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Hegazy MA, Ahmed SM, Sultan SM, Afifi OF, Mohamed MA, Azab AE, Hassanen MA, Zaben RK. Metabolic dysfunction-associated steatotic liver disease and omega-6 polyunsaturated fatty acids: Friends or foes. World J Hepatol 2025; 17:102286. [PMID: 40177210 PMCID: PMC11959670 DOI: 10.4254/wjh.v17.i3.102286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide. Its prevalence is closely linked to the dramatic rise in obesity and non-communicable diseases. MASLD exhibits a progressive trajectory that may culminate in development of hepatic cirrhosis, thereby predisposing affected individuals to an elevated likelihood of hepatocarcinogenesis. Diet, especially dietary fatty acids, serves as a key link between nutrient intake and MASLD pathogenesis. AIM To explore the impact of various omega-6 fatty acid subtypes on the pathogenesis and therapeutic strategies of MASLD. METHODS A systematic literature search was conducted across Web of Science, PubMed, Cochrane Central, Scopus, and Embase databases from inception through June 2024 to identify all original studies linking different subtypes of omega-6 polyunsaturated fatty acids to the pathogenesis and management of MASLD. The search strategy explored the linkage between omega-6 polyunsaturated fatty acids and their subtypes, including linoleic acid (LA), gamma-linolenic acid (GLA), arachidonic acid, conjugated LA, and docosapentaenoic acid, in relation to MASLD and cardiometabolic risk. RESULTS By employing the specified search strategy, a total of 83 articles were identified as potentially eligible. During the title, abstract, and full-text screening phases, 27 duplicate records were removed, leaving 56 records for relevance screening. Of these, 43 records were excluded for reasons such as irrelevance and language restrictions (limited to English), resulting in 13 full-text articles being included for detailed assessment (10 human studies,1 animal study, and 2 review articles). Although certain subtypes, as GLA, dihomo-GLA, omega-6-derived oxylipins, and most arachidonic acid-derived eicosanoids, exhibit pro-inflammatory effects, our findings suggest that other subtypes such as LA, cis-9, trans-11 conjugated LA, and docosapentaenoic acid have beneficial effects on fatty liver, cardiometabolic risk factors, and inflammation, even at high intake levels. CONCLUSION The varying health effects of omega-6 fatty acids, ranging from anti-inflammatory to pro-inflammatory impacts on the liver, leave the question of their recommendation for MASLD patients unresolved. This underscores the importance of careful selection when considering omega-6 supplementation.
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Affiliation(s)
- Mona A Hegazy
- Department of Internal Medicine, Kasr Aliny Hospital, Faculty of Medicine, Cairo University, Cairo 12556, Egypt.
| | - Safaa M Ahmed
- Department of Neonatology, Mounira General Hospital, Cairo 4262130, Egypt
| | - Shaimaa M Sultan
- Department of Maternal and Pediatric Health, Shubra Elkhema Medical Administration, Qalyubia 13768, Egypt
| | - Osama F Afifi
- Department of Neonatology, Ashmoun Hospital, Menofia 32811, Egypt
| | - Manal A Mohamed
- Department of Internal Medicine, Elnasr Hospital, Helwan 11731, Egypt
| | - Alshimaa E Azab
- Department of Anesthesia, Al Helal Insurance Hospital, Qism Shebin 32514, Egypt
| | - Mohamed A Hassanen
- Department of Clinical Nutrition, Egyptian Fellowship, Cairo 11559, Egypt
| | - Rakan K Zaben
- Department of Clinical Nutrition, Egyptian Fellowship, Cairo 11559, Egypt
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Ling L, Li R, Xu M, Zhou J, Hu M, Zhang X, Zhang XJ. Species differences of fatty liver diseases: comparisons between human and feline. Am J Physiol Endocrinol Metab 2025; 328:E46-E61. [PMID: 39636211 DOI: 10.1152/ajpendo.00014.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 12/07/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most widespread chronic liver disease that poses significant threats to public health due to changes in dietary habits and lifestyle patterns. The transition from simple steatosis to nonalcoholic steatohepatitis (NASH) markedly increases the risk of developing cirrhosis, hepatocellular carcinoma, and liver failure in patients. However, there is only one Food and Drug Administration-approved therapeutic drug in the world, and the clinical demand is huge. There is significant clinical heterogeneity among patients with NAFLD, and it is challenging to fully understand human NAFLD using only a single animal model. Interestingly, felines, like humans, are particularly prone to spontaneous fatty liver disease. This review summarized and compared the etiology, clinical features, pathological characteristics, and molecular pathogenesis between human fatty liver and feline hepatic lipidosis (FHL). We analyzed the key similarities and differences between those two species, aiming to provide theoretical foundations for developing effective strategies for the treatment of NAFLD in clinics.
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Affiliation(s)
- Like Ling
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Ruilin Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Mengqiong Xu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Junjie Zhou
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Manli Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xin Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
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Tepebaşı MY, Savran M, Coşan S, Taştan ŞA, Aydın B. The protective role of selenium against high-fructose corn syrup-induced kidney damage: a histopathological and molecular analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:7829-7837. [PMID: 38734838 PMCID: PMC11450133 DOI: 10.1007/s00210-024-03149-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/05/2024] [Indexed: 05/13/2024]
Abstract
With the growth of the food industry, fructose, the intake of which increases with food, causes obesity and metabolic syndrome. Kidney damage may develop from metabolic syndrome. Selenium (Se) participates in the structure of antioxidant enzymes and has a medicinal effect. In this work, the protective impact of Se on kidney damage produced by high-fructose corn syrup (HFCS) via endoplasmic reticulum (ER) stress was examined. The study comprised four groups, each consisting of ten experimental animals: control, HFCS (20%-HFCS), HFCS (20%-HFCS), + Se (0.3 mg/kg/day/po), and Se (0.3 mg/kg/day/po) alone. The duration of the experiment was 6 weeks. Kidney tissues were stained with hematoxylin and eosin for histological examination. Immunohistochemical analysis was conducted to assess TNF-α and caspase-3 levels. The spectrophotometric evaluation was performed to measure TOS (total oxidant status), TAS (total antioxidant status), and OSI (oxidative stress index) levels. The PERK, ATF4, CHOP, BCL-2, and caspase-9 gene expression levels were assessed by the RT-qPCR method. After Se treatment, histopathological abnormalities and TNF-α and caspase-3 levels in the HFCS+Se group decreased (p < 0.001). While TOS and OSI levels increased dramatically in the HFCS group, TAS values decreased significantly but improved after Se application (p < 0.001). The expression levels of the genes PERK, ATF4, CHOP, and caspase-9 were significantly lower in the HFCS group when compared to the HFCS+Se group (p < 0.05). Our findings suggest that Se may protect against ER stress, oxidative stress, apoptosis, and kidney damage caused by high-dose fructose consumption.
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Affiliation(s)
| | - Mehtap Savran
- Department of Medical Pharmacology, University of Süleyman Demirel, Isparta, Turkey
| | - Samet Coşan
- Department of Medical Pharmacology, University of Süleyman Demirel, Isparta, Turkey
| | | | - Bünyamin Aydın
- Department of Internal Medicine, Kütahya University of Health Sciences, Kütahya, Turkey
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Xiong Y, Shi X, Xiong X, Li S, Zhao H, Song H, Wang J, Zhang L, You S, Ji G, Liu B, Wu N. A systematic review and meta-analysis of randomized controlled trials: effects of mediterranean diet and low-fat diet on liver enzymes and liver fat content of NAFLD. Food Funct 2024; 15:8248-8257. [PMID: 39076035 DOI: 10.1039/d4fo01461h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a leading cause of several chronic diseases, imposing a significant global economic burden. The Mediterranean diet (MD) and low-fat diet (LFD) are the two primary recommended dietary patterns that exhibit distinct positive effects on treating NAFLD. Objective: To investigate which of the two diets, MD and LFD, is more effective in the treatment of NAFLD. Methods: Randomized controlled trials (RCTs) up to April 2024 were searched for in PubMed, Web of Science, Medline, Scopus and Embase. Interventions included MD or LFD, with primary outcome measures being intrahepatic lipid, liver stiffness, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, gamma-glutamyl transferase, and homeostasis model assessment of insulin resistance. Secondary outcomes included weight, waist circumference, and body mass index. Use of random effects meta-analysis to assess outcomes of interest. Results: meta-analysis revealed no significant differences between MD and LFD in improving liver enzymes, liver fat, and related indices in NAFLD patients. Our findings provide compelling evidence for patients and healthcare professionals, allowing patients to choose a dietary pattern that aligns with their preferences and disease conditions. In summary, both MD and LFD can equivalently ameliorate NAFLD in the short term. Conclusions: Our results show that MD and LFD have similar therapeutic effects on liver enzymes and liver fat content in patients with NAFLD in the short term. Furthermore, our meta-analysis results have also opened up a new avenue of thought as to whether similar effects are achieved by alternating MD and LFD on alternate days.
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Affiliation(s)
- Yalan Xiong
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Xinyu Shi
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Xinying Xiong
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Shenyu Li
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hanhua Zhao
- Department of Sport Science, College of Education, Zhejiang University, Hangzhou, China
| | - Hualing Song
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jianying Wang
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Lei Zhang
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Shengfu You
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Baocheng Liu
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Na Wu
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Shi X, Xiong Y, Song H, Rong F, Tang N, Zhu L, Li S, Wang J, Zhang L, You S, Ji G, Liu B, Wu N. Progress and hotspot of diet or exercise therapy in the treatment of non-alcoholic fatty liver disease. Front Nutr 2024; 11:1326092. [PMID: 38628270 PMCID: PMC11018916 DOI: 10.3389/fnut.2024.1326092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 03/15/2024] [Indexed: 04/19/2024] Open
Abstract
INTRODUCTION The primary treatment for non-alcoholic fatty liver disease (NAFLD) is modifying lifestyle through dietary or exercise interventions. In recent decades, it has received increasing attention. However, the lack of bibliometric analysis has posed a challenge for researchers seeking to understand the overall trends in this field. METHODS As of February 3rd, 2024, 876 articles on treating NAFLD through diet or exercise therapy from 2013 to 2023 had been retrieved. Two software tools, VOSviewer and CiteSpace, were utilized to analyze the growth of publications, countries, institutions, authors, journals, citations, and keywords. Additionally, the keywords with strong citation burstiness were identified to determine the changes and future trends of research hotspots in this field. RESULTS China had the highest number of articles, followed by the United States and South Korea. Yonsei University and Nutrients were the institutions and journals with the most significant contributions. Professor Younossi Zobair M, from the United States, is the most prolific author in this field. Through analyzing the keywords, three research hotspots were identified: research on the pathogenesis of NAFLD, research on the treatment modalities of NAFLD, and research on the risk factors and diagnosis methods of NAFLD. In recent years, the research emphasis in this field has changed, suggesting that future research will focus on two frontier keywords: "oxidative stress" and "aerobic capacity." CONCLUSION In the past eleven years, the attention in this field was still rising, and the authors, journals, countries and so on had formed a considerable cooperative relationship. There were also many highly influential and productive researchers in this field. It is speculated that new research will continue around "aerobic exercise" and "oxidative stress" in the future.
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Affiliation(s)
- Xinyu Shi
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yalan Xiong
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hualing Song
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fen Rong
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nan Tang
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Leping Zhu
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shenyu Li
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianying Wang
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Zhang
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shengfu You
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Baocheng Liu
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Na Wu
- School of Public Health, Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Brown MG, Feller LE, Trupkiewicz JG, Hutchinson EK, Izzi JM. Comparing different strategies to reduce hepatocellular damage in obese common marmosets (Callithrix jacchus). J Med Primatol 2024; 53:e12683. [PMID: 37946549 DOI: 10.1111/jmp.12683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Obesity in common marmosets (Callithrix jacchus) can lead to various liver pathologies. In other species, reduced caloric intake and weight loss improve prognosis, and, often, hepatoprotectants are used to halt or reverse hepatocellular damage from fat deposition in the liver. There are no published therapies for reducing hepatocellular damage in obese marmosets. METHODS Fifteen obese marmosets were used to evaluate the ability of caloric restriction and pharmacologic therapy (S-adenosylmethionine + milk thistle extract, or SMT), alone and combined, to reduce elevated liver enzymes. Body weight and serum chemistries were measured every 4 weeks for 6 months. RESULTS Across treatment groups, there was a significant reduction in liver enzymes ALT and AST over time. SMT alone significantly reduced liver enzymes ALT and AST at 6 months from baseline. CONCLUSIONS Caloric restriction and SMT, alone and combined, are effective at reducing liver enzyme levels in obese marmosets.
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Affiliation(s)
- Mallory Gwendolyn Brown
- Research Animal Resources, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Laine Elizabeth Feller
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - John Gregory Trupkiewicz
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Eric Kenneth Hutchinson
- Research Animal Resources, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jessica Marie Izzi
- Research Animal Resources, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Hakkarainen K, Rantakokko P, Koponen J, Ruokojärvi P, Korkalainen M, Salomaa V, Jula A, Männistö S, Perola M, Lundqvist A, Männistö V, Åberg F. Persistent organic pollutants associate with liver disease in a Finnish general population sample. Liver Int 2023; 43:2177-2185. [PMID: 37312647 DOI: 10.1111/liv.15645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/30/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIMS Persistent organic pollutants (POPs) have multiple adverse effects on human health. Recent studies show a possible association with liver disease, but population-based data are scarce. In this population-based study, we studied the associations between POPs and biomarkers of liver disease and incident liver disease. METHODS This study consisted of 2789 adults that participated in the environmental toxin subset of the Finnish health-examination survey, FINRISK 2007. Toxins were measured from serum samples, and standard liver tests and dynamic aspartate aminotransferase-alanine aminotransferase ratio (dAAR) were measured as biomarkers of liver function. Associations between POPs and the biomarkers were then analysed using linear regression. Associations between POPs and incident liver disease (n = 36) were analysed by Cox regression. RESULTS Organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and several perfluorinated alkyl substances exhibited statistically significant positive associations with several biomarkers of liver injury (betacoefficient per SD 0.04-0.14, p < 0.05). These associations were stronger in subgroups of individuals with obesity or non-alcoholic fatty liver disease. OCPs, PCBs and perfluoro-octanoic acid also had significant positive associations with dAAR, which can be used to predict risk of incident severe liver outcomes (beta coefficient per SD 0.05-0.08, p < 0.05). OCPs and PCBs were also significantly and positively associated with incident liver disease (hazard ratio per SD 1.82 95% CI 1.21-2.73, p < 0.01 and hazard ratio per SD 1.69, 95% CI 1.07-2.68, p < 0.05 respectively). CONCLUSIONS Several POPs show positive associations with markers of liver injury and incident liver disease, suggesting that environmental toxins are important risk factors for chronic liver disease.
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Affiliation(s)
| | | | - Jani Koponen
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | | | | | - Veikko Salomaa
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Antti Jula
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Satu Männistö
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Markus Perola
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | | | - Ville Männistö
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Fredrik Åberg
- Transplantation and Liver Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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Choudhary P, Boamah B, Hon Ng S, White A, Weber LP, Wilson HL. Solidified saturated fats coating subunit vaccines greatly extended vaccine booster release and contributed to a Th1/Th2 mixed immune response in mice. Vaccine 2023; 41:3989-4001. [PMID: 37230887 DOI: 10.1016/j.vaccine.2023.05.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/02/2023] [Accepted: 05/08/2023] [Indexed: 05/27/2023]
Abstract
Delayed release of vaccine coupled with a soluble vaccine acts as a primer and a booster with only a single administration, which would be very beneficial to livestock producers. We developed a subdermal pellet consisting of solid-phase pure stearic acid (SA) or palmitic acid (PA) that was used to encapsulate a small volume liquid vaccine consisting of fluorescently labeled *Ovalbumin (Cy5-*OVA) formulated with Emulsigen-D +/- Poly I:C (EMP) adjuvants. Mice were also immunized via the subcutaneous route with Cy5-*OVA-EMP (soluble liquid). The vaccine leached out of the pellet with very little dissolution of the fat itself resulting in the sustained subdermal delivery of antigens and adjuvants. Cy5-*OVA was still visible 60 days post administration in mice immunized with stearic acid-coated or palmitic acid-coated pellets. In these mice, persistently high IgG1 and IgG2a antibody titres were detected as well as significant IFNγ production at least 60 days post-injection. These responses were significantly higher than those observed after a single subcutaneous injection of the vaccine. A repeat trial with the pellets alone +/- the soluble vaccine showed comparable immune responses after surgical implantation of the pellet, suggesting that pellet alone may be sufficient. The PA-coated vaccines led to dermal inflammation in the mice that would limit usefulness of this vehicle, but this was largely absent when SA was used to coat the pellets. These data suggest that the SA-coated adjuvanted vaccine prolonged the release of the vaccine and triggered a comparable immune response to the mice that received the two liquid injections, and a single pellet vaccine should be tested as a novel immunization method for livestock.
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Affiliation(s)
- Pooja Choudhary
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan S7N5E3, Canada
| | - Bright Boamah
- Toxicology Graduate Program, University of Saskatchewan, 44 Campus Drive, Saskatoon, Saskatchewan S7N 5B3, Canada
| | - Siew Hon Ng
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan S7N5E3, Canada
| | - Aaron White
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan S7N5E3, Canada; Department of Veterinary Microbiology Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada
| | - Lynn P Weber
- Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada
| | - Heather L Wilson
- Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan S7N5E3, Canada; Department of Veterinary Microbiology Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada; School of Public Health, Vaccinology and Immunotherapeutics, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan, Canada.
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Sani A, Lawal Abdullahi I, Darma AI. Hepatotoxicity and ALAD Activity Profile for Prediction of NOAEL of Metal Welding Fumes in Albino Rats. Biol Trace Elem Res 2023; 201:1781-1791. [PMID: 35525901 DOI: 10.1007/s12011-022-03273-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/28/2022] [Indexed: 11/27/2022]
Abstract
Metal fume pollutants of urban Kano, a city of over 10 million people, and widespread metal works have increased exposure with related health effects. Few data on metal fume toxicity and atmospheric levels have been documented in Nigeria and Kano in particular. Hence, the work was aimed at evaluating the metal fume toxicity to laboratory rat species for setting the permissible limit of exposure in urban Kano. The investigation involved the collection of metal welding fumes and subsequent laboratory analysis. Experimental animals were then exposed intratracheally to varying doses of the fumes which were equivalent to normal metal workers' daily routine of 2, 4, and 8 h for 3, 5, 10, and 20 years. Following euthanization, whole blood samples were collected and functions of liver and delta-aminolevunilic acid dehydratase were evaluated in the serum. Exposure to the fumes has caused significant mortality that was observed to be dose-dependent and statistically different (p < 0.05); moreover, the fumes had synergistically affected the functions of liver. In addition, the fumes had increased (statistically) the activity delta-aminolevinilic acid dehydratase. This has indicated that exposure to metal welding fumes being multi-elemental is toxic and had produced mortality at exposure to higher doses of metal welding fumes. It was therefore established from the study that no-observed-adverse-effect level (NOAEL) for metal welding fumes is 25.73 mg with LD50 of 270 mg which corresponds to the metal worker's 4-h shifts daily for 5 years under existing working conditions. It was recommended that regular monitoring should be put in place to limit exposure and extent of engagement in metal works beyond NOAEL levels.
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Affiliation(s)
- Ali Sani
- Department of Instrument Science and Engineering, School of Electronics, Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
- Department of Biological Sciences, Bayero University Kano, P.M.B. 3011, Kano, Nigeria.
| | | | - Aminu Inuwa Darma
- Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing, People's Republic of China
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Taylor R, Armstrong L, Bhattacharya A, Henry Z, Brinker A, Buckley B, Kong B, Guo G. Myclobutanil-mediated alteration of liver-gut FXR signaling in mice. Toxicol Sci 2023; 191:387-399. [PMID: 36511616 PMCID: PMC9936201 DOI: 10.1093/toxsci/kfac129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The effects of exposure to Myclobutanil, a triazole fungicide, on the development and progression of nonalcoholic fatty liver disease (NAFLD) are unclear, but activation of nuclear receptors (NRs) is a known mechanism of azole-induced liver toxicity. Farnesoid X receptor (FXR) is a NR and is highly expressed in the liver and intestine. Activation of FXR tightly regulates bile acid (BA), lipid and glucose homeostasis, and inflammation partly through the induction of fibroblast growth factor 15 (FGF15; human ortholog FGF19). FXR activation is downregulated during NAFLD and agonists are currently being explored as potential therapeutic strategy. In this study, we aimed to clarify the effects of Myclobutanil exposure on FXR activation and NAFLD development. Reporter assay showed Myclobutanil treatment, following FXR activation with potent FXR agonist (GW4064), resulted in a dose-dependent decrease of FXR activity. Furthermore, a 10-day study in male mice demonstrated that cotreatment with Myclobutanil led to an 80% reduction of GW4064-induced ileal expression of Fgf15. In a diet-induced NAFLD study, low-fat diet (LFD) fed mice administered myclobutanil displayed decreased FXR activity in the liver and ileum, while high-fat-high-sugar-diet (HFHSD) fed mice showed an increase in hepatic FXR activity and an induction of target genes regulated by constitutive androstane receptor and/or pregnane X receptor. Our work demonstrates Myclobutanil inhibits FXR activity and modulates FXR activity differentially in mice fed LFD or HFHSD. Our studies suggest the importance of understanding how Myclobutanil could contribute to BA dysregulation in disease states such as NAFLD.
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Affiliation(s)
- Rulaiha Taylor
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.,Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA.,Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA
| | - Laura Armstrong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.,Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA.,Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA
| | - Zakiyah Henry
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.,Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA.,Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA
| | - Anita Brinker
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Brian Buckley
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA
| | - Bo Kong
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.,Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA.,Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA
| | - Grace Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.,Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, USA.,Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA.,VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, USA
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11
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Effects of Different Vegetable Oils on the Nonalcoholic Fatty Liver Disease in C57/BL Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2023; 2023:4197955. [PMID: 36691598 PMCID: PMC9867581 DOI: 10.1155/2023/4197955] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 01/15/2023]
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, affecting 22-28% of the adult population and more than 50% of obese people all over the world. Modulation of the fatty acids in diet as a means of prevention against nonalcoholic fatty liver disease in animal models (NAFLD) remains unclear. The treatment of NAFLD has not been described in specific guidelines so far. Thus, the justification for the study is to check modifications in macronutrients composition, fatty acids, in particular, play a significant role in the treatment of NAFLD regardless of weight loss. Aim To investigate different vegetable oils in prevention and progression of NAFLD in animal models. Methods For the experiment were used fifty C57BL/6J mice male fed with high fat and fructose diet (HFD) to induce the NAFLD status and they received different commercial vegetable oils for 16 weeks to prevent steatosis. Liver steatosis and oxidative stress parameters were analyzed using biochemical and histological methods. Fatty acids profile in the oils and in the liver samples was obtained. Results The high fat and fructose diet led to obesity and the vegetable oils offered were effective in maintaining body weight similar to the control group. At the end of the experiment (16 weeks), the HFHFr group had a greater body weight compared to control and treated groups (HFHFr: 44.20 ± 2.34 g/animal vs. control: 34.80 ± 3.45 g/animal; p < 0.001; HFHFr/OL: 35.40 ± 4.19 g/animal; HFHFr/C: 36.10 ± 3.92 g/animal; HFHFr/S: 36.25 ± 5.70 g/animal; p < 0.01). Furthermore, the HFD diet has caused an increase in total liver fat compared to control (p < 0.01). Among the treated groups, the animals receiving canola oil showed a reduction of hepatic and retroperitoneal fat (p < 0.05). These biochemical levels were positively correlated with the hepatic histology findings. Hepatic levels of omega-3 decreased in the olive oil and high fat diet groups compared to the control group, whereas these levels increased in the groups receiving canola and soybean oil compared to control and the high fat groups. Conclusion In conclusion, the commercial vegetable oils either contributed to the prevention or reduction of induced nonalcoholic fatty liver with high fat and fructose diet, especially canola oil.
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Montemayor S, Mascaró CM, Ugarriza L, Casares M, Llompart I, Abete I, Zulet MÁ, Martínez JA, Tur JA, Bouzas C. Adherence to Mediterranean Diet and NAFLD in Patients with Metabolic Syndrome: The FLIPAN Study. Nutrients 2022; 14:3186. [PMID: 35956364 PMCID: PMC9370227 DOI: 10.3390/nu14153186] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/25/2022] [Accepted: 08/02/2022] [Indexed: 01/27/2023] Open
Abstract
Unhealthy diet is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). Previous studies showed the benefits of a Mediterranean diet (MedDiet) on Metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases, which usually have a pathophysiological relationship with NAFLD. To assess the effect of adherence to a MedDiet on NAFLD in MetS patients after lifestyle intervention, this multicentre (Mallorca and Navarra, Spain) prospective randomized trial, with personalized nutritional intervention based on a customized MedDiet, coupled with physical activity promotion was performed to prevent, and reverse NAFLD among patients with MetS. The current analysis included 138 patients aged 40 to 60 years old, Body Mass Index (BMI) 27-40 kg/m2, diagnosed with NAFLD using MRI, and MetS according to the International Diabetes Federation (IDF). A validated food frequency questionnaire was used to assess dietary intake. Adherence to Mediterranean diet by means of a 17-item validated questionnaire, anthropometrics, physical activity, blood pressure, blood biochemical parameters, and intrahepatic fat contents (IFC) were measured. The independent variable used was changes in MedDiet adherence, categorized in tertiles after 6 months follow-up. Subjects with high adherence to the MedDiet showed higher decreases in BMI, body weight, WC, SBP, DBP, and IFC. An association between improvement in adherence to the MedDiet and amelioration of IFC after 6-month follow-up was observed. High adherence to the MedDiet is associated with better status of MetS features, and better values of IFC.
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Affiliation(s)
- Sofía Montemayor
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
| | - Catalina M. Mascaró
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
| | - Lucía Ugarriza
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- Camp Redó Primary Health Care Center, 07010 Palma de Mallorca, Spain
| | - Miguel Casares
- Radiodiagnosis Service, Red Asistencial Juaneda, 07011 Palma de Mallorca, Spain;
| | - Isabel Llompart
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- Clinical Analysis Service, University Hospital Son Espases, 07120 Palma de Mallorca, Spain
| | - Itziar Abete
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.)
- Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain;
| | - María Ángeles Zulet
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.)
- Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain;
| | - J. Alfredo Martínez
- Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, 31008 Pamplona, Spain;
- Cardiometabolics Precision Nutrition Program, IMDEA Food, CEI UAM-CSIC, 28049 Madrid, Spain
| | - Josep A. Tur
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.)
| | - Cristina Bouzas
- Research Group on Community Nutrition and Oxidative Stress, University of the Balearic Islands-IUNICS, 07122 Palma de Mallorca, Spain; (S.M.); (C.M.M.); (L.U.); (I.L.); (C.B.)
- Health Institute of the Balearic Islands (IDISBA), 07120 Palma de Mallorca, Spain
- CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; (I.A.); (M.Á.Z.)
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Zhao P, Fan S, Gao Y, Huang M, Bi H. Nuclear Receptor-Mediated Hepatomegaly and Liver Regeneration: An Update. Drug Metab Dispos 2022; 50:636-645. [PMID: 35078806 DOI: 10.1124/dmd.121.000454] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 01/04/2022] [Indexed: 02/13/2025] Open
Abstract
Nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, are critical in cell growth, proliferation, differentiation, metabolism, and numerous biologic events. NRs have been reported to play important roles in hepatomegaly (liver enlargement) and liver regeneration by regulating target genes or interacting with other signals. In this review, the roles and involved molecular mechanisms of NRs in hepatomegaly and liver regeneration are summarized and the future perspectives of NRs in the treatment of liver diseases are discussed. SIGNIFICANCE STATEMENT: NRs play critical roles in hepatomegaly and liver regeneration, indicating the potential of NRs as targets to promote liver repair after liver injury. This paper reviews the characteristics and molecular mechanisms of NRs in regulating hepatomegaly and liver regeneration, providing more evidence for NRs in the treatment of related liver diseases.
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Affiliation(s)
- Pengfei Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (P.Z., S.F., Y.G., M.H., H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China (H.B.)
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14
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Taylor RE, Bhattacharya A, Guo GL. Environmental Chemical Contribution to the Modulation of Bile Acid Homeostasis and Farnesoid X Receptor Signaling. Drug Metab Dispos 2022; 50:456-467. [PMID: 34759011 PMCID: PMC11022932 DOI: 10.1124/dmd.121.000388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 11/05/2021] [Indexed: 11/22/2022] Open
Abstract
Maintaining bile acid (BA) homeostasis is important and regulated by BA activated receptors and signaling pathways. Farnesoid X receptor (FXR) and its regulated target networks in both the liver and the intestines are critical in suppressing BA synthesis and promoting BA transport and enterohepatic circulation. In addition, FXR is critical in regulating lipid metabolism and reducing inflammation, processes critical in the development of cholestasis and fatty liver diseases. BAs are modulated by, but also control, gut microflora. Environmental chemical exposure could affect liver disease development. However, the effects and the mechanisms by which environmental chemicals interact with FXR to affect BA homeostasis are only emerging. In this minireview, our focus is to provide evidence from reports that determine the effects of environmental or therapeutic exposure on altering homeostasis and functions of BAs and FXR. Understanding these effects will help to determine liver disease pathogenesis and provide better prevention and treatment in the future. SIGNIFICANCE STATEMENT: Environmental chemical exposure significantly contributes to the development of cholestasis and nonalcoholic steatohepatitis (NASH). The impact of exposures on bile acid (BA) signaling and Farnesoid X receptor-mediated gut-liver crosstalk is emerging. However, there is still a huge gap in understanding how these chemicals contribute to the dysregulation of BA homeostasis and how this dysregulation may promote NASH development.
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Affiliation(s)
- Rulaiha E Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (R.E.T., A.B., G.L.G.); Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey (G.L.G.); Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, New Brunswick, New Jersey (G.L.G.); and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (R.E.T., A.B., G.L.G.); Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey (G.L.G.); Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, New Brunswick, New Jersey (G.L.G.); and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (R.E.T., A.B., G.L.G.); Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, New Jersey (G.L.G.); Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, New Brunswick, New Jersey (G.L.G.); and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
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15
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FIRAT SN, DURHAN A, EREL S, ÇULHA C. The relationship between non-alcoholic fatty liver disease and breast cancer: a retrospective case-control study. JOURNAL OF HEALTH SCIENCES AND MEDICINE 2022. [DOI: 10.32322/jhsm.993960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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16
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Drożdż K, Nabrdalik K, Hajzler W, Kwiendacz H, Gumprecht J, Lip GYH. Metabolic-Associated Fatty Liver Disease (MAFLD), Diabetes, and Cardiovascular Disease: Associations with Fructose Metabolism and Gut Microbiota. Nutrients 2021; 14:103. [PMID: 35010976 PMCID: PMC8746577 DOI: 10.3390/nu14010103] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition associated with type 2 diabetes (T2DM) and cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies NAFLD, the current nomenclature has been revised, and the term metabolic-associated fatty liver disease (MAFLD) has been proposed. The new definition emphasizes the bidirectional relationships and increases awareness in looking for fatty liver disease among patients with T2DM and CVD or its risk factors, as well as looking for these diseases among patients with NAFLD. The most recommended treatment method of NAFLD is lifestyle changes, including dietary fructose limitation, although other treatment methods of NAFLD have recently emerged and are being studied. Given the focus on the liver-gut axis targeting, bacteria may also be a future aim of NAFLD treatment given the microbiome signatures discriminating healthy individuals from those with NAFLD. In this review article, we will provide an overview of the associations of fructose consumption, gut microbiota, diabetes, and CVD in patients with NAFLD.
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Affiliation(s)
- Karolina Drożdż
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool L14 3PE, UK
| | - Weronika Hajzler
- Doctoral School, Department of Pediatric Hematology and Oncology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland;
| | - Hanna Kwiendacz
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
| | - Gregory Y. H. Lip
- Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (K.D.); (H.K.); (J.G.); (G.Y.H.L.)
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool L14 3PE, UK
- Department of Clinical Medicine, Aalborg University, 9100 Aalborg, Denmark
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Lavorato VN, de Miranda DC, Drummond FR, Rezende LMT, do Carmo Gouveia Pelúzio M, Silva ME, Natali AJ. Combined action of açai and aerobic exercise training on the development of NAFLD induced by a high-fat diet: a preliminary exploration. SPORT SCIENCES FOR HEALTH 2021. [DOI: 10.1007/s11332-021-00831-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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18
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Salter DM, Wei W, Nahar PP, Marques E, Slitt AL. Perfluorooctanesulfonic Acid (PFOS) Thwarts the Beneficial Effects of Calorie Restriction and Metformin. Toxicol Sci 2021; 182:82-95. [PMID: 33844015 DOI: 10.1093/toxsci/kfab043] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A combination of calorie restriction (CR), dietary modification, and exercise is the recommended therapy to reverse obesity and nonalcoholic fatty liver disease. In the liver, CR shifts hepatic metabolism from lipid storage to lipid utilization pathways, such as AMP-activated protein kinase (AMPK). Perfluorooctanesulfonic acid (PFOS), a fluorosurfactant previously used in stain repellents and anti-stick materials, can increase hepatic lipids in mice following relatively low-dose exposures. To test the hypothesis that PFOS administration interferes with CR, adult male C57BL/6N mice were fed ad libitum or a 25% reduced calorie diet concomitant with either vehicle (water) or 100 μg PFOS/kg/day via oral gavage for 6 weeks. CR alone improved hepatic lipids and glucose tolerance. PFOS did not significantly alter CR-induced weight loss, white adipose tissue mass, or liver weight over 6 weeks. However, PFOS increased hepatic triglyceride accumulation, in both mice fed ad libitum and subjected to CR. This was associated with decreased phosphorylated AMPK expression in liver. Glucagon (100 nM) treatment induced glucose production in hepatocytes, which was further upregulated with PFOS (2.5 μM) co-treatment. Next, to explore whether the observed changes were related to AMPK signaling, HepG2 cells were treated with metformin or AICAR alone or in combination with PFOS (25 μM). PFOS interfered with glucose-lowering effects of metformin, and AICAR treatment partially impaired PFOS-induced increase in glucose production. In 3T3-L1 adipocytes, metformin was less effective with PFOS co-treatment. Overall, PFOS administration disrupted hepatic lipid and glucose homeostasis and interfered with beneficial glucose-lowering effects of CR and metformin.
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Affiliation(s)
- Deanna M Salter
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA
| | - Wei Wei
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA
| | - Pragati P Nahar
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA
| | - Emily Marques
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA
| | - Angela L Slitt
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA
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Seminotti B, Roginski AC, Zanatta Â, Amaral AU, Fernandes T, Spannenberger KP, da Silva LHR, Ribeiro RT, Leipnitz G, Wajner M. S-adenosylmethionine induces mitochondrial dysfunction, permeability transition pore opening and redox imbalance in subcellular preparations of rat liver. J Bioenerg Biomembr 2021; 53:525-539. [PMID: 34347214 DOI: 10.1007/s10863-021-09914-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 07/17/2021] [Indexed: 01/03/2023]
Abstract
S-adenosylmethionine (AdoMet) predominantly accumulates in tissues and biological fluids of patients affected by liver dysmethylating diseases, particularly glycine N-methyltransferase, S-adenosylhomocysteine hydrolase and adenosine kinase deficiencies, as well as in some hepatic mtDNA depletion syndromes, whose pathogenesis of liver dysfunction is still poorly established. Therefore, in the present work, we investigated the effects of S-adenosylmethionine (AdoMet) on mitochondrial functions and redox homeostasis in rat liver. AdoMet decreased mitochondrial membrane potential and Ca2+ retention capacity, and these effects were fully prevented by cyclosporin A and ADP, indicating mitochondrial permeability transition (mPT) induction. It was also verified that the thiol-alkylating agent NEM prevented AdoMet-induced ΔΨm dissipation, implying a role for thiol oxidation in the mPT pore opening. AdoMet also increased ROS production and provoked protein and lipid oxidation. Furthermore, AdoMet reduced GSH levels and the activities of aconitase and α-ketoglutarate dehydrogenase. Free radical scavengers attenuated AdoMet effects on lipid peroxidation and GSH levels, supporting a role of ROS in these effects. It is therefore presumed that disturbance of mitochondrial functions associated with mPT and redox unbalance may represent relevant pathomechanisms of liver damage provoked by AdoMet in disorders in which this metabolite accumulates.
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Affiliation(s)
- Bianca Seminotti
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ana Cristina Roginski
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ângela Zanatta
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Alexandre Umpierrez Amaral
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Avenida Sete de Setembro, 1621, Erechim, RS, 99709-910, Brazil
| | - Thabata Fernandes
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Kaleb Pinto Spannenberger
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Lucas Henrique Rodrigues da Silva
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Rafael Teixeira Ribeiro
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.,Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio 21111, Porto Alegre, RS, 90035-003, Brazil
| | - Moacir Wajner
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. .,Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Prédio 21111, Porto Alegre, RS, 90035-003, Brazil. .,Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, RS, 90035-007, Brazil.
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20
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Jiang H, Lin Q, Ma L, Luo S, Jiang X, Fang J, Lu Z. Fructose and fructose kinase in cancer and other pathologies. J Genet Genomics 2021; 48:531-539. [PMID: 34326012 DOI: 10.1016/j.jgg.2021.06.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022]
Abstract
Fructose metabolism and fructose kinase KHK-C/A are key factors in the development of lipid oversynthesis-promoted metabolic disorders and cancer. Here, we summarize and discuss the current knowledge about the specific features of fructose metabolism and the distinct roles of KHK-C and KHK-A in metabolic liver diseases and their relevant metabolic disorders and cancer, and we highlight the specific protein kinase activity of KHK-A in tumor development. In addition, different approaches that have been used to inhibit KHK and the exploration of KHK inhibitors in clinical treatment are introduced.
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Affiliation(s)
- Hongfei Jiang
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao 266061, China
| | - Qian Lin
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao 266061, China
| | - Leina Ma
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao 266061, China
| | - Shudi Luo
- Zhejiang University Cancer Center, Hangzhou 310029, China
| | - Xiaoming Jiang
- Zhejiang University Cancer Center, Hangzhou 310029, China
| | - Jing Fang
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao 266061, China.
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Zhejiang University Cancer Center, Hangzhou 310029, China.
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21
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Esmail M, Anwar S, Kandeil M, El-Zanaty AM, Abdel-Gabbar M. Effect of Nigella sativa, atorvastatin, or L-Carnitine on high fat diet-induced obesity in adult male Albino rats. Biomed Pharmacother 2021; 141:111818. [PMID: 34126354 DOI: 10.1016/j.biopha.2021.111818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 06/01/2021] [Accepted: 06/07/2021] [Indexed: 12/19/2022] Open
Abstract
Obesity is increasing rapidly across the globe. It is widely accepted that natural products with a long safety background may modulate obesity. The current work aimed to investigate the effect of Nigella sativa, atorvastatin, or L-Carnitine on high-fat diet-induced obesity in white male albino rats. A regular basal diet was fed to 7 rats, and a high-fat diet (HFD) was fed to 24 rats throughout the study for 12 weeks. The HFD group was split equally into four subgroups, each containing six rats. The first group fed on HFD with no medication, the second group received HFD+ Nigella sativa, the third group received HFD+ atorvastatin, and the fourth group received HFD+L-carnitine. At the beginning of the seventh week (the start of the treatment regimen), Nigella sativa, atorvastatin, or L-Carnitine were administered for six weeks. Glucose, body weight, serum atherogenic index (AI), ALT, and AST activities were analyzed. The pathological alterations in the hepatic tissues were examined microscopically and scored. The results revealed that the HFD diet significantly increased the final body weight, serum AI, and serum levels of liver enzymes. Treatment with L-carnitine or Nigella sativa significantly normalized the lipid profile and decreased the final body weight, serum AI, and Serum ALT. Histopathological examination of the liver of HFD received rats showed features of steatosis, which were mitigated by the administration of Nigella sativa or L-Carnitine, while atorvastatin had no significant effect on the improvement of hepatic lesions. Collectively, study findings showed that Nigella sativa or L-Carnitine has mitigated effects on metabolic and histopathological changes in the liver tissues of rats fed with HFD.
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Affiliation(s)
- Mohammed Esmail
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Shehata Anwar
- Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62511, Beni-Suef, Egypt.
| | - Mohammed Kandeil
- Biochemistry Department, Faculty of Veterinary Medicine, Beni-Suef University, P.O. Box 62511, Beni-Suef, Egypt
| | - Ali Mahmoud El-Zanaty
- Chemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Mohammed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
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22
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Imai J, Kitamoto S, Kamada N. The pathogenic oral-gut-liver axis: new understandings and clinical implications. Expert Rev Clin Immunol 2021; 17:727-736. [PMID: 34057877 DOI: 10.1080/1744666x.2021.1935877] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Oral health is closely related to extra-oral disease status, as may be represented by the manifestations of gastrointestinal and liver diseases. AREAS COVERED This review focuses on the roles that the oral-gut or the oral-gut-liver axis play in the pathogenesis of inflammatory bowel disease, colorectal cancer, metabolic fatty liver disease, and nonalcoholic steatohepatitis. The discussion will begin with clinical data, including data from preclinical animal models, to elucidate mechanisms. We will also discuss ways to target oral dysbiosis and oral inflammation to treat gastrointestinal and liver diseases. EXPERT OPINION Several studies have demonstrated that oral pathobionts can translocate to the gastrointestinal tract where they contribute to inflammation and tumorigenesis. Furthermore, oral bacteria that migrate to the gastrointestinal tract can disseminate to the liver and cause hepatic disease. Thus, oral bacteria that ectopically colonize the intestine may serve as biomarkers for gastrointestinal and liver diseases. Also, understanding the characteristics of the oral-gut and oral-gut-liver microbial and immune axes will provide new insights into the pathogenesis of these diseases.
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Affiliation(s)
- Jin Imai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan
| | - Sho Kitamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
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23
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Allopurinol ameliorates high fructose diet induced hepatic steatosis in diabetic rats through modulation of lipid metabolism, inflammation, and ER stress pathway. Sci Rep 2021; 11:9894. [PMID: 33972568 PMCID: PMC8110790 DOI: 10.1038/s41598-021-88872-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 04/06/2021] [Indexed: 02/03/2023] Open
Abstract
Excess fructose consumption contributes to development obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD). Uric acid (UA), a metabolite of fructose metabolism, may have a direct role in development of NAFLD, with unclear mechanism. This study aimed to evaluate role of fructose and UA in NAFLD and explore mechanisms of allopurinol (Allo, a UA lowering medication) on NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a high fructose diet (HFrD), with Long-Evans Tokushima Otsuka (LETO) rats used as a control. There were six groups: LETO, LETO-Allo, OLETF, OLETF-Allo, OLETF-HFrD, and OLETF-HFrD-Allo. HFrD significantly increased body weight, epididymal fat weight, and serum concentrations of UA, cholesterol, triglyceride, HbA1c, hepatic enzymes, HOMA-IR, fasting insulin, and two hour-glucose after intraperitoneal glucose tolerance tests, as well as NAFLD activity score of liver, compared to the OLETF group. Allopurinol treatment significantly reduced hepatic steatosis, epididymal fat, serum UA, HOMA-IR, hepatic enzyme levels, and cholesterol in the OLETF-HFrD-Allo group. Additionally, allopurinol significantly downregulated expression of lipogenic genes, upregulated lipid oxidation genes, downregulated hepatic pro-inflammatory cytokine genes, and decreased ER-stress induced protein expression, in comparison with the OLETF-HFrD group. In conclusion, allopurinol ameliorates HFrD-induced hepatic steatosis through modulation of hepatic lipid metabolism, inflammation, and ER stress pathway. UA may have a direct role in development of fructose-induced hepatic steatosis, and allopurinol could be a candidate for prevention or treatment of NAFLD.
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24
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Kilanczyk E, Banales JM, Wunsch E, Barbier O, Avila MA, Mato JM, Milkiewicz M, Milkiewicz P. S-adenosyl-L-methionine (SAMe) halts the autoimmune response in patients with primary biliary cholangitis (PBC) via antioxidant and S-glutathionylation processes in cholangiocytes. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165895. [PMID: 32681864 DOI: 10.1016/j.bbadis.2020.165895] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 01/14/2023]
Abstract
S-adenosyl-L-methionine is an endogenous molecule with hepato-protective properties linked to redox regulation and methylation. Here, the potential therapeutic value of SAMe was tested in 17 patients with PBC, a cholestatic disease with autoimmune phenomena targeting small bile ducts. Nine patients responded to SAMe (SAMe responders) with increased serum protein S-glutathionylation. That posttranslational protein modification was associated with reduction of serum anti-mitochondrial autoantibodies (AMA-M2) titers and improvement of liver biochemistry. Clinically, SAMe responders were younger at diagnosis, had longer duration of the disease and lower level of serum S-glutathionylated proteins at entry. SAMe treatment was associated with negative correlation between protein S-glutathionylation and TNFα. Furthermore, AMA-M2 titers correlated positively with INFγ and FGF-19 while negatively with TGFβ. Additionally, cirrhotic PBC livers showed reduced levels of glutathionylated proteins, glutaredoxine-1 (Grx-1) and GSH synthase (GS). The effect of SAMe was also analyzed in vitro. In human cholangiocytes overexpressing miR-506, which induces PBC-like features, SAMe increased total protein S-glutathionylation and the level of γ-glutamylcysteine ligase (GCLC), whereas reduced Grx-1 level. Moreover, SAMe protected primary human cholangiocytes against mitochondrial oxidative stress induced by tBHQ (tert-Butylhydroquinone) via raising the level of Nrf2 and HO-1. Finally, SAMe reduced apoptosis (cleaved-caspase3) and PDC-E2 (antigen responsible of the AMA-M2) induced experimentally by glycochenodeoxycholic acid (GCDC). These data suggest that SAMe may inhibit autoimmune events in patients with PBC via its antioxidant and S-glutathionylation properties. These findings provide new insights into the molecular events promoting progression of PBC and suggest potential therapeutic application of SAMe in PBC.
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Affiliation(s)
- E Kilanczyk
- Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland
| | - J M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Ikerbasque, CIBERehd, San Sebastian, Spain
| | - E Wunsch
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - O Barbier
- Laboratory of Molecular Pharmacology, CHU de Québec Research Center, Faculty of Pharmacy, Laval University, Québec City, QC G1V 0A6, Canada
| | - M A Avila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra and CIBERehd, Pamplona 31008, Spain
| | - J M Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, Derio 48160, Bizkaia, Spain
| | - M Milkiewicz
- Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland.
| | - P Milkiewicz
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland; Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
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25
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Ouyang Y, Wu Q, Li J, Sun S, Sun S. S-adenosylmethionine: A metabolite critical to the regulation of autophagy. Cell Prolif 2020; 53:e12891. [PMID: 33030764 PMCID: PMC7653241 DOI: 10.1111/cpr.12891] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/21/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a mechanism that enables cells to maintain cellular homeostasis by removing damaged materials and mobilizing energy reserves in conditions of starvation. Although nutrient availability strongly impacts the process of autophagy, the specific metabolites that regulate autophagic responses have not yet been determined. Recent results indicate that S-adenosylmethionine (SAM) represents a critical inhibitor of methionine starvation-induced autophagy. SAM is primarily involved in four key metabolic pathways: transmethylation, transsulphuration, polyamine synthesis and 5'-deoxyadenosyl 5'-radical-mediated biochemical transformations. SAM is the sole methyl group donor involved in the methylation of DNA, RNA and histones, modulating the autophagic process by mediating epigenetic effects. Moreover, the metabolites of SAM, such as homocysteine, glutathione, decarboxylated SAM and spermidine, also exert important influences on the regulation of autophagy. From our perspective, nuclear-cytosolic SAM is a conserved metabolic inhibitor that connects cellular metabolic status and the regulation of autophagy. In the future, SAM might be a new target of autophagy regulators and be widely used in the treatment of various diseases.
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Affiliation(s)
- Yang Ouyang
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Qi Wu
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Juanjuan Li
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Si Sun
- Department of Clinical LaboratoryRenmin Hospital of Wuhan UniversityWuhanChina
| | - Shengrong Sun
- Department of Breast and Thyroid SurgeryRenmin Hospital of Wuhan UniversityWuhanChina
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26
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Transcript and protein marker patterns for the identification of steatotic compounds in human HepaRG cells. Food Chem Toxicol 2020; 145:111690. [DOI: 10.1016/j.fct.2020.111690] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/20/2020] [Accepted: 08/11/2020] [Indexed: 12/18/2022]
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27
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Jiao T, Yao X, Zhao Y, Zhou Y, Gao Y, Fan S, Chen P, Li X, Jiang Y, Yang X, Gonzalez FJ, Huang M, Bi H. Dexamethasone-Induced Liver Enlargement Is Related to PXR/YAP Activation and Lipid Accumulation but Not Hepatocyte Proliferation. Drug Metab Dispos 2020; 48:830-839. [PMID: 32561593 PMCID: PMC7497622 DOI: 10.1124/dmd.120.000061] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
Dexamethasone (Dex), a widely prescribed anti-inflammatory drug, was reported to induce liver enlargement (hepatomegaly) in clinical practice and in animal models. However, the underlying mechanisms are not elucidated. Dex is a known activator of pregnane X receptor (PXR). Yes-associated protein (YAP) has been implicated in chemically induced liver enlargement. Here, the roles of PXR and YAP pathways were investigated in Dex-induced hepatomegaly. Upregulation of PXR downstream proteins, including cytochrome P450 (CYP) 3A11, 2B10, and organic anion transporter polypeptide 2 (OATP2), indicated PXR signaling was activated after high dose of Dex (50 mg/kg, i.p.), and Dex at 100 μM activated PXR in the dual-luciferase reporter gene assay. Dex also increased the expression of total YAP, nuclear YAP, and YAP downstream proteins, including connective tissue growth factor and cysteine-rich angiogenic inducer 61, indicating activation of the YAP pathway. Furthermore, nuclear translocation of YAP was promoted by activation of PXR. However, hepatocyte proliferation was inhibited with significant decrease in the expression of proliferation-related proteins cyclin D1 and proliferating cell nuclear antigen as well as other regulatory factors, such as forkhead box protein M1, c-MYC, and epidermal growth factor receptor. The inhibitory effect of Dex on hepatocyte proliferation was likely due to its anti-inflammation effect of suppression of inflammation factors. β-catenin staining revealed enlarged hepatocytes, which were mostly attributable to the accumulation of lipids, such as triglycerides. In summary, high-dose Dex increased liver size accompanied by enlarged hepatocytes, and this was due to the activation of PXR/YAP and their effects on lipid accumulation but not hepatocyte proliferation. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly. SIGNIFICANCE STATEMENT: This study identified the roles of pregnane X receptor (PXR) and yes-associated protein (YAP) pathways in dexamethasone (Dex)-induced hepatomegaly. Dex induced PXR/YAP activation, enlarged hepatocytes, and promoted liver enlargement with lipid accumulation, such as triglycerides. However, hepatocyte proliferation was inhibited by the anti-inflammatory effect of Dex. These findings provide new insights for understanding the mechanism of Dex-induced hepatomegaly.
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Affiliation(s)
- Tingying Jiao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xinpeng Yao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yingyuan Zhao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yanying Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Panpan Chen
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xuan Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Xiao Yang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Frank J Gonzalez
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (T.J., X.P.Y., Yi.Z., Ya.Z., Y.G., S.F., P.C., X.L., Y.J., X.Y., M.H., H.B.) and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (F.J.G.)
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28
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Yang Z, Yu Y, Sun N, Zhou L, Zhang D, Chen H, Miao W, Gao W, Zhang C, Liu C, Yang X, Wu X, Gao Y. Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD. J Ginseng Res 2020; 47:376-384. [DOI: 10.1016/j.jgr.2020.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/01/2020] [Accepted: 07/29/2020] [Indexed: 10/23/2022] Open
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29
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Nia AM, Khanipov K, Barnette BL, Ullrich RL, Golovko G, Emmett MR. Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma. BMC Genomics 2020; 21:453. [PMID: 32611366 PMCID: PMC7329445 DOI: 10.1186/s12864-020-06869-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/24/2020] [Indexed: 01/04/2023] Open
Abstract
Background One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z > 13), which can lead to the induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation-induced HCC. Results We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression. Conclusions A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation and may also have important implications for the discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.
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Affiliation(s)
- Anna M Nia
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Kamil Khanipov
- Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Brooke L Barnette
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Robert L Ullrich
- The Radiation Effects Research Foundation (RERF), Hiroshima, Japan
| | - George Golovko
- Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA
| | - Mark R Emmett
- Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA. .,Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77550, USA.
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Kaelin BR, McKenzie CM, Hempel KW, Lang AL, Arteel GE, Beier JI. Adipose tissue-liver crosstalk during pathologic changes caused by vinyl chloride metabolites in mice. Toxicol Appl Pharmacol 2020; 399:115068. [PMID: 32445754 DOI: 10.1016/j.taap.2020.115068] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/06/2020] [Accepted: 05/19/2020] [Indexed: 12/20/2022]
Abstract
Volatile organic compounds (VOCs), such as vinyl chloride (VC), can be directly toxic at high concentrations. However, we have shown that 'nontoxic' exposures to VC and its metabolite chloroethanol (CE) enhances experimental non-alcoholic fatty liver disease (NAFLD), suggesting an unpredicted interaction. Importantly, VOC exposure has been identified as a potential risk factor for the development of obesity and its sequelae in humans. As there is a known axis between adipose and hepatic tissue in NAFLD, the impact of CE on white adipose tissue (WAT) inflammation and lipolysis was investigated. Mice were administered CE (or vehicle) once, after 10 weeks of being fed high-fat or low-fat diet (LFD). CE significantly enhanced hepatic steatosis and inflammation caused by HFD. HFD significantly increased the size of epididymal fat pads, which was enhanced by CE. The relative size of adipocyte lipid droplets increased by HFD + CE, which was also correlated with increased expression of lipid-associated proteins (e.g., PLINs). CE also enhanced HFD-induced indices of WAT inflammation, and ER stress. Hepatic-derived circulating FGF21, a major modulator of WAT lipolysis, which is hypothesized to thereby regulate hepatic steatosis, was significantly increased by CE in animals fed HFD. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH, involving the liver-adipose axis in this process. Specifically, CE enhances local inflammation and alters lipid metabolism and WAT-mediated hepatic steatosis due to changes in WAT lipolysis.
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Affiliation(s)
- Brenna R Kaelin
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Collin M McKenzie
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Karl W Hempel
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Anna L Lang
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, United States of America; Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 40292, United States of America.
| | - Gavin E Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
| | - Juliane I Beier
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, United States of America; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15213, United States of America.
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Abstract
Abstract
Introduction
Ten percent of cirrhotic patients are known to have a high risk of postoperative complications. Ninety percent of bariatric patients suffer from non-alcoholic fatty liver disease (NAFLD), and 50% of them may develop non-alcoholic steatohepatitis (NASH) which can progress to cirrhosis. The aim of this study was to assess whether the presence of cirrhosis at the time of bariatric surgery is associated with an increased rate and severity of short- and long-term cirrhotic complications.
Methods
A cohort of 110 bariatric patients, between May 2003 and February 2018, who had undergone liver biopsy at the time of bariatric surgery were reassessed for histological outcome and divided into two groups based on the presence (C, n = 26) or absence (NC, n = 84) of cirrhosis. The NC group consisted of NASH (n = 49), NAFLD (n = 24) and non-NAFLD (n = 11) liver histology. Medical notes were retrospectively assessed for patient characteristics, development of 30-day postoperative complications, severity of complications (Clavien-Dindo (CD) classification) and length of stay. The C group was further assessed for long-term cirrhosis-related outcomes.
Results
The C group was older (52 years vs 43 years) and had lower BMI (46 kg/m2 vs 52 kg/m2) and weight (126 kg vs 145 kg) compared to the NC group (p < 0.05). The C group had significantly higher overall complication rate (10/26 vs 14/84, p < 0.05) and severity of complications (CD class ≥ III, 12% vs 7%, p < 0.05) when compared to the NC group. The length of stay was similar between the two groups (5 days vs 4 days). The C group had significant improvement in model end-stage liver disease scores (7 vs 6, p < 0.01) with median follow-up of 4.5 years (range 2–11 years). There were no long-term cirrhosis-related complications or mortality in our studied cohort (0/26).
Conclusion
Bariatric surgery in cirrhotic patients has a higher risk of immediate postoperative complications. Long-term cirrhosis-related complications or mortality was not increased in this small cohort. Preoperative identification of liver cirrhosis may be useful for risk stratification, optimisation and informed consent. Bariatric surgery in well-compensated cirrhotic patients may be used as an aid to improve long-term outcome.
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Koplay M, Gok M, Sivri M. The association between coronary artery disease and nonalcoholic fatty liver disease and noninvasive imaging methods. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2019. [DOI: 10.29333/ejgm/110689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Wu X, Zheng H, Yang R, Luan X, Zhang L, Jin Q, Jin Y, Xue J. Mouse trefoil factor 3 ameliorated high-fat-diet-induced hepatic steatosis via increasing peroxisome proliferator-activated receptor-α-mediated fatty acid oxidation. Am J Physiol Endocrinol Metab 2019; 317:E436-E445. [PMID: 31211621 DOI: 10.1152/ajpendo.00454.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Hepatic trefoil factor 3 (Tff3) was identified as a potential protein for the treatment of diabetes, yet the effect of Tff3 on nonalcoholic fatty liver disease (NAFLD) has never been explored. Here, we found that the expression of hepatic Tff3 was significantly decreased in NAFLD mice models, suggesting that Tff3 was a potential marker gene for NAFLD. Restoring the expression of Tff3 in the liver of NAFLD mice, including diabetic (db), obese (ob/ob), and diet-induced obese mice, with adenovirus-mediated Tff3 (Ad-Tff3) apparently attenuates the fatty liver phenotype. In contrast, adenovirus-mediated knockdown of Tff3 (Ad-shTff3) in C57BL/6J mice results in an obvious fatty liver phenotype. Furthermore, our molecular experiments indicated that hepatic Tff3 could alleviate hepatic steatosis via upregulating the expression of peroxisome proliferator-activated receptor-α (PPARα) directly, thereby enhancing the fatty acid oxidation process in the liver. Notably, we found that Tff3 attenuates the fatty liver phenotype independent of modulation of lipogenesis and improves the capacity of anti-inflammation. Overall, our results suggested that hepatic Tff3 could be effectively used as a potential therapy target for the treatment of NAFLD.
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Affiliation(s)
- Xiaojie Wu
- Department of Immunology, Binzhou Medical University, Yantai, China
- Central Laboratory, Binzhou People's Hospital, Binzhou, China
| | - Hongze Zheng
- Central Laboratory, Binzhou People's Hospital, Binzhou, China
| | - Rui Yang
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Xiying Luan
- Department of Immunology, Binzhou Medical University, Yantai, China
| | - Lingyun Zhang
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Qingsong Jin
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Yongjun Jin
- Department of Endocrinology, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, China
| | - Jiangnan Xue
- Department of Immunology, Binzhou Medical University, Yantai, China
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Mohammed A H, Adel Amin K. Alteration of Serum and Hepatic Trace Element Level in Non-alcoholic Fatty Liver Disease-induced by High-fat Sucrose Diet. ACTA ACUST UNITED AC 2019. [DOI: 10.3923/ajsr.2019.323.332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Tayyem RF, Al-Dayyat HM, Rayyan YM. Relationship between lifestyle factors and nutritional status and non-alcoholic fatty liver disease among a group of adult Jordanians. Arab J Gastroenterol 2019; 20:44-49. [PMID: 30872135 DOI: 10.1016/j.ajg.2019.01.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 12/02/2018] [Accepted: 01/26/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND STUDY AIMS Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. NAFLD may progress from simple steatosis to nonalcoholic steatohepatitis, cirrhosis and finally decompensated liver failure. This study aims at assessing the relationship between lifestyle factors and nutrients intake and the development of non-alcoholic fatty liver disease (NAFLD) in a group of Jordanian adults 30-60 years of age. PATIENTS AND METHODS In this case-control study, a total of 120 Jordanian adults 30-60 years of age were recruited. Sixty NAFLD patients and 60 control subjects were enrolled. The diagnosis of NAFLD was made based on the basis of ultrasonography. Weight, height and waist circumference (WC) were measured and body mass index (BMI) was calculated. Nutrients intake and physical activity level were assessed using validated questionnaires. RESULTS The results showed that patients with NAFLD had a higher significant difference in BMI, WC, and weight compared to controls (p = 0.001). Physical activity level was significantly higher in control subjects than in cases (p = 0.001). The metabolic parameters were significantly different both groups. The mean daily intakes of macronutrients were significantly higher in cases than in control subjects (p = 0.001). A significant difference was detected in the daily intake of some vitamins and minerals among cases compared to control subjects (p < 0.05). CONCLUSION The present study supports the findings of the presence of a relationship between macro- and micronutrients intake and some anthropometric and biochemical variables and NAFLD.
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Affiliation(s)
- Reema Fayez Tayyem
- Department of Nutrition and Food Technology, Faculty of Agriculture, University of Jordan, Amman, Jordan.
| | - Hanaa Mahmoud Al-Dayyat
- Department of Nutrition and Food Technology, Faculty of Agriculture, University of Jordan, Amman, Jordan
| | - Yaser Mohammed Rayyan
- Department of Gastroenterology & Hepatology, School of Medicine, University of Jordan, Amman, Jordan
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Jiang Y, Feng D, Ma X, Fan S, Gao Y, Fu K, Wang Y, Sun J, Yao X, Liu C, Zhang H, Xu L, Liu A, Gonzalez FJ, Yang Y, Gao B, Huang M, Bi H. Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice. Hepatology 2019; 69:343-358. [PMID: 30048004 PMCID: PMC6324985 DOI: 10.1002/hep.30131] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Accepted: 05/30/2018] [Indexed: 12/13/2022]
Abstract
Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically modified mice and animal models. Lineage labeling using AAV-Tbg-Cre-treated Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP mice was performed and Pxr-null mice or AAV Yap short hairpin RNA (shRNA)-treated mice were used to confirm the role of PXR or yes-associated protein (YAP). Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type (WT) and PXR-humanized mice, but not in Pxr-null mice, by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with YAP and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. Conclusion: These findings revealed a function of PXR in enlarging liver size and changing liver cell fate by activation of the YAP signaling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate.
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Affiliation(s)
- Yiming Jiang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xiaochao Ma
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Shicheng Fan
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yue Gao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Kaili Fu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Ying Wang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiahong Sun
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Xinpeng Yao
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Conghui Liu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Huizhen Zhang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Leqian Xu
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Aiming Liu
- Medical School of Ningbo University, Ningbo, China
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Yingzi Yang
- Harvard School of Dental Medicine, Boston, MA, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Min Huang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Huichang Bi
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.,Correspondence to: Hui-chang Bi, Ph.D., School of Pharmaceutical Sciences, Sun Yat-sen University, 132# Waihuandong Road, Guangzhou University City, Guangzhou 510006, P. R. China, Phone: +86-20-39943470, Fax: +86-20-39943000,
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Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway. J Transl Med 2018; 16:319. [PMID: 30458883 PMCID: PMC6245862 DOI: 10.1186/s12967-018-1685-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/09/2018] [Indexed: 01/07/2023] Open
Abstract
Background Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca2+) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature. Methods The pharmacological effects were studied in high-fat-diet or methionine–choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat. Results The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca2+]c) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca2+]c. By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca2+]c via direct inhibition of SERCA. Conclusions The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH. Electronic supplementary material The online version of this article (10.1186/s12967-018-1685-2) contains supplementary material, which is available to authorized users.
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Yu X, Ren LP, Wang C, Zhu YJ, Xing HY, Zhao J, Song GY. Role of X-Box Binding Protein-1 in Fructose-Induced De Novo Lipogenesis in HepG2 Cells. Chin Med J (Engl) 2018; 131:2310-2319. [PMID: 30246717 PMCID: PMC6166463 DOI: 10.4103/0366-6999.241799] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND A high consumption of fructose leads to hepatic steatosis. About 20-30% of triglycerides are synthesized via de novo lipogenesis. Some studies showed that endoplasmic reticulum stress (ERS) is involved in this process, while others showed that a lipotoxic environment directly influences ER homeostasis. Here, our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 (XBP-1), one marker of ERS, on hepatic lipid accumulation stimulated by high fructose. METHODS HepG2 cells were incubated with different concentrations of fructose. Upstream regulators of de novo lipogenesis (i.e., carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1c [SREBP-1c]) were measured by polymerase chain reaction and key lipogenic enzymes (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD-1]) by Western blotting. The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid (TUDCA) or the ERS inducer thapsigargin. Finally, the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection. RESULTS Exposure to high fructose increased triglyceride levels in a dose- and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels of FAS, ACC, and SCD-1, concomitant with XBP-1 conversion to an active spliced form. Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin. Triglyceride level in XBP-1-deficient group decreased significantly compared with high-fructose group (4.41 ± 0.54 μmol/g vs. 6.52 ± 0.38 μmol/g, P < 0.001), as mRNA expressions of SREBP-1c (2.92 ± 0.46 vs. 5.08 ± 0.41, P < 0.01) and protein levels of FAS (0.53 ± 0.06 vs. 0.85 ± 0.05, P = 0.01), SCD-1 (0.65 ± 0.06 vs. 0.90 ± 0.04, P = 0.04), and ACC (0.38 ± 0.03 vs. 0.95 ± 0.06, P < 0.01) decreased. Conversely, levels of triglyceride (4.22 ± 0.54 μmol/g vs. 2.41 ± 0.35 μmol/g, P < 0.001), mRNA expression of SREBP-1c (2.70 ± 0.33 vs. 1.00 ± 0.00, P < 0.01), and protein expression of SCD-1 (0.93 ± 0.06 vs. 0.26 ± 0.05, P < 0.01), ACC (0.98 ± 0.09 vs. 0.43 ± 0.03, P < 0.01), and FAS (0.90 ± 0.33 vs. 0.71 ± 0.02, P = 0.04) in XBP-1s-upregulated group increased compared with the untransfected group. CONCLUSIONS ERS is associated with de novo lipogenesis, and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.
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Affiliation(s)
- Xian Yu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050051, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Lu-Ping Ren
- Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Chao Wang
- Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Ya-Jun Zhu
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Han-Ying Xing
- Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Jing Zhao
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
| | - Guang-Yao Song
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050051, China
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
- Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang, Hebei 050051, China
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Vincenzi B, Russo A, Terenzio A, Galvano A, Santini D, Vorini F, Antonelli-Incalzi R, Vespasiani-Gentilucci U, Tonini G. The use of SAMe in chemotherapy-induced liver injury. Crit Rev Oncol Hematol 2018; 130:70-77. [PMID: 30196914 DOI: 10.1016/j.critrevonc.2018.06.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 06/22/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023] Open
Abstract
Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.
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Affiliation(s)
- B Vincenzi
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy.
| | - A Russo
- Department of Surgery and Oncology, Section of Medical Oncology, University of Palermo, Italy
| | - A Terenzio
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
| | - A Galvano
- Department of Surgery and Oncology, Section of Medical Oncology, University of Palermo, Italy
| | - D Santini
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
| | - F Vorini
- Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Internal Medicine and Hepatology, Campus Bio-Medico University, Rome, Italy
| | | | - U Vespasiani-Gentilucci
- Interdisciplinary Center for Biomedical Research (CIR), Laboratory of Internal Medicine and Hepatology, Campus Bio-Medico University, Rome, Italy
| | - G Tonini
- Medical Oncology Unit, Campus Bio-Medico University, Rome, Italy
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Abstract
Nonalcoholic steatohepatitis (NASH) is a serious and rapidly growing problem affecting a population that was not previously recognized as high risk. Although treatments are limited, shedding light on those with a predisposition may allow for primary prevention, as there is presently no cure other than liver transplant. This study examines the risk factors, genetic predisposition, pathophysiology, and treatment options.
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Lee J, Homma T, Kobayashi S, Ishii N, Fujii J. Unveiling systemic organ disorders associated with impaired lipid catabolism in fasted SOD1-deficient mice. Arch Biochem Biophys 2018; 654:163-171. [PMID: 30056077 DOI: 10.1016/j.abb.2018.07.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 07/08/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022]
Abstract
Oxidative stress triggers the formation of lipid droplets in the liver by stimulating lipogenesis and simultaneously suppresses lipoprotein secretion under hypernutritional conditions. Herein we report on the observation of systemic organ failure that is associated with lipid droplet accumulation in fasting, SOD1-knockout (KO) mice. Upon a three-day fasting period, the KO mice were observed to be vulnerable, could not be rescued by refeeding and had largely died, while wild-type mice were totally recovered. Visceral fat was rapidly consumed during fasting, which resulted in energy shortage and increased fatality in the KO mice. Lipid droplets had accumulated and continued to remain in KO mouse organs that routinely catalyze fatty acids via β-oxidation, even though the levels of free fatty acids and β-hydroxybutyrate, a ketone body, in blood plasma were less in KO mice compared to WT mice during the fasting period. The fasting-triggered organ failure in the KO mice was effectively mitigated by feeding a high calorie-diet for 2 weeks prior to fasting, even though the mice had an excessive accumulation of lipid droplets in the liver. These collective data suggest that the lipid-catabolizing system is the sensitive target of oxidative stress triggered by fasting conditions in the KO mice.
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Affiliation(s)
- Jaeyong Lee
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
| | - Takujiro Homma
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
| | - Sho Kobayashi
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
| | - Naoki Ishii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan
| | - Junichi Fujii
- Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Japan.
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Rivera DS, Lindsay CB, Codocedo JF, Carreño LE, Cabrera D, Arrese MA, Vio CP, Bozinovic F, Inestrosa NC. Long-Term, Fructose-Induced Metabolic Syndrome-Like Condition Is Associated with Higher Metabolism, Reduced Synaptic Plasticity and Cognitive Impairment in Octodon degus. Mol Neurobiol 2018; 55:9169-9187. [DOI: 10.1007/s12035-018-0969-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 02/16/2018] [Indexed: 12/22/2022]
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López-Lemus UA, Garza-Guajardo R, Barboza-Quintana O, Rodríguez-Hernandez A, García-Rivera A, Madrigal-Pérez VM, Guzmán-Esquivel J, García-Labastida LE, Soriano-Hernández AD, Martínez-Fierro ML, Rodríguez-Sánchez IP, Sánchez-Duarte E, Cabrera-Licona A, Ceja-Espiritu G, Delgado-Enciso I. Association Between Nonalcoholic Fatty Liver Disease and Severe Male Reproductive Organ Impairment (Germinal Epithelial Loss): Study on a Mouse Model and on Human Patients. Am J Mens Health 2018; 12:639-648. [PMID: 29577833 PMCID: PMC5987961 DOI: 10.1177/1557988318763631] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Metabolic syndrome (MS) has been associated with testicular damage. Nonalcoholic fatty liver disease (NAFLD) is a multisystemic disease that affects different organs, but its effect on the testes is unknown. A study analyzing germ cell involvement on BALB/c mice was carried out. A parallel comparative study was conducted that investigated alterations in the germinal epithelium of male humans that died from an unrelated acute event. The complete medical histories and histologic samples of the thoracic aorta, liver tissue, and testicular tissue from the deceased subjects were collected. The degree of germinal epithelial loss (DGEL) was evaluated and the clinical and histologic data were compared between individuals with and without NAFLD. The only metabolic or morphologic variable that caused a significant difference in the DGEL, in both the animal model and humans, was the presence of liver steatosis. The percentage of steatosis was also correlated with the percentage of the DGEL. In humans, steatosis (greater than 20%) increased the risk 12-fold for presenting with a severe DGEL (OR: 12.5; 95% CI [1.2, 128.9]; p = .03). There was no association with age above 50 years or MS components. Steatosis grade was also correlated with atherosclerosis grade. NAFLD was a strongly associated factor implicated in severe DGEL, as well as the testis was identified as a probable target organ for damage caused by the disease. This finding could result in the search for new approach strategies in the management of men with fertility problems. Further studies are required to confirm these results.
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Affiliation(s)
| | - Raquel Garza-Guajardo
- 2 Department of Pathological Anatomy and Cytopathology, University Hospital "Dr José Eleuterio González," Autonomous University of Nuevo León, Monterrey, Nuevo León, Mexico
| | - Oralia Barboza-Quintana
- 2 Department of Pathological Anatomy and Cytopathology, University Hospital "Dr José Eleuterio González," Autonomous University of Nuevo León, Monterrey, Nuevo León, Mexico
| | | | | | | | - José Guzmán-Esquivel
- 3 Unidad de Investigación del Hospital General de Zona Nº 1. IMSS, Colima, Mexico
| | - Laura E García-Labastida
- 2 Department of Pathological Anatomy and Cytopathology, University Hospital "Dr José Eleuterio González," Autonomous University of Nuevo León, Monterrey, Nuevo León, Mexico
| | | | - Margarita L Martínez-Fierro
- 5 Molecular Medicine Laboratory, Academic Unit of Human Medicine and Health Sciences. Universidad Autónoma de Zacatecas, Zacatecas, Mexico
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Wat E, Wang Y, Chan K, Law HW, Koon CM, Lau KM, Leung PC, Yan C, Lau CBS. An in vitro and in vivo study of a 4-herb formula on the management of diet-induced metabolic syndrome. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 42:112-125. [PMID: 29655677 DOI: 10.1016/j.phymed.2018.03.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 01/16/2018] [Accepted: 03/15/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Metabolic syndrome is the cluster of risk factors that leads to increased episodes of cardiovascular disease (CVD). These risk factors include but are not limited to obesity, non-alcoholic fatty liver (NAFLD), dyslipidemia, and type 2 diabetes. Since the pathogenesis of metabolic syndrome has multiple metabolic origins, there is no single treatment for it. Pharmacological approaches consist of separate drugs which target at individual risk factors which pose various side effects. Functional foods or nutraceuticals which have potentially important anti-obesity properties have thus attracted great attention. Schisandrae Fructus is a Chinese herb traditionally used as a liver tonic. Silymarin, an extract of the milk thistle (Silybum marianum), is a dietary supplement that is widely used in western society for the prevention and treatment of liver problems. Crataegus Fructus (hawthorn) is traditionally used to promote digestion and dissipate food stagnation. Momordica charantia (bitter melon) is traditionally used for treatment of diabetes in Ayurvedic Medicine. HYPOTHESIS/PURPOSE We aimed to develop a multi-targeted herbal formula to target on the multiple risk factors of metabolic syndrome using individual herbs. This proposed herbal formula include sylimarin and Schisandrae Fructus, for NAFLD; Crataegus Fructus for obesity and hyperlipidemia; and Momordica charantia for hyperglycemia. STUDY DESIGN AND METHODS For in vitro study, we carried out insulin-induced 3T3-L1 adipocytes differentiation and fluorescent tagged cholesterol-treated Caco-2 cell assay to study for adipogenesis and cholesterol uptake into Caco-2 cells, respectively. Oleic acid-induced HepG2 cell assay was used to study for oleic acid-induced fatty liver, and brush border membrane vesicles (BBMV) assay was used to study for glucose uptake from the gut. For in vivo study, we performed an 8-week and a 12-week treatment studies, with each study comprising of 4 groups of C57Bl/6 male mice given: (i) Normal-chow diet; (ii)-(iv) High-fat diet (contains 21% fat and 0.15% cholesterol). After the initial 8 weeks of normal chow or high-fat diet feeding to induce obesity, animals were given: (i) Normal-chow diet; (ii) High-fat diet; (iii) High-fat diet + 2% herbal formula; or (iv) High-fat diet + 4% herbal formula as treatment for another 8 weeks or 12 weeks. RESULTS Our in vitro results suggested Crataegus Fructus aqueous extract exerted potent inhibitory effects on 3T3-L1 preadipocytes differentiation and cholesterol uptake into Caco-2 cells. Schisandrae Fructus aqueous extract and milk thistle exerted inhibitory effects on oleic acid-induced fatty liver in HepG2 cells. Momordica charantia extract on the other hand, exerted significant inhibitory effect on glucose uptake into BBMV. Our in vivo results showed that our herbal formula exhibited a trend to reduce diet-induced increase in body weight and fat pad mass (epididymal, perirenal and inguinal fat); and significantly reduced diet-induced increase in liver weight, liver lipid, and plasma lipid dose-dependently. Besides, high-fat diet induced a significant reduction in adiponectin level which was significantly improved by herbal formula supplementation at 4%. There was however no significant effect of the herbal formula on diet-induced increase in plasma glucose or insulin levels at either dose. Herbal formula also significantly reduced diet-induced inflammation in the liver at both doses. CONCLUSIONS Taken together, these data suggested the potential of our novel multi-targeted herbal formula to be used as a therapeutic agent for diet-induced metabolic syndrome, with special emphasis on NAFLD.
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Affiliation(s)
- Elaine Wat
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Yanping Wang
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ken Chan
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Hon Wai Law
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chi Man Koon
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Kit Man Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Choly Yan
- Venture Tycoon Limited, 21/F, Man Shing Industrial Building, Kowloon, Hong Kong
| | - Clara Bik San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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de Castro GS, Calder PC. Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids. Clin Nutr 2018; 37:37-55. [DOI: 10.1016/j.clnu.2017.01.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 12/12/2016] [Accepted: 01/10/2017] [Indexed: 02/08/2023]
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Huang F, Wang J, Yu F, Tang Y, Ding G, Yang Z, Sun Y. Protective Effect of Meretrix meretrix Oligopeptides on High-Fat-Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. Mar Drugs 2018; 16:md16020039. [PMID: 29360762 PMCID: PMC5852467 DOI: 10.3390/md16020039] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/09/2018] [Accepted: 01/20/2018] [Indexed: 12/15/2022] Open
Abstract
The present study investigated the effects of MMO (Meretrix meretrix oligopeptides) on mice fed a high-fat diet. Mice were fed either a normal control diet (NC) or a high-fat diet (HFD) without or with MMO (50 mg/kg or 250 mg/kg) for four weeks. Levels of ALT, AST, liver tissue GSH-Px, and SOD activities, MDA levels were measured using commercially available kits; HE staining was performed to analyze pathologic changes of the liver; a TEM assay was performed to measure the ultrastructural alterations of the mitochondria, and Western blotting was performed to detect the expression of gene proteins related to lipid metabolism, inflammation, and liver apoptosis. After six weeks, body weight, ALT, AST, and MDA levels were significantly increased, and GSH-Px levels and SOD activities were significantly decreased in the HFD control group compared with the NC group. Consumption of the HFD compared with the NC caused fatty liver abnormal mitochondria with loss of cristae, intramitochondrial granules, and a swollen and rarefied matrix. Administration of MMO significantly decreased body weight gain, and ALT, AST, and MDA levels; increased SOD activity and GSH-Px levels; alleviated fatty liver steatosis; decreased the early apoptosis population; downregulated SREBP-1c, Bax, Caspase-9, Caspase-3, TNF-α, and NF-κB protein levels; and upregulated PPAR-α, Bcl-2, and AMPK-α, compared with the HFD control group. MMO exhibited protective effects in mice with NAFLD by regulating the NF-κB anti-inflammation signaling pathways to inhibit inflammation, regulate AMPK-α, PPAR-α and SREBP-1c to improve lipid metabolism disorder, and regulate Bcl-2/Bax anti-apoptosis signaling pathways to prevent liver cell apoptosis. These results suggest that dietary supplementation with MMO ameliorates high-fat-diet-induced NAFLD.
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Affiliation(s)
- Fangfang Huang
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Jiajia Wang
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Fangmiao Yu
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Yunping Tang
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Guofang Ding
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Zuisu Yang
- School of Food Science and Pharmacy, Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University, Zhoushan 316000, China.
| | - Yu Sun
- Zhejiang Provincial Key Engineering Technology Research Center of Marine Biomedical Products, Zhejiang Ocean University Donghai Science and Technology College, Zhoushan 316000, China.
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Himoto T, Masaki T. Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease. Nutrients 2018; 10:nu10010088. [PMID: 29342898 PMCID: PMC5793316 DOI: 10.3390/nu10010088] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 01/04/2018] [Accepted: 01/05/2018] [Indexed: 02/06/2023] Open
Abstract
Zinc (Zn) is an essential trace element which has favorable antioxidant, anti-inflammatory, and apoptotic effects. The liver mainly plays a crucial role in maintaining systemic Zn homeostasis. Therefore, the occurrence of chronic liver diseases, such as chronic hepatitis, liver cirrhosis, or fatty liver, results in the impairment of Zn metabolism, and subsequently Zn deficiency. Zn deficiency causes plenty of metabolic abnormalities, including insulin resistance, hepatic steatosis and hepatic encephalopathy. Inversely, metabolic abnormalities like hypoalbuminemia in patients with liver cirrhosis often result in Zn deficiency. Recent studies have revealed the putative mechanisms by which Zn deficiency evokes a variety of metabolic abnormalities in chronic liver disease. Zn supplementation has shown beneficial effects on such metabolic abnormalities in experimental models and actual patients with chronic liver disease. This review summarizes the pathogenesis of metabolic abnormalities deriving from Zn deficiency and the favorable effects of Zn administration in patients with chronic liver disease. In addition, we also highlight the interactions between Zn and other trace elements, vitamins, amino acids, or hormones in such patients.
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Affiliation(s)
- Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa 761-0123, Japan.
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0123, Japan.
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Wat E, Ng CF, Koon CM, Zhang C, Gao S, Tomlinson B, Lau CBS. The adjuvant value of Herba Cistanches when used in combination with statin in murine models. Sci Rep 2017; 7:9391. [PMID: 28839280 PMCID: PMC5570940 DOI: 10.1038/s41598-017-10008-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 08/02/2017] [Indexed: 12/31/2022] Open
Abstract
Statins are well known to have muscle toxicity problem. Herba Cistanches (HC) is a Chinese herb traditionally used for pain in the loins and knees. Our previous in vitro study suggested that it could protect against statin-induced muscle toxicity. However, its in vivo protective effect has never been investigated. The objective of this study was to determine if the aqueous extract of HC (HCE) could prevent simvastatin-induced muscle toxicity in rats, and whether HCE could also exert beneficial effects on reducing high-fat diet-induced hypercholesterolemia and elevated liver cholesterol, thereby reducing the dose of simvastatin when used in combined therapy. From our results, HCE significantly restored simvastatin-induced reduction in muscle weights and reduced elevated plasma creatine kinase in rats. HCE also improved simvastatin-induced reduction in muscle glutathione levels, muscle mitochondrial membrane potential, and reduced simvastatin-induced muscle inflammation. Furthermore, HCE could exert reduction on liver weight, total liver lipid levels and plasma lipid levels in high-fat-fed mice. In conclusion, our study provided in vivo evidence that HCE has potential protective effect on simvastatin-induced toxicity in muscles, and also beneficial effects on diet-induced non-alcoholic fatty liver and hyperlipidemia when being used alone or in combination with simvastatin at a reduced dose.
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Affiliation(s)
- Elaine Wat
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chun Fai Ng
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chi Man Koon
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Cheng Zhang
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Si Gao
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Brian Tomlinson
- Division of Clinical Pharmacology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Clara Bik San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. .,State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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Dietary Composition Independent of Weight Loss in the Management of Non-Alcoholic Fatty Liver Disease. Nutrients 2017; 9:nu9080800. [PMID: 28933748 PMCID: PMC5579594 DOI: 10.3390/nu9080800] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 07/18/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022] Open
Abstract
Poor dietary composition is an important factor in the progression of non-alcoholic fatty liver disease (NAFLD). The majority of NAFLD patients follow diets with overconsumption of simple carbohydrates, total and saturated fat, with reduced intake of dietary fiber and omega-3 rich foods. Although lifestyle modifications including weight loss and exercise remain the keystone of NAFLD management, modifying dietary composition with or without a calorie-restricted diet may also be a feasible and sustainable strategy for NAFLD treatment. In the present review article, we highlight the potential therapeutic role of a “high quality healthy diet” to improve hepatic steatosis and metabolic dysfunction in patients with NAFLD, independent of caloric restriction and weight loss. We provide a literature review evaluating the evidence behind dietary components including fiber-, meat- and omega-3-rich diets and, pending further evidence, we concur with the EASL-EASD-EASO Clinical Guidelines recommendation of the Mediterranean diet as the diet of choice in these patients.
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50
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Geng C, Xu H, Zhang Y, Gao Y, Li M, Liu X, Gao M, Wang X, Liu X, Fang F, Chang Y. Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1. SCIENCE CHINA-LIFE SCIENCES 2017; 60:1234-1241. [PMID: 28667519 DOI: 10.1007/s11427-016-9027-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/17/2017] [Indexed: 12/17/2022]
Abstract
In this study, treatment of C57BL/6J (wild type, WT) mice fed a high-fat diet (HFD) with retinoic acid (RA) decreased body weight and subcutaneous and visceral fat content, reversed the apparent hepatosteatosis, and reduced hepatic intracellular triglyceride and serum alanine transaminase (ALT) and aspartate aminotransferase (AST) concentrations. Moreover, RA treatment improved glucose tolerance and insulin sensitivity in WT mice fed a HFD. However, these RA-induced effects in WT mice fed a HFD were alleviated in liver specific Sirtuin 1 (Sirt1) deficient (LKO) mice fed a HFD. Furthermore, RA also could not improve glucose tolerance and insulin sensitivity in LKO mice fed a HFD. The mechanism studies indicated that RA indeed increased the expression of hepatic Sirt1 and superoxide dismutase 2 (Sod2), and inhibited the expression of sterol regulatory element binding protein 1c (Srebp-1c) in WT mice in vivo and in vitro. RA decreased mitochondrial reactive oxygen species (ROS) production in WT primary hepatocytes and increased mitochondrial DNA (mtDNA) copy number in WT mice liver. However, these RA-mediated molecular effects were also abolished in the liver and primary hepatocytes from LKO mice. In summary, RA protected against HFD-induced hepatosteatosis by decreasing Srebp-1c expression and improving antioxidant capacity through a Sirt1-mediated mechanism.
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Affiliation(s)
- Chao Geng
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Haifeng Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Yinliang Zhang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Yong Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Meixia Li
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaoyan Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Mingyue Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xiaojuan Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China
| | - Xiaojun Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Fude Fang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
| | - Yongsheng Chang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.
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