-sectional study. Eur J Nutr 2018; 58:2263-2270. [PMID: 30019089 DOI: 10.1007/s00394-018-1776-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 07/11/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, ballooning, and in some cases, fibrosis, which can progress to cirrhosis and carcinoma. The progression of NASH is closely related to oxidative stress. Dietary intake of antioxidants has been suggested in protection against oxidative damage and related clinical complications. Thus, we evaluated the potential association of dietary total antioxidant capacity (TAC) with disease severity in NASH patients, as well as with anthropometric and body composition markers and biochemical parameters. METHODS Thirty-three outpatients with a mean age of 48.4 ± 1.9 years were evaluated. Dietary TAC was estimated from a quantitative food frequency questionnaire. NASH severity, determined by liver biopsy, lifestyle characteristics, occurrence of comorbidities, anthropometry, body composition, and biochemical parameters were assessed. RESULTS NASH patients who had a higher dietary TAC had fewer ballooned hepatocytes compared to those with a lower TAC (p = 0.024). The patients with the highest dietary TAC had a reduction of approximately 20% in the risk of having many ballooned hepatocytes (OR 0.791; 95% CI 0.643-0.974; p = 0.027). There was no association of steatosis, lobular inflammation, and fibrosis with dietary TAC. The same occurred for lifestyle characteristics, occurrence of comorbidities, anthropometry, body composition, and biochemical parameters. CONCLUSION Dietary TAC is higher in patients with lower hepatic injury (ballooning), suggesting a possible role of food intake naturally high in its antioxidant capacity in reducing free radical production and, consequently, oxidative stress.
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Affiliation(s)
- Daiane Gonçalves de Oliveira
- Departamento de Nutrição, Universitary Hospital, School of Medicine, Federal University of Juiz de Fora, Bairro Martelos, s/n, CEP 36036-330, Juiz de Fora, Minas Gerais, Brazil. .,Nutrition Department, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil.
| | - Fabiana de Faria Ghetti
- Departamento de Nutrição, Universitary Hospital, School of Medicine, Federal University of Juiz de Fora, Bairro Martelos, s/n, CEP 36036-330, Juiz de Fora, Minas Gerais, Brazil
| | | | | | - Juliano Machado de Oliveira
- Departamento de Nutrição, Universitary Hospital, School of Medicine, Federal University of Juiz de Fora, Bairro Martelos, s/n, CEP 36036-330, Juiz de Fora, Minas Gerais, Brazil
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Mahamid M, Mahroum N, Bragazzi NL, Shalaata K, Yavne Y, Adawi M, Amital H, Watad A. Folate and B12 Levels Correlate with Histological Severity in NASH Patients. Nutrients 2018; 10:440. [PMID: 29614799 PMCID: PMC5946225 DOI: 10.3390/nu10040440] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/27/2018] [Accepted: 03/30/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The correlation between abnormal vitamin serum levels and chronic liver disease has been previously described in literature. However, the association between the severity of folate serum levels (B9), vitamin B12 and nonalcoholic steatohepatitis (NASH) has not been widely evaluated. Therefore, the aim of this study was to investigate the existence of such a correlation in a cohort of NASH patients. METHODS All patients aged 18 years and older who were diagnosed with biopsy-proven NASH at the EMMS hospital in Nazareth during the years 2015-2017 were enrolled in this study. Data regarding demographic, clinical and laboratory parameters was collected. Patients with other liver diseases were excluded. RESULTS Eighty-three NASH patients were enrolled during the study period. The mean age was 41 ± 11 years and the majority of patients were male. Mean values of folate and B12 were 9.85 ± 10.90 ng/mL and 387.53 ± 205.50 pg/mL, respectively. Half of the patients were presented with a grade 1 steatosis (43.4%), a grade 2 fibrosis (50.6%) and a grade 3 activity score (55.4%). The fibrosis grade was significantly correlated with low folate levels on multivariate analysis (p-value < 0.01). Similarly, low B12 levels were significantly associated with a higher fibrosis grade and NASH activity (p-value < 0.001 and p-value < 0.05 respectively). CONCLUSION Our study demonstrated a statistically significant correlation between low levels of folate and vitamin B12 with the histological severity of NASH. These findings could have diagnostic and therapeutic implications for patient management and follow-up.
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Affiliation(s)
- Mahmud Mahamid
- Endoscopy Unit, Nazareth Hospital EMMS, 16100 Nazareth, Israel.
- Azrieli Faculty of Medicine, Bar-Ilan University, 13195 Safed, Israel.
| | - Naim Mahroum
- Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, 52621 Tel-Aviv, Israel.
| | - Nicola Luigi Bragazzi
- School of Public Health, Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.
| | - Kasem Shalaata
- Azrieli Faculty of Medicine, Bar-Ilan University, 13195 Safed, Israel.
- Internal Medicine Department, Nazareth Hospital EMMS, 16100 Nazareth, Israel.
| | - Yarden Yavne
- Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, 52621 Tel-Aviv, Israel.
| | | | - Howard Amital
- Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, 52621 Tel-Aviv, Israel.
| | - Abdulla Watad
- Department of Medicine 'B', Sheba Medical Center, Tel-Hashomer, Israel, Sackler Faculty of Medicine, Tel-Aviv University, 52621 Tel-Aviv, Israel.
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Suárez M, Boqué N, Del Bas JM, Mayneris-Perxachs J, Arola L, Caimari A. Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease. Nutrients 2017; 9:E1052. [PMID: 28937599 PMCID: PMC5691669 DOI: 10.3390/nu9101052] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/01/2017] [Accepted: 09/11/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH). Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology for their treatment other than weight loss and a change in lifestyle habits, such as a hypocaloric diet and physical exercise. In this framework, there is increasing evidence that several food bioactives and dietary patterns are effective for reversing and preventing the onset of these pathologies. Some studies have claimed that better responses are obtained when treatments are performed under a multifaceted approach, using different bioactive compounds that act against complementary targets. Thus, in this work, current strategies for treating NAFLD and NASH based on multi-ingredient-based supplements or the Mediterranean diet, a dietary pattern rich in bioactive compounds, are reviewed. Furthermore, the usefulness of omics techniques to design effective multi-ingredient nutritional interventions and to predict and monitor their response against these disorders is also discussed.
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Affiliation(s)
- Manuel Suárez
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus Sescelades, Tarragona 43007, Spain.
| | - Noemí Boqué
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Josep M Del Bas
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Jordi Mayneris-Perxachs
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Lluís Arola
- Nutrigenomics Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV), Campus Sescelades, Tarragona 43007, Spain.
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
| | - Antoni Caimari
- Technological Unit of Nutrition and Health, EURECAT-Technology Centre of Catalonia, Avinguda Universitat 1, Reus 43204, Spain.
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Ando W, Yokomori H, Otori K, Oda M. The Apelin Receptor APJ in Hematopoietic Stem Cells/Progenitor Cells in the Early Stage of Non-Alcoholic Steatohepatitis. J Clin Med Res 2017; 9:809-811. [PMID: 28811860 PMCID: PMC5544488 DOI: 10.14740/jocmr3103w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 06/29/2017] [Indexed: 12/20/2022] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with or without fibrosis. The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). The present study aimed to evaluate APJ as an indicator of the pathophysiology of early-stage NASH. Methods APJ expression was evaluated in six tissue samples with histologically proven early-stage NASH using immunohistochemistry (IHC) and immunoelectron microscopy (IEM). Results On IHC, in control liver tissue, APJ was mainly localized in the aortic artery, although APJ was detected only slightly in the sinusoids. In early NASH liver tissue, on IEM, APJ was observed mainly at the sites of sinusoidal lining cells around the central vein and periportal regions, and at arterial capillaries in the portal tract. With regard to endothelial cells (ECs), one sample showed a hematopoietic stem cell (HSC)/progenitor cell (HPC) partially wrapped with an EC. Conclusion HSCs/HPCs expressing APJ may contribute to the angiogenesis of liver tissue in early-stage NASH.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan
| | - Katsuya Otori
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Masaya Oda
- Departments of Internal Medicine, Sanno Hospital, International University of Health and Welfare, Tokyo, Japan
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Lazaridis N, Tsochatzis E. Current and future treatment options in non-alcoholic steatohepatitis (NASH). Expert Rev Gastroenterol Hepatol 2017; 11:357-369. [PMID: 28276821 DOI: 10.1080/17474124.2017.1293523] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. Diagnosis of NASH requires a liver biopsy and is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Although NASH is the most common cause of liver disease in the west world and among the top three indications for liver transplantation, there are no universally accepted pharmacological therapies and therapeutic advances have been slow. Areas covered: Current evidence about lifestyle interventions, bariatric surgery and pharmacotherapy is reviewed. Dietary recommendations and lifestyle interventions have shown promising results but are difficult to maintain. At the moment, there is no universally approved medical treatment for NASH. Pioglitazone and vitamin E are recommended by guidelines in selected patients. An increasing number of phase II and III trials in non-cirrhotic NASH are currently recruiting and their preliminary results discussed. Expert commentary: As NASH is classified as a medical condition of an unmet therapeutic need, it has gained an accelerated access pathway for drug approval based on surrogate endpoints. It is therefore expected that within the next five years, there will be at least one approved agent for the pharmacological treatment of pre-cirrhotic NASH.
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Affiliation(s)
- Nikos Lazaridis
- a UCL Institute for Liver and Digestive Health , Royal Free Hospital and UCL , London , UK
| | - Emmanuel Tsochatzis
- a UCL Institute for Liver and Digestive Health , Royal Free Hospital and UCL , London , UK
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12
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He XX, Wu XL, Chen RP, Chen C, Liu XG, Wu BJ, Huang ZM. Effectiveness of Omega-3 Polyunsaturated Fatty Acids in Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. PLoS One 2016; 11:e0162368. [PMID: 27711128 PMCID: PMC5053538 DOI: 10.1371/journal.pone.0162368] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Accepted: 08/22/2016] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome with the main characteristic of diffuse liver cells with fatty changes. The clinical evolution of NAFLD includes simple non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, and even hepatocellular carcinoma. METHODS AND FINDINGS We conducted this review to identify the effectiveness of omega-3 polyunsaturated fatty acids (ω-3 PUFA) in NAFLD. We searched PubMed, Cochrane Library and Embase. All randomized controlled trials (RCTs) of ω-3 PUFA treatment for NAFLD were considered. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as inverse variance (IV), fixed or random, with 95% confidence intervals (CIs). We included seven RCTs involving 442 patients (227 for the experimental group and 215 for the control group). All the patients were divided into two groups: one treated with ω-3 PUFA and the other was the control group (generally placebo). The demographics of the ω-3 PUFA and control groups were comparable. Beneficial changes in alanine aminotransferase (ALT) (IV 95% CI: -7.61 [-12.83 to -2.39], p = 0.004), total cholesterol (TC) (IV 95% CI: -13.41 [-21.44 to -5.38], p = 0.001), triglyceride (TG) (IV 95% CI: -43.96 [-51.21 to -36.71], p<0.00001) and high-density lipoprotein cholesterol (HDL-C) (IV 95% CI: 6.97 [2.05 to 11.90], p = 0.006) favored ω-3 PUFA treatment. Omega-3 PUFA tended towards a beneficial effect on aspartate aminotransferase (AST) (IV 95% CI: -6.89 [-17.71 to 3.92], p = 0.21), γ-glutamyl transferase (GGT) (IV 95% CI: -8.28 [-18.38 to 1.83], p = 0.11) and low-density lipoprotein cholesterol (LDL-C) (IV 95% CI: -7.13 [-14.26 to 0.0], p = 0.05). CONCLUSIONS Supplementation with ω-3 PUFA is a practical and effective treatment for NAFLD to decrease ALT, TC and increase HDL-C, especially to decrease TG. Omega-3 PUFA also has a tendency toward a beneficial effect on AST, GGT and LDL-C. More high-quality, large RCTs are needed to validate our findings.
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Affiliation(s)
- Xi-Xi He
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiao-Li Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Ren-Pin Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Chao Chen
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiao-Gang Liu
- Department of Gastroenterology, Ningxia People’s Hospital, Yinchuan, Ningxia, China
| | - Bin-Jiao Wu
- Department of Acupuncture and Moxibustion, The People’s Hospital of Yueqing, Wenzhou, Zhejiang Province, China
| | - Zhi-Ming Huang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- * E-mail:
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Koh H, Kim S, Kim MJ, Kim HG, Shin HJ, Lee MJ. Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis. World J Gastroenterol 2015; 21:9741-9748. [PMID: 26361421 PMCID: PMC4562958 DOI: 10.3748/wjg.v21.i33.9741] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/23/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the possibility of treatment effect monitoring using hepatic fat quantification magnetic resonance (MR) in pediatric nonalcoholic steatohepatitis (NASH).
METHODS: We retrospectively reviewed the medical records of patients who received educational recommendations and vitamin E for NASH and underwent hepatic fat quantification MR from 2011 to 2013. Hepatic fat fraction (%) was measured using dual- and triple-echo gradient-recalled-echo sequences at 3T. The compliant and non-compliant groups were compared clinically, biochemically, and radiologically.
RESULTS: Twenty seven patients (M:F = 24:3; mean age: 12 ± 2.3 years) were included (compliant group = 22, non-compliant = 5). None of the baseline findings differed between the 2 groups, except for triglyceride level (compliant vs non-compliant, 167.7 mg/dL vs 74.2 mg/dL, P = 0.001). In the compliant group, high-density lipoprotein increased and all other parameters decreased after 1-year follow-up. However, there were various changes in the non-compliant group. Dual-echo fat fraction (-19.2% vs 4.6, P < 0.001), triple-echo fat fraction (-13.4% vs 3.5, P < 0.001), alanine aminotransferase (-110.7 IU/L vs -10.6 IU/L, P = 0.047), total cholesterol (-18.1 mg/dL vs 3.8 mg/dL, P = 0.016), and triglyceride levels (-61.3 mg/dL vs 11.2 mg/dL, P = 0.013) were significantly decreased only in the compliant group. The change in body mass index and dual-echo fat fraction showed a positive correlation (ρ = 0.418, P = 0.030).
CONCLUSION: Hepatic fat quantification MR can be a non-invasive, quantitative and useful tool for monitoring treatment effects in pediatric NASH.
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Chen N, Yin S, Song X, Fan L, Hu H. Vitamin B₂ Sensitizes Cancer Cells to Vitamin-C-Induced Cell Death via Modulation of Akt and Bad Phosphorylation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2015; 63:6739-6748. [PMID: 26165392 DOI: 10.1021/acs.jafc.5b01909] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Vitamin C is an essential dietary nutrient that has a variety of biological functions. Recent studies have provided promising evidence for its additional health benefits, including anticancer activity. Vitamin B2, another essential dietary nutrient, often coexists with vitamin C in some fruits, vegetables, or dietary supplements. The objective of the present study is to determine whether the combination of vitamin C and B2 can achieve a synergistic anticancer activity. MDA-MB-231, MCF-7, and A549 cells were employed to evaluate the combinatory effects of vitamin C and B2. We found that the combination of vitamin C and B2 resulted in a synergistic cell death induction in all cell lines tested. Further mechanistic investigations revealed that vitamin B2 sensitized cancer cells to vitamin C through inhibition of Akt and Bad phosphorylation. Our findings identified vitamin B2 as a promising sensitizer for improving the efficacy of vitamin-C-based cancer chemoprevention and chemotherapy.
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Affiliation(s)
- Ni Chen
- ‡Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, People's Republic of China
| | - Shutao Yin
- ‡Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, People's Republic of China
| | - Xinhua Song
- ‡Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, People's Republic of China
| | - Lihong Fan
- §College of Veterinary Medicine, China Agricultural University, No. 2 Yunamingyuan West Road, Haidian District, Beijing 100193, People's Republic of China
| | - Hongbo Hu
- ‡Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, People's Republic of China
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Ipsen DH, Tveden-Nyborg P, Lykkesfeldt J. Does vitamin C deficiency promote fatty liver disease development? Nutrients 2014; 6:5473-99. [PMID: 25533004 PMCID: PMC4276979 DOI: 10.3390/nu6125473] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 11/05/2014] [Accepted: 11/15/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity and the subsequent reprogramming of the white adipose tissue are linked to human disease-complexes including metabolic syndrome and concurrent non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The dietary imposed dyslipidemia promotes redox imbalance by the generation of excess levels of reactive oxygen species and induces adipocyte dysfunction and reprogramming, leading to a low grade systemic inflammation and ectopic lipid deposition, e.g., in the liver, hereby promoting a vicious circle in which dietary factors initiate a metabolic change that further exacerbates the negative consequences of an adverse life-style. Large epidemiological studies and findings from controlled in vivo animal studies have provided evidence supporting an association between poor vitamin C (VitC) status and propagation of life-style associated diseases. In addition, overweight per se has been shown to result in reduced plasma VitC, and the distribution of body fat in obesity has been shown to have an inverse relationship with VitC plasma levels. Recently, a number of epidemiological studies have indicated a VitC intake below the recommended daily allowance (RDA) in NAFLD-patients, suggesting an association between dietary habits, disease and VitC deficiency. In the general population, VitC deficiency (defined as a plasma concentration below 23 μM) affects around 10% of adults, however, this prevalence is increased by an adverse life-style, deficiency potentially playing a broader role in disease progression in specific subgroups. This review discusses the currently available data from human surveys and experimental models in search of a putative role of VitC deficiency in the development of NAFLD and NASH.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, Frederiksberg C, 1870 Copenhagen, Denmark.
| | - Pernille Tveden-Nyborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, Frederiksberg C, 1870 Copenhagen, Denmark.
| | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, Frederiksberg C, 1870 Copenhagen, Denmark.
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