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Lee KJ, Yang SB, Lee JH, Seo B, Won HS, Park J. Preparation and Therapeutic Evaluation of Engineered Semaglutide and Statin-Lipid Conjugate-Based Nanoparticle. Pharmaceutics 2025; 17:480. [PMID: 40284475 PMCID: PMC12030043 DOI: 10.3390/pharmaceutics17040480] [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: 02/27/2025] [Revised: 03/21/2025] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Fatty liver disease and obesity are among the most prevalent health conditions in modern society and have recently garnered significant attention. Semaglutide, a well-known anti-obesity drug, has been widely used for diabetes and obesity treatment; however, nanotherapeutics utilizing semaglutide have not yet been developed. Methods: A novel statin-lipid conjugate was synthesized using rosuvastatin and ursodeoxycholic acid, a liver-protective agent. This conjugate was then formulated with semaglutide through hydrophobic interactions to create a new nanoparticle system. The physicochemical properties of the nanoparticles were analyzed, and their therapeutic efficacy was evaluated in a high-fat diet (HFD)-induced animal model. Results: The statin-lipid conjugate was successfully synthesized, forming novel nanoparticles with semaglutide in an aqueous solution. These nanoparticles exhibited distinct properties compared to conventional semaglutide formulations. In animal experiments, the treatment group demonstrated a 30.24% reduction in body weight and a 46.80% improvement in liver function markers compared to the control group. Conclusions: This study introduces a novel semaglutide-based nanoparticle (SRLC NP) system that overcomes key limitations of conventional semaglutide therapy by providing enhanced bioavailability, extended circulation time, and improved cellular uptake. These findings highlight the potential of SRLC NPs as a clinically translatable nanotherapeutic approach for more effective, sustained, and patient-friendly obesity and fatty liver disease treatment.
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Affiliation(s)
| | | | | | | | | | - Jooho Park
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju 27478, Republic of Korea; (K.-J.L.)
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Kang W, Yang S, Roh J, Choi D, Lee H, Lee JH, Park T. MOR23 deficiency exacerbates hepatic steatosis in mice. FASEB J 2024; 38:e70107. [PMID: 39417398 PMCID: PMC11580716 DOI: 10.1096/fj.202401468rr] [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: 06/27/2024] [Revised: 09/24/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024]
Abstract
Hepatic steatosis, a common liver disorder, can progress to severe conditions such as nonalcoholic steatohepatitis and cirrhosis. While olfactory receptors are primarily known for detecting odorants, emerging evidence suggests that they also influence liver lipid metabolism. This study generated a mouse model with a specific knockout of olfactory receptor 23 (MOR23) to investigate its role in hepatic steatosis. MOR23 knockout mice on a normal diet showed a slight increase in liver weight compared to wild-type (WT) mice. When fed a high-fat diet (HFD), these knockout mice exhibited accelerated hepatic steatosis, indicated by increased liver weight and hepatic triglyceride levels. Our findings suggest that the cyclic adenosine monophosphate/protein kinase A/AMP-activated protein kinase pathway is involved in the role of MOR23, leading to the upregulation of peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1-α, and their target β-oxidation genes in the liver. MOR23 also appeared to regulate lipogenesis and free fatty acid uptake in HFD-fed mice, potentially by influencing sterol regulatory element-binding protein 1 activity. Notably, administering a potential MOR23 ligand, cedrene, attenuated hepatic steatosis in WT mice, but these effects were largely nullified in MOR23 knockout mice. These findings provide valuable insights into the in vivo role of MOR23 in hepatic steatosis development.
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Affiliation(s)
- Wesuk Kang
- Department of Food and Nutrition, BK21 FOURYonsei UniversitySeoulRepublic of Korea
| | - Suhjin Yang
- Department of Food and Nutrition, BK21 FOURYonsei UniversitySeoulRepublic of Korea
| | - Jiyun Roh
- Department of Food and Nutrition, BK21 FOURYonsei UniversitySeoulRepublic of Korea
| | - Dabin Choi
- Department of Food and Nutrition, BK21 FOURYonsei UniversitySeoulRepublic of Korea
| | - Han‐Woong Lee
- Department of Biochemistry, College of Life Science and BiotechnologyYonsei University, Gemcro, Inc.SeoulRepublic of Korea
| | - Jae Hoon Lee
- Department of Biochemistry, College of Life Science and BiotechnologyYonsei University, Gemcro, Inc.SeoulRepublic of Korea
| | - Taesun Park
- Department of Food and Nutrition, BK21 FOURYonsei UniversitySeoulRepublic of Korea
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Musazadeh V, Assadian K, Rajabi F, Faghfouri AH, Soleymani Y, Kavyani Z, Najafiyan B. The effect of synbiotics on liver enzymes, obesity indices, blood pressure, lipid profile, and inflammation in patients with non-alcoholic fatty liver: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2024; 208:107398. [PMID: 39241935 DOI: 10.1016/j.phrs.2024.107398] [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: 03/22/2024] [Revised: 07/30/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Patients with non-alcoholic fatty liver disease (NAFLD) benefit from using synbiotics. However, findings from existing trials remain contentious. Therefore, this meta-analysis evaluated the effects of synbiotics on liver enzymes, blood pressure, inflammation, and lipid profiles in patients with NAFLD. METHODS We searched PubMed, Embase, Cochrane, Scopus, and Web of Science for randomized controlled trials (RCTs) regarding synbiotics supplementation in patients with NAFLD. RESULTS The meta-analysis revealed that synbiotics supplementation significantly improved liver enzymes (AST, WMD: -9.12 IU/L; 95 % CI: -13.19 to -5.05; ALT, WMD: -8.53 IU/L; 95 % CI: -15.07 to -1.99; GGT, WMD: -10.42 IU/L; 95 % CI: -15.19 to -5.65), lipid profile (TC, WMD: -7.74 mg/dL; 95 % CI: -12.56 to -2.92), obesity indices (body weight, WMD: -1.95 kg; 95 % CI: -3.69 to -0.22; WC, WMD: -1.40 cm; 95 % CI: -2.71 to -0.10), systolic blood pressure (SBP, WMD: -6.00 mmHg; 95 % CI: -11.52 to -0.49), and inflammatory markers (CRP, WMD: -0.69 mg/L; 95 % CI: -1.17 to -0.21; TNF-α, WMD: -14.01 pg/mL; 95 % CI: -21.81 to -6.20). CONCLUSION Overall, supplementation with synbiotics positively improved liver enzymes, obesity indices, and inflammatory cytokines in patients with NAFLD.
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Affiliation(s)
- Vali Musazadeh
- Student Research Committee, School of Public Health, Iran University of Medical Sciences, Tehran, Iran; Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Fatemeh Rajabi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14115-154, Iran
| | - Amir Hossein Faghfouri
- Maternal and Childhood Obesity Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Yosra Soleymani
- Department of Nursing, Islamic Azad University of Hamedan, Iran
| | - Zeynab Kavyani
- Department of Clinical Nutrition, Faculty of Nutrition Sciences and Food Industries, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behnam Najafiyan
- Pharmaceutical Sciences Research Center, Faculty of pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Rishi JK, Timme K, White HE, Kerns KC, Keating AF. Trajectory of primordial follicle depletion is accelerated in obese mice in response to 7,12-dimethylbenz[a]anthracene exposure†. Biol Reprod 2024; 111:483-495. [PMID: 38625059 PMCID: PMC11327319 DOI: 10.1093/biolre/ioae059] [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: 12/28/2023] [Revised: 03/11/2024] [Accepted: 04/11/2024] [Indexed: 04/17/2024] Open
Abstract
Both obesity and exposure to environmental genotoxicants, such as 7,12-dimethylbenz[a]anthracene, negatively impair female reproductive health. Hyperphagic lean KK.Cg-a/a (n = 8) and obese KK.Cg-Ay/J (n = 10) mice were exposed to corn oil as vehicle control (CT) or 7,12-dimethylbenz[a]anthracene (1 mg/kg/day) for 7d intraperitoneally, followed by a recovery period. Obesity increased liver and spleen weight (P < 0.05), and 7,12-dimethylbenz[a]anthracene exposure decreased uterine weight (P < 0.05) in obese mice. Primordial follicle loss (P < 0.05) caused by 7,12-dimethylbenz[a]anthracene exposure was observed in obese mice only. Primary (lean P < 0.1; obese P < 0.05) and secondary (lean P < 0.05, obese P < 0.1) follicle loss initiated by 7,12-dimethylbenz[a]anthracene exposure continued across recovery. Reduced pre-antral follicle number in lean mice (P < 0.05), regardless of 7,12-dimethylbenz[a]anthracene exposure, was evident with no effect on antral follicles or corpora lutea number. Immunofluorescence staining of DNA damage marker, γH2AX, did not indicate ongoing DNA damage but TRP53 abundance was decreased in follicles (P < 0.05) of 7,12-dimethylbenz[a]anthracene-exposed obese mice. In contrast, increased (P < 0.05) superoxide dismutase was observed in the corpora lutea of 7,12-dimethylbenz[a]anthracene-exposed obese mice and reduced (P < 0.05) TRP53 abundance was noted in preantral and antral follicles of 7,12-dimethylbenz[a]anthracene-exposed obese mice. This study indicates that obesity influences ovotoxicity caused by a genotoxicant, potentially involving accelerated primordial follicle activation and hampering normal follicular dynamics.
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Affiliation(s)
- Jaspreet K Rishi
- Department of Animal Science, Iowa State University, Ames, IA 50011, United States
| | - Kelsey Timme
- Department of Animal Science, Iowa State University, Ames, IA 50011, United States
| | - Hunter E White
- Department of Animal Science, Iowa State University, Ames, IA 50011, United States
| | - Karl C Kerns
- Department of Animal Science, Iowa State University, Ames, IA 50011, United States
| | - Aileen F Keating
- Department of Animal Science, Iowa State University, Ames, IA 50011, United States
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Funuyet-Salas J, Martín-Rodríguez A, Pérez-San-Gregorio MÁ, Vale L, Robinson T, Anstee QM, Romero-Gómez M. Health-related quality of life in non-alcoholic fatty liver disease: A cross-cultural study between Spain and the United Kingdom. PLoS One 2024; 19:e0300362. [PMID: 38709751 PMCID: PMC11073709 DOI: 10.1371/journal.pone.0300362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/24/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND It is unclear what biopsychosocial factors influence the impact of NAFLD on health-related quality of life (HRQoL), and if these factors are equally important predictors between different nationalities. METHODS HRQoL (CLDQ) was measured in both Southern European (Spain, n = 513) and Northern European (United Kingdom -UK-, n = 224) cohorts of patients with NAFLD in this cross-sectional study. For each cohort, participant data were recorded on histological grade of steatohepatitis, stage of fibrosis and biopsychosocial variables. Regression analysis was used to explore which of these variables predicted HRQoL. Moderated mediation models were conducted using SPSS PROCESS v3.5 macro. RESULTS Participants with severe fibrosis reported more fatigue, systemic symptoms and worry, and lower HRQoL than those with none/mild fibrosis, regardless of place of origin. In addition, body mass index (BMI) and gender were found to be significant predictors of HRQoL in both Spanish and UK participants. Female gender was associated with worse emotional function, higher BMI and more fatigue, which predicted lower participants' HRQoL. UK participants showed more systemic symptoms and worry than Spanish participants, regardless of liver severity. The negative effects of gender on HRQoL through emotional function, BMI and fatigue were reported to a greater degree in UK than in Spanish participants. CONCLUSIONS UK participants showed a greater impairment in HRQoL as compared to Spanish participants. Higher fibrosis stage predicted lower HRQoL, mainly in the Spanish cohort. Factors such as female gender or higher BMI contributed to the impact on HRQoL in both cohorts of patients and should be considered in future multinational intervention studies in NAFLD.
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Affiliation(s)
| | - Agustín Martín-Rodríguez
- Faculty of Psychology, Department of Personality, Assessment, and Psychological Treatment, University of Seville, Seville, Spain
| | - María Ángeles Pérez-San-Gregorio
- Faculty of Psychology, Department of Personality, Assessment, and Psychological Treatment, University of Seville, Seville, Spain
| | - Luke Vale
- Faculty of Medical Sciences, Population Health Sciences Institute, Health Economics Group, Newcastle University, Newcastle upon Tyne, United Kingdom
- National Institute for Health Research (NIHR) Newcastle In Vitro Diagnostics Co-Operative and NIHR Applied Research Collaboration North East and North Cumbria, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Tomos Robinson
- Faculty of Medical Sciences, Population Health Sciences Institute, Health Economics Group, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Quentin M. Anstee
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Manuel Romero-Gómez
- Institute of Biomedicine of Seville, UCM Digestive Diseases and Ciberehd, Virgen del Rocío University Hospital, University of Seville, Seville, Spain
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Suppli MP, Høgedal A, Bagger JI, Chabanova E, van Hall G, Forman JL, Christensen MB, Albrechtsen NJW, Holst JJ, Knop FK. Signs of Glucagon Resistance After a 2-Week Hypercaloric Diet Intervention. J Clin Endocrinol Metab 2024; 109:955-967. [PMID: 37967235 DOI: 10.1210/clinem/dgad666] [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: 09/21/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/17/2023]
Abstract
CONTEXT Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of patients with type 2 diabetes. Hyperglucagonemia may develop due to steatosis-induced hepatic glucagon resistance resulting in impaired hepatic amino acid turnover and ensuing elevations of circulating glucagonotropic amino acids. OBJECTIVE We evaluated whether glucagon resistance could be induced in healthy individuals by a hypercaloric diet intervention designed to increase hepatic fat content. METHODS We recruited 20 healthy male individuals to follow a hypercaloric diet and a sedentary lifestyle for 2 weeks. Amino acid concentrations in response to infusion of glucagon were assessed during a pancreatic clamp with somatostatin and basal insulin. The reversibility of any metabolic changes was assessed 8 weeks after the intervention. Hepatic steatosis was assessed by magnetic resonance spectroscopy. RESULTS The intervention led to increased hepatic fat content (382% [206%; 705%], P < .01). Glucagon infusion led to a decrease in the concentration of total amino acids on all experimental days, but the percentage change in total amino acids was reduced (-2.5% ± 0.5% vs -0.2% ± 0.7%, P = .015) and the average slope of the decline in the total amino acid concentration was less steep (-2.0 ± 1.2 vs -1.2 ± 0.3 μM/min, P = .016) after the intervention compared to baseline. The changes were normalized at follow-up. CONCLUSION Our results indicate that short-term unhealthy behavior, which increases hepatic fat content, causes a reversible resistance to the effect of glucagon on amino acid concentrations in healthy individuals, which may explain the hyperglucagonemia associated with obesity and diabetes.
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Affiliation(s)
- Malte Palm Suppli
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Astrid Høgedal
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Jonatan Ising Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
| | - Elizaveta Chabanova
- Department of Radiology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
| | - Julie Lyng Forman
- Section of Biostatistics, Department of Public Health, University of Copenhagen, DK-1353 Copenhagen, Denmark
| | - Mikkel Bring Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark
| | - Nicolai Jacob Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Department of Clinical Biochemistry, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Engin AB. Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:131-166. [PMID: 39287851 DOI: 10.1007/978-3-031-63657-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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On JY, Kim SH, Kim JM, Park S, Kim KH, Lee CH, Kim SK. Effects of Fermented Artemisia annua L. and Salicornia herbacea L. on Inhibition of Obesity In Vitro and In Mice. Nutrients 2023; 15:2022. [PMID: 37432154 DOI: 10.3390/nu15092022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/19/2023] [Accepted: 04/19/2023] [Indexed: 07/12/2023] Open
Abstract
Plant extracts including secondary metabolites have anti-inflammatory and anti-obesity activities. This study was conducted to investigate the anti-obesity properties of fermented Artemisia annua (AW) and Salicornia herbacea (GW) in vitro and in mice. The metabolite profiling of AW and GW extracts was performed using UHPLC-LTQ-Orbitrap-MS/MS, and gene expression was analyzed using real-time PCR for adipocyte difference factors. The anti-obesity effects in mice were measured using serum AST, ALT, glucose, TG, and cholesterol levels. Metabolites of the plant extracts after fermentation showed distinct differences with increasing anti-obesity active substances. The efficacy of inhibitory differentiation adipogenesis of 3T3-L1 adipocytes was better for GW than AW in a concentration-dependent manner. RT-PCR showed that the GW extract significantly reduced the expression of genes involved in adipocyte differentiation and fat accumulation (C/EBPα, PPARγ, and Fas). In C57BL/6 mice fed the HFD, the group supplemented with AW and GW showed reduced liver weight, NAS value, and fatty liver by suppressing liver fat accumulation. The GW group significantly reduced ALT, blood glucose, TG, total cholesterol, and LDL-cholesterol. This study displayed significant metabolite changes through biotransformation in vitro and the increasing anti-obesity effects of GW and AW in mice. GW may be applicable as functional additives for the prevention and treatment of obesity.
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Affiliation(s)
- Jeong-Yeon On
- Department of Animal Science and Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Su-Hyun Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
| | - Jeong-Mee Kim
- Institute of Animal Resource Center, Konkuk University, Seoul 05029, Republic of Korea
| | - Sungkwon Park
- Department of Food Science and Biotechnology, Sejong University, Seoul 05006, Republic of Korea
| | - Ki-Hyun Kim
- Animal Welfare Research Team, National Institute of Animal Science, RDA, Wanju 55365, Republic of Korea
| | - Choong-Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea
- Research Institute for Bioactive-Metabolome Network, Konkuk University, Seoul 05029, Republic of Korea
| | - Soo-Ki Kim
- Department of Animal Science and Technology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
- Institute of Animal Resource Center, Konkuk University, Seoul 05029, Republic of Korea
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Polysaccharides from Ostrea rivularis rebuild the balance of gut microbiota to ameliorate non-alcoholic fatty liver disease in ApoE -/- mice. Int J Biol Macromol 2023; 235:123853. [PMID: 36863676 DOI: 10.1016/j.ijbiomac.2023.123853] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/10/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023]
Abstract
The purpose of this study was to investigate the preventive effects of polysaccharide from Ostrea rivularis (ORP) on high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) in mice and the underlying mechanism. The results showed that NAFLD model group mice had significant fatty liver lesions. ORP could significantly reduce TC, TG and LDL level, and increase HDL level in serum of HFD mice. Besides, it could also reduce the contents of serum AST and ALT and alleviate pathological changes of fatty liver disease. ORP could also enhance the intestinal barrier function. 16sRNA analysis showed that ORP could reduce the abundance of Firmicutes and Proteobacteria and the ratio of Firmicutes/ Bacteroidetes at the phylum level. These results suggested that ORP could regulate the composition of gut microbiota in NAFLD mice, enhance intestinal barrier function, reduce intestinal permeability, and finally delay the progress and reduce the occurrence of NAFLD. In brief, ORP is an ideal polysaccharide for prevention and treatment of NAFLD, which can be developed as functional food or candidate drugs.
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Musazadeh V, Karimi A, Malekahmadi M, Ahrabi SS, Dehghan P. Omega-3 polyunsaturated fatty acids in the treatment of non-alcoholic fatty liver disease: An umbrella systematic review and meta-analysis. Clin Exp Pharmacol Physiol 2023; 50:327-334. [PMID: 36692292 DOI: 10.1111/1440-1681.13750] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/17/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023]
Abstract
There has been conflicting evidence from meta-analyses on the effect of polyunsaturated fatty acids (PUFA) on non-alcoholic fatty liver disease (NAFLD). Therefore, in this umbrella meta-analysis, we are evaluating whether omega-3 PUFA supplementation has any benefit in treating NAFLD. Electronic databases such as PubMed, Web of Science, Scopus, Embase and Google Scholar were assessed to October 2022. This meta-analysis included all meta-analyses that examined the effect of PUFAs on liver fat and liver function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT)]. Meta-analysis was conducted using a random effects model. Subgroup analyses and sensitivity analyses were also performed. In total, eight articles involving 6,561 participants met the eligibility criteria. Advantageous impacts PUFA supplementation were observed on ALT (ESWMD = -6.72 IU/L; 95% CI: -8.61, -4.84; p < 0.001, and ESSMD = -0.52 IU/L; 95% CI: -0.84, -0.20, p < 0.001), AST (ESWMD = -3.73 IU/L, 95% CI: -5.93, -1.53, p < 0.001, and ESSMD = -0.65 IU/L; 95% CI: -1.08, -0.22, p = 0.003), GGT levels (ESWMD = -4.20 IU/L, 95% CI: -6.85, -1.55, p = 0.002), and liver fat (ESWMD = -5.16; 95% CI: -8.49, -1.82, p < 0.001). Intervention with omega-3 PUFAs improves ALT, AST, GGT, and liver fat in patients with NAFLD. Thus, omega-3 PUFAs could be considered as a therapeutic option in the treatment of NAFLD.
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Affiliation(s)
- Vali Musazadeh
- Student Research Committee, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Karimi
- Nutrition Research Center, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.,Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Malekahmadi
- Nutrition Department, Faculty of Medicine, Mashhad University of Medical Science, Mashhad, Iran
| | - Sana Sedgh Ahrabi
- Student Research Committee, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Dehghan
- Nutrition Research Center, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
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Song W, Yoo SH, Jang J, Baik SJ, Lee BK, Lee HW, Park JS. Association between Sarcopenic Obesity Status and Nonalcoholic Fatty Liver Disease and Fibrosis. Gut Liver 2023; 17:130-138. [PMID: 36472070 PMCID: PMC9840924 DOI: 10.5009/gnl220041] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/10/2022] [Accepted: 05/13/2022] [Indexed: 12/12/2022] Open
Abstract
Background/Aims There are no data regarding the association between sarcopenic obesity status and nonalcoholic fatty liver disease (NAFLD) and NAFLD-associated liver fibrosis. Therefore, we aimed to investigate the relationship between sarcopenic obesity status (sarcopenia only, obesity only, and sarcopenic obesity) and NAFLD and liver fibrosis in Korean adults. Methods In total, 2,191 subjects completed a health checkup program, including abdominal ultrasonography and FibroScan. Subjects were classified into the following four categories: optimal body composition (nonobese and nonsarcopenic), sarcopenia only (nonobese), obesity only (nonsarcopenic), and sarcopenic obesity. Sarcopenic obesity was stratified by the skeletal muscle mass index and body fat using bioelectrical impedance analysis. NAFLD was diagnosed by ultrasonography, and liver fibrosis was assessed using transient elastography in subjects with NAFLD. Results The prevalence of NAFLD and liver fibrosis significantly increased according to the sarcopenic obesity status. In the logistic regression analysis, after adjusting for multiple risk factors, the odds ratio (OR) for the risk of NAFLD was largest in the sarcopenic obesity group (OR, 3.68; 95% confidence interval [CI], 2.94 to 4.60), followed by the obesity only (OR, 2.25; 95% CI, 1.67 to 3.03) and sarcopenia only (OR, 1.92; 95% CI, 1.30 to 2.84) groups, when compared with the optimal group. Additionally, liver fibrosis was independently associated with sarcopenic obesity status (OR 4.69, 95% CI 1.95 to 11.29; OR 4.17, 95% CI 1.56 to 11.17; OR 3.80, 95% CI 0.86 to 16.75, respectively). Conclusions These results demonstrated that sarcopenic obesity was independently associated with NAFLD and liver fibrosis and increased the risk of NAFLD and liver fibrosis more than obesity or sarcopenia alone.
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Affiliation(s)
- Wolhwa Song
- Divisions of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Hwan Yoo
- Divisions of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jinsun Jang
- Divisions of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Su Jung Baik
- Healthcare Research Team, Health Promotion Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byoung Kwon Lee
- Healthcare Research Team, Health Promotion Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun Woong Lee
- Divisions of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea,Hyun Woong Lee, ORCIDhttps://orcid.org/0000-0002-6958-3035, E-mail
| | - Jong Suk Park
- Divisions of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea,Corresponding AuthorJong Suk Park, ORCIDhttps://orcid.org/0000-0002-5385-1373, E-mail
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12
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What do we know about nutrient-based strategies targeting molecular mechanisms associated with obesity-related fatty liver disease? Ann Hepatol 2023; 28:100874. [PMID: 36371078 DOI: 10.1016/j.aohep.2022.100874] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022]
Abstract
Obesity is a risk factor for developing nonalcoholic fatty liver disease (NAFLD), and the associated molecular mechanisms could be targeted with nutrient-based strategies. Therefore, it is necessary to review the current mechanisms to propose further treatments. Obesity facilitates the onset of insulin resistance, lipidic abnormalities, hepatic fat accumulation, lipid peroxidation, mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and inflammation, all related to further steatosis progression and fibrosis. Microbiota alterations can also influence liver disease by the translocation of pathogenic bacteria, energy extraction from short chain fatty acids (SCFAs), intestinal suppression of the expression of fasting-induced adipose factor (FIAF), reduction of bile acids, and altered choline metabolism. There are also genetic polymorphisms in metabolic proteins that predispose to a higher risk of liver diseases, such as those found in the patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) or also known as lysophosphatidylinositol acyltransferase 1 (LPIAT1), transmembrane channel-like 4 genes (TMC4), fat mass and obesity-associated protein (FTO), the b Klotho (KLB) and carboxylesterase (CES1). No clear dietary guidelines target all mechanisms related to NAFLD development and progression. However, energy and carbohydrate intake restriction, regular physical exercise, supplementation of antioxidants, and restoration of gut microbiota seem to have beneficial effects on the new proposed features of NAFLD.
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13
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Elmhamudi A, Abubakar A, Ugail H, Thomson B, Wilson C, Turner M, Manas D, Tingle S, Colenutt S, Sen G, Hunter J, Sun M, Scully J. Deep Learning Assisted Kidney Organ Image Analysis for Assessing the Viability of Transplantation. 2022 14TH INTERNATIONAL CONFERENCE ON SOFTWARE, KNOWLEDGE, INFORMATION MANAGEMENT AND APPLICATIONS (SKIMA) 2022:204-209. [DOI: 10.1109/skima57145.2022.10029406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- Ali Elmhamudi
- University of Bradford,Centre for Visual Computing, Faculty of Engineering and Informatics,Bradford,United Kingdom
| | - Aliyu Abubakar
- University of Bradford,Centre for Visual Computing, Faculty of Engineering and Informatics,Bradford,United Kingdom
| | - Hassan Ugail
- University of Bradford,Centre for Visual Computing, Faculty of Engineering and Informatics,Bradford,United Kingdom
| | - Brian Thomson
- University of Bradford,Centre for Visual Computing, Faculty of Engineering and Informatics,Bradford,United Kingdom
| | - Colin Wilson
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - Mark Turner
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - Derek Manas
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - Samuel Tingle
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - Sam Colenutt
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - Gourab Sen
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at Cambridge and Newcastle Universities,Newcastle upon Tyne,United Kingdom
| | - James Hunter
- University of Oxford,Nuffield Department of Surgical Sciences,Oxford,United Kingdom
| | - Meng Sun
- University of Oxford,Nuffield Department of Surgical Sciences,Oxford,United Kingdom
| | - Jackie Scully
- Disability Innovation Institute UNSW, University of New South Wales,Kensington,Australia
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14
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Moylan CA, Mavis AM, Jima D, Maguire R, Bashir M, Hyun J, Cabezas MN, Parish A, Niedzwiecki D, Diehl AM, Murphy SK, Abdelmalek MF, Hoyo C. Alterations in DNA methylation associate with fatty liver and metabolic abnormalities in a multi-ethnic cohort of pre-teenage children. Epigenetics 2022; 17:1446-1461. [PMID: 35188871 PMCID: PMC9586600 DOI: 10.1080/15592294.2022.2039850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/09/2022] [Accepted: 02/01/2022] [Indexed: 11/03/2022] Open
Abstract
Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90 mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7-12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3-13.4%) and MRE was 2.5 kPa (range, 1.5-3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR<5%). The top two CpGs, cg25474373 and cg07264203, mapped to or near RFTN2 and PRICKLE2 genes. These two CpG sites were also significantly associated with a NAFLD diagnosis. As higher LFC associates with an adverse cardiometabolic profile already in childhood, altered DNAm may identify these children early in disease course for targeted intervention. Larger, longitudinal studies are needed to validate these findings and determine mechanistic relevance.
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Affiliation(s)
- Cynthia A. Moylan
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alisha M. Mavis
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
| | - Dereje Jima
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Rachel Maguire
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Mustafa Bashir
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Jeongeun Hyun
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Melanie N. Cabezas
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alice Parish
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Donna Niedzwiecki
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Anna Mae Diehl
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Susan K. Murphy
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Manal F. Abdelmalek
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Cathrine Hoyo
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
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15
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Yeung CLS, Yam JWP. Therapy-induced modulation of extracellular vesicles in hepatocellular carcinoma. Semin Cancer Biol 2022; 86:1088-1101. [PMID: 35158067 DOI: 10.1016/j.semcancer.2022.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 01/27/2023]
Abstract
Despite rapid development of anti-tumorigenic treatments, the clinical outcome for hepatocellular carcinoma (HCC) is still far from satisfactory. With a deeper understanding about tumor microenvironment (TME), the critical role of extracellular vesicles (EVs) as intercellular liaison has come into spotlight. The dynamic functionality of these nanoparticles revealed cancer cells can employ both tumor and non-tumorous components for their own benefit, so as to mediate cell-to-cell communication and interchange of oncogenic biomolecules. Increasing studies on HCC-derived EVs have identified various irregulated biomolecules, that may serve as biomarkers or therapeutic targets. In this review, we first introduce the current knowledge about EVs and how they operate to maintain a healthy liver microenvironment. We then summarize some of the aberrant observations reported on HCC-derived EVs and how they contribute to HCC pathogenesis. Finally, we describe how current treatments for HCC alter behavior of EVs, which may shed light for potential prognostic markers and therapeutic strategies.
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Affiliation(s)
- Cherlie Lot Sum Yeung
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Liver Research (The University of Hong Kong), Hong Kong.
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16
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Musazadeh V, Roshanravan N, Dehghan P, Ahrabi SS. Effect of Probiotics on Liver Enzymes in Patients With Non-alcoholic Fatty Liver Disease: An Umbrella of Systematic Review and Meta-Analysis. Front Nutr 2022; 9:844242. [PMID: 35677540 PMCID: PMC9169800 DOI: 10.3389/fnut.2022.844242] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 05/02/2022] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become prevalent in recent decades, especially in developed countries; yet the approaches for preventing and treating NAFLD are not clear. This study aimed to summarize meta-analyses of randomized controlled trials that examined the effects of probiotics on NAFLD. We systematically searched PubMed, Scopus, Embase, Web of Science, and Cochrane Central Library databases up to August 2021. All Meta-analysis studies assessing the effect of probiotics on liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Gamma-glutamyl transferase (GGT)] were included. Meta-analysis was conducted using a random-effects model. Sensitivity and subgroup analyses were also performed. The umbrella study covered ten eligible studies involving 5,162 individuals. Beneficial effects of probiotics supplementation were revealed on ALT (ES = −10.54 IU/L; 95% CI: −12.70, −8.39; p < 0.001; I2 = 60.9%, p = 0.006), AST (ES = −10.19 IU/L, 95%CI: −13.08, −7.29, p < 0.001; I2 = 79.8%, p < 0.001), and GGT (ES = −5.88 IU/L, 95% CI: −7.09, −4.67, p = 0.009; I2 = 0.0%, p = 0.591) levels. Probiotics have ameliorating effects on ALT, AST, and GGT levels in patients with NAFLD. Overall, Probiotics could be recommended as an adjuvant therapeutic method for the management of NAFLD.
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Affiliation(s)
- Vali Musazadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Roshanravan
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Dehghan
- Faculty of Nutrition and Food Science, Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- *Correspondence: Parvin Dehghan,
| | - Sana Sedgh Ahrabi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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17
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Prasad M, Rajagopal P, Devarajan N, Veeraraghavan VP, Palanisamy CP, Cui B, Patil S, Jayaraman S. A comprehensive review on high fat diet-induced diabetes mellitus: An epigenetic view. J Nutr Biochem 2022; 107:109037. [PMID: 35533900 DOI: 10.1016/j.jnutbio.2022.109037] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 01/08/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022]
Abstract
Modern lifestyle, genetics, nutritional overload through high-fat diet attributed prevalence and diabetes outcomes with various complications primarily due to obesity in which energy-dense diets frequently affect metabolic health. One possible issue usually associated with elevated chronic fat intake is insulin resistance, and hyperglycaemia constitutes an important function in altering the carbohydrates and lipids metabolism. Similarly, in assessing human susceptibility to weight gain and obesity, genetic variations play a central role, contributing to keen interest in identifying the possible role of epigenetics as a mediator of gene-environmental interactions influencing the production of type 2 diabetes mellitus and its related concerns. Epigenetic modifications associated with the acceptance of a sedentary lifestyle and environmental stress factors in response to energy intake and expenditure imbalances complement genetic alterations and lead to the production and advancement of metabolic disorders such as diabetes and obesity. Methylation of DNA, histone modifications and increases in the expression of non-coding RNAs can result in reduced transcriptional activity of key β-cell genes thus creating insulin resistance. Epigenetics contribute to changes in the expression of the underlying insulin resistance and insufficiency gene networks, along with low-grade obesity-related inflammation, increased ROS generation and DNA damage in multi organs. This review focused on epigenetic mechanisms and metabolic regulations associated with high fat diet (HFD)-induced diabetes mellitus.
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Affiliation(s)
- Monisha Prasad
- Centre for Molecular Medicine and diagnostic (CoMManD), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
| | - Ponnulakshmi Rajagopal
- Central Research Laboratory, Meenakhsi Ammal Dental College and Hospitals, Academy of Higher Education and Research, Chennai, 600 095, India
| | - Nalini Devarajan
- Central Research Laboratory, Meenakhsi Academy of Higher Education and Research, West K.K. Nagar, Chennai, 600 078, India
| | - Vishnu Priya Veeraraghavan
- State Key Laboratory of Biobased Materials and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, China
| | - Chella Perumal Palanisamy
- State Key Laboratory of Biobased Materials and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, China
| | - Bo Cui
- State Key Laboratory of Biobased Materials and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan, 250353, China
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia
| | - Selvaraj Jayaraman
- Centre for Molecular Medicine and diagnostic (CoMManD), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India.
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18
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Lee-Kim V, Morkem R, Barber D, Flemming JA, Kehar M. Awareness, management, and practice patterns of pediatric NAFLD by primary care physicians. Paediatr Child Health 2022; 27:93-98. [PMID: 35599680 DOI: 10.1093/pch/pxab057] [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: 08/25/2020] [Accepted: 07/25/2021] [Indexed: 11/15/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Primary-care physicians (PCPs) play a key role in identifying patients requiring specialist referral. In this study, we aim to determine PCPs' practice patterns for paediatric NAFLD, as knowledge gaps have been reported for adult NAFLD. Methods A survey was sent to 60 PCPs in the Eastern Ontario Network from July 2019 to January 2020. Results Thirty-seven (62%) PCPs responded to the survey. Twenty-one incorrectly considered the prevalence of paediatric NAFLD to be ≤10%. The majority (35/36) cared for less than five paediatric NAFLD patients. Thirty-four (92%) were only 'slightly familiar' or 'not familiar at all' with paediatric NAFLD. Only one PCP routinely screens for NAFLD. Only one PCP was aware of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) clinical guidelines for paediatric NAFLD. Twenty-five (68%) correctly selected lifestyle modifications as a treatment option. Lack of confidence in the knowledge of NAFLD was the most common barrier for managing paediatric cases. Conclusion The majority of PCPs are not screening for paediatric NAFLD and are not familiar with its clinical spectrum, citing a lack of knowledge regarding NAFLD as the greatest barrier. This may cause delays in diagnosis and a presentation with advanced fibrosis at the time of specialist referral. Dissemination and implementation of clinical guidelines have the potential to improve knowledge and screening rates for NAFLD in children at the primary-care level.
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Affiliation(s)
- Victoria Lee-Kim
- Department of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Rachael Morkem
- Department of Family Medicine, Queen's University, Kingston, Ontario, Canada
| | - David Barber
- Department of Family Medicine, Queen's University, Kingston, Ontario, Canada
| | - Jennifer A Flemming
- Department of Medicine, Queen's University, Kingston, Ontario, Canada.,Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Mohit Kehar
- Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.,Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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19
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Dong Y, Yu M, Wu Y, Xia T, Wang L, Song K, Zhang C, Lu K, Rahimnejad S. Hydroxytyrosol Promotes the Mitochondrial Function through Activating Mitophagy. Antioxidants (Basel) 2022; 11:893. [PMID: 35624756 PMCID: PMC9138034 DOI: 10.3390/antiox11050893] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Emerging evidence suggests that mitochondrial dysfunction mediates the pathogenesis for non-alcoholic fatty liver disease (NAFLD). Hydroxytyrosol (HT) is a key component of extra virgin olive oil which can exert beneficial effects on NAFLD through modulating mitochondria. However, the mechanism of the impacts of HT still remains elusive. Thus, an in vivo and a series of in vitro experiments were carried out to examine the impacts of hydroxytyrosol (HT) on lipid metabolism and mitochondrial function in fish. For the in vivo experiment, two diets were produced to contain 10% and 16% fat as normal-fat and high-fat diets (NFD and HFD) and two additional diets were prepared by supplementing 200 mg/kg of HT to the NFD and HFD. The test diets were fed to triplicate groups of spotted seabass (Lateolabrax maculatus) juveniles for 8 weeks. The results showed that feeding HFD leads to increased fat deposition in the liver and induces oxidative stress, both of which were ameliorated by HT application. Furthermore, transmission electron microscopy revealed that HFD destroyed mitochondrial cristae and matrix and induced severe hydropic phenotype, while HT administration relieved these alterations. The results of in vitro studies using zebrafish liver cell line (ZFL) showed that HT promotes mitochondrial function and activates PINK1-mediated mitophagy. These beneficial effects of HT disappeared when the cells were treated with cyclosporin A (Csa) as a mitophagy inhibitor. Moreover, the PINK1-mediated mitophagy activation by HT was blocked when compound C (CC) was used as an AMPK inhibitor. In conclusion, our findings demonstrated that HT alleviates fat accumulation, oxidative stress and mitochondrial dysfunction, and its effects are deemed to be mediated via activating mitophagy through the AMPK/PINK1 pathway.
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Affiliation(s)
- Yanzou Dong
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Manhan Yu
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
- Key Laboratory of Swine Nutrition and Feed Science of Fujian Province, Fujian Aonong Biological Science and Technology Group Co., Ltd., Zhangzhou 363000, China;
| | - Youlin Wu
- Key Laboratory of Swine Nutrition and Feed Science of Fujian Province, Fujian Aonong Biological Science and Technology Group Co., Ltd., Zhangzhou 363000, China;
| | - Tian Xia
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Ling Wang
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Kai Song
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Chunxiao Zhang
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Kangle Lu
- Key Laboratory for Feed Quality Testing and Safety, Fisheries College, Jimei University, Xiamen 361021, China; (Y.D.); (M.Y.); (T.X.); (L.W.); (K.S.); (C.Z.)
| | - Samad Rahimnejad
- South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, Zatisi 728/II, 389 25 Vodnany, Czech Republic;
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20
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Aneni EC, Saeed GJ, Bittencourt MS, Cainzos-Achirica M, Osondu CU, Budoff M, Parise ER, Santos RD, Nasir K. Cardiometabolic disorders, inflammation and the incidence of non-alcoholic fatty liver disease: A longitudinal study comparing lean and non-lean individuals. PLoS One 2022; 17:e0266505. [PMID: 35385529 PMCID: PMC8985996 DOI: 10.1371/journal.pone.0266505] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 03/22/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND There is limited knowledge about the risk of non-alcoholic fatty liver disease (NAFLD) associated with cardiometabolic disorders in lean persons. This study examines the contribution of cardiometabolic disorders to NAFLD risk among lean individuals and compares to non-lean individuals. METHODS We analyzed longitudinal data from 6,513 participants of a yearly voluntary routine health testing conducted at the Hospital Israelita Albert Einstein, Brazil. NAFLD was defined as hepatic ultrasound diagnosed fatty liver in individuals scoring below 8 on the alcohol use disorders identification test. Our main exposure variables were elevated blood glucose, elevated blood pressure (BP), presence of atherogenic dyslipidemia (AD, defined as the combination of elevated triglycerides and low HDL cholesterol) and physical inactivity (<150 minutes/week of moderate activity). We further assessed the risk of NAFLD with elevations in waist circumference and high sensitivity C-reactive protein (HsCRP). RESULTS Over 15,580 person-years (PY) of follow-up, the incidence rate of NAFLD was 7.7 per 100 PY. In multivariate analysis adjusting for likely confounders, AD was associated with a 72% greater risk of NAFLD (IRR: 1.72 [95% CI:1.32-2.23]). Elevated blood glucose (IRR: 1.71 [95%CI: 1.29-2.28]) and physical inactivity (IRR: 1.46 [95%CI: 1.28-1.66]) were also independently associated with increased risk of NAFLD. In lean individuals, AD, elevated blood glucose and elevated BP were significantly associated with NAFLD although for elevated blood glucose, statistical significance was lost after adjusting for possible confounders. Physical inactivity and elevations in HsCRP were not associated with the risk of NAFLD in lean individuals only. Among lean (and non-lean) individuals, there was an independent association between progressively increasing waist circumference and NAFLD. CONCLUSION Cardiometabolic risk factors are independently associated with NAFLD. However, there are significant differences in the metabolic risk predictors of NAFLD between lean and non-lean individuals. Personalized cardiovascular disease risk stratification and appropriate preventive measures should be considered in both lean and non-lean individuals to prevent the development of NAFLD.
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Affiliation(s)
- Ehimen C. Aneni
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States of America
| | - Gul Jana Saeed
- Center for Sleep and Cardiovascular Outcomes Research, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Marcio Sommer Bittencourt
- Center for Clinical and Epidemiological Research, University Hospital and State of São Paulo Cancer Institute (ICESP), University of São Paulo, São Paulo, Brazil
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Miguel Cainzos-Achirica
- Division of Cardiovascular Prevention and Wellness, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, United States of America
- Center for Outcomes Research, Houston Methodist Research Institute, Houston, TX, United States of America
| | | | - Matthew Budoff
- The Lundquist Institute for Biomedical Innovation, Los Angeles, CA, United States of America
- David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America
| | | | - Raul D. Santos
- Hospital Israelita Albert Einstein, São Paulo, Brazil
- Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil
| | - Khurram Nasir
- Division of Cardiovascular Prevention and Wellness, Houston Methodist DeBakey Heart and Vascular Center, Houston, TX, United States of America
- Center for Outcomes Research, Houston Methodist Research Institute, Houston, TX, United States of America
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21
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Nobarani S, Alaei-Shahmiri F, Aghili R, Malek M, Poustchi H, Lahouti M, Khamseh ME. Visceral Adipose Tissue and Non-alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes. Dig Dis Sci 2022; 67:1389-1398. [PMID: 33788095 DOI: 10.1007/s10620-021-06953-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022]
Abstract
AIM To explore the association of visceral adipose tissue (VAT) area and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS This was a cross-sectional study comprising 100 patients with T2DM and 100 non-T2DM individuals, matched for age, sex, and body mass index (BMI). Transient elastography was used to assess hepatic steatosis and liver stiffness measurements (LSM). Controlled attenuation parameter (CAP) was used to quantify hepatic steatosis. To distinguish grades of hepatic steatosis, cutoff values were as follows: S1 ≥ 302, S2 ≥ 331, and S3 ≥ 337 dB/m. Moreover, VAT area was measured by dual-energy X-ray absorptiometry in accordance with validated protocols. RESULTS CAP score was significantly higher in participants with T2DM (294.61 ± 3.82 vs. 269.86 ± 3.86 dB/ m; P < 0.001). Furthermore, 42% of participants with T2DM had hepatic steatosis (S > S1: 302 dB/m), while this figure was 26% in non-T2DM group (P < 0.003). The mean liver stiffness measurement was also significantly higher in patients with T2DM (5.53 vs. 4.79 kPa; P < 0.001). VAT area was greater in patients with T2DM compared to non-T2DM individuals: 163.79 ± 47.98 cm2 versus 147.49 ± 39.09 cm2, P = 0.009. However, total and truncal fat mass were not different between the two groups. Age, BMI, waist circumference, ALT, CAP, and LSM were significantly associated with VAT area. BMI and VAT area were the important determinants of steatosis in both groups of participants with and without T2DM. Moreover, the VAT area was associated with the severity of hepatic steatosis and liver stiffness, independent of anthropometric measures of obesity. CONCLUSION VAT area is a major determinant of the severity of hepatic steatosis and liver stiffness in patient with T2DM.
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Affiliation(s)
- Sohrab Nobarani
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No. 10, Firoozeh St., South Vali-asr Ave., Vali-Asr Sq., Tehran, Iran
| | - Fariba Alaei-Shahmiri
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No. 10, Firoozeh St., South Vali-asr Ave., Vali-Asr Sq., Tehran, Iran
| | - Rokhsareh Aghili
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No. 10, Firoozeh St., South Vali-asr Ave., Vali-Asr Sq., Tehran, Iran
| | - Mojtaba Malek
- Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Lahouti
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No. 10, Firoozeh St., South Vali-asr Ave., Vali-Asr Sq., Tehran, Iran
| | - Mohammad E Khamseh
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No. 10, Firoozeh St., South Vali-asr Ave., Vali-Asr Sq., Tehran, Iran.
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22
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Tandoroost A, Moradi S, Moradinazar M, Moradi S, Pasdar Y, Nayebi A, Marzbani B. Body composition and risk of non-alcoholic fatty liver disease: A case control study. MEDITERRANEAN JOURNAL OF NUTRITION AND METABOLISM 2022. [DOI: 10.3233/mnm-210570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: While evidence has been a highlight that obesity may be associated with the increased incidence of Nonalcoholic fatty liver disease (NAFLD), these data have depended on defective measures of obesity such as body mass index (BMI), and usually have not the well-known relationship between body composition with NAFLD. METHODS: In a case-control study of people aged 20– 65 years, we directly measured body composition (using bioelectrical impedance analysis), height, weight, and waist and hip circumferences who referred to radiology clinics in Kermanshah, Iran. Dietary intake was assessed by the food frequency questionnaire (FFQ). RESULTS: Among 221 people examined, 103 cases with NAFLD and 119 as control were established. The risk of NAFLD was positively associated with higher BMI and the components of the body composition. These associations were strengthened after adjusting for potential confounders including gender, age, marital status, education, smoking, alcohol consumption, and physical activity CONCLUSION: An increasing prevalence of obesity may be associated with the increasing incidence of NAFLD as observed in many populations. We observed an increased risk of NAFLD associated with increased BMI, central adiposity, and the fat component of weight, but found no association with nonfat mass.
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Affiliation(s)
- Arash Tandoroost
- Student Research Committee, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sara Moradi
- Student Research Committee, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Moradinazar
- Research Center for Environmental Determinants ofHealth (RCEDH), Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shima Moradi
- Department of Nutritional Sciences, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yahya Pasdar
- Department of Nutritional Sciences, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Atiyeh Nayebi
- Department of Nutritional Sciences, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Behjat Marzbani
- Research Center for Environmental Determinants ofHealth (RCEDH), Kermanshah University of Medical Sciences, Kermanshah, Iran
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23
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Yasar O, Long P, Harder B, Marshall H, Bhasin S, Lee S, Delegge M, Roy S, Doyle O, Leavitt N, Rigg J. Machine learning using longitudinal prescription and medical claims for the detection of non-alcoholic steatohepatitis (NASH). BMJ Health Care Inform 2022; 29:bmjhci-2021-100510. [PMID: 35354641 PMCID: PMC8968511 DOI: 10.1136/bmjhci-2021-100510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 03/13/2022] [Indexed: 12/26/2022] Open
Abstract
Objectives To develop and evaluate machine learning models to detect patients with suspected undiagnosed non-alcoholic steatohepatitis (NASH) for diagnostic screening and clinical management. Methods In this retrospective observational non-interventional study using administrative medical claims data from 1 463 089 patients, gradient-boosted decision trees were trained to detect patients with likely NASH from an at-risk patient population with a history of obesity, type 2 diabetes mellitus, metabolic disorder or non-alcoholic fatty liver (NAFL). Models were trained to detect likely NASH in all at-risk patients or in the subset without a prior NAFL diagnosis (at-risk non-NAFL patients). Models were trained and validated using retrospective medical claims data and assessed using area under precision recall curves and receiver operating characteristic curves (AUPRCs and AUROCs). Results The 6-month incidences of NASH in claims data were 1 per 1437 at-risk patients and 1 per 2127 at-risk non-NAFL patients. The model trained to detect NASH in all at-risk patients had an AUPRC of 0.0107 (95% CI 0.0104 to 0.0110) and an AUROC of 0.84. At 10% recall, model precision was 4.3%, which is 60× above NASH incidence. The model trained to detect NASH in the non-NAFL cohort had an AUPRC of 0.0030 (95% CI 0.0029 to 0.0031) and an AUROC of 0.78. At 10% recall, model precision was 1%, which is 20× above NASH incidence. Conclusion The low incidence of NASH in medical claims data corroborates the pattern of NASH underdiagnosis in clinical practice. Claims-based machine learning could facilitate the detection of patients with probable NASH for diagnostic testing and disease management.
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Affiliation(s)
| | - Patrick Long
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - Brett Harder
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - Hanna Marshall
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - Sanjay Bhasin
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - Suyin Lee
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - Mark Delegge
- Therapeutic Center of Excellence, IQVIA, Durham, North Carolina, USA
| | - Stephanie Roy
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | | | - Nadea Leavitt
- Real World Solutions, IQVIA, Plymouth Meeting, Pennsylvania, USA
| | - John Rigg
- Real World Solutions, IQVIA, London, UK
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24
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Marchlewicz E, McCabe C, Djuric Z, Hoenerhoff M, Barks J, Tang L, Song PX, Peterson K, Padmanabhan V, Dolinoy DC. Gestational exposure to high fat diets and bisphenol A alters metabolic outcomes in dams and offspring, but produces hepatic steatosis only in dams. CHEMOSPHERE 2022; 286:131645. [PMID: 34426127 PMCID: PMC8595757 DOI: 10.1016/j.chemosphere.2021.131645] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/29/2021] [Accepted: 07/21/2021] [Indexed: 05/07/2023]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Perinatal development is a critical window for altered, lifelong health trajectory, and evidence supports the role of perinatal programming in chronic metabolic diseases. To examine the impact of diet and bisphenol A (BPA) on the developmental trajectory of NAFLD in offspring, we exposed dams from pre-gestation through lactation to a human-relevant dose of oral BPA coupled with intake of high fat Western or Mediterranean-style diets. We assessed hepatic steatosis by quantifying hepatic triglycerides (TGs) and metabolic health by measuring body weight, relative organ weights, and serum hormone levels in dams and offspring at postnatal day 10 (PND10) and 10-months of age. In dams, consumption of the Western or Mediterranean diet increased hepatic TGs 1.7-2.4-fold, independent of BPA intake. Among offspring, both perinatal diet and BPA exposure had a greater impact on metabolic outcomes than on hepatic steatosis. At PND10, serum leptin levels were elevated 2.6-4.8-fold in pups exposed to the Mediterranean diet, with a trend for sex-specific effects on body and organ weights. At 10-months, sex-specific increases in organ weight and hormone levels were observed in mice perinatally exposed to Western + BPA or Mediterranean + BPA. These findings suggest lifestage-specific interaction of perinatal exposures to experimental diets and BPA on offspring metabolic health without effects on NAFLD later in life. Importantly, alterations in dam phenotype by diet and BPA exposure appear to impact offspring health trajectory, emphasizing the need to define dam diet in assessing effects of environmental exposures on offspring health.
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Affiliation(s)
- Elizabeth Marchlewicz
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Carolyn McCabe
- Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Zora Djuric
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Mark Hoenerhoff
- In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - John Barks
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Lu Tang
- Department of Biostatistics, University of Pittsburgh, Pittsburg, PA, USA
| | - Peter X Song
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Karen Peterson
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA; Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Vasantha Padmanabhan
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dana C Dolinoy
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA; Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
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25
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Wang S, Sheng F, Zou L, Xiao J, Li P. Hyperoside attenuates non-alcoholic fatty liver disease in rats via cholesterol metabolism and bile acid metabolism. J Adv Res 2021; 34:109-122. [PMID: 35024184 PMCID: PMC8655136 DOI: 10.1016/j.jare.2021.06.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) results from increased hepatic total cholesterol (TC) and total triglyceride (TG) accumulation. In our previous study, we found that rats treated with hyperoside became resistant to hepatic lipid accumulation. OBJECTIVES The present study aims to investigate the possible mechanisms responsible for the inhibitory effects of hyperoside on the lipid accumulation in the liver tissues of the NAFLD rats. METHODS Label-free proteomics and metabolomics targeting at bile acid (BA) metabolism were applied to disclose the mechanisms for hyperoside reducing hepatic lipid accumulation among the NAFLD rats. RESULTS In response to hyperoside treatment, several proteins related to the fatty acid degradation pathway, cholesterol metabolism pathway, and bile secretion pathway were altered, including ECI1, Acnat2, ApoE, and BSEP, etc. The expression of nuclear receptors (NRs), including farnesoid X receptor (FXR) and liver X receptor α (LXRα), were increased in hyperoside-treated rats' liver tissue, accompanied by decreased protein expression of catalyzing enzymes in the hepatic de novo lipogenesis and increased protein level of enzymes in the classical and alternative BA synthetic pathway. Liver conjugated BAs were less toxic and more hydrophilic than unconjugated BAs. The BA-targeted metabolomics suggest that hyperoside could decrease the levels of liver unconjugated BAs and increase the levels of liver conjugated BAs. CONCLUSIONS Taken together, the results suggest that hyperoside could improve the condition of NAFLD by regulating the cholesterol metabolism as well as BAs metabolism and excretion. These findings contribute to understanding the mechanisms by which hyperoside lowers the cholesterol and triglyceride in NAFLD rats.
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Key Words
- ACC, Acetyl-CoA carboxylase
- AMPK, AMP-activated protein kinase
- Apo, apolipoprotein
- BAs, bile acids
- BSH, bile salt hydrolase
- Bile acid metabolism
- CYP27A1, sterol 27-hydroxylase
- CYP7A1, cholesterol 7α-hydroxylase
- Cholesterol metabolism
- FGF15/19, fibroblast growth factor 15/19
- FXR, farnesoid X receptor
- Hyperoside
- LC-MS, the combination of high-performance liquid chromatography and mass spectrometry
- LXRα, liver X receptor α
- Label-free proteomics
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- PMSF, phenylmethylsulfonyl fluoride
- QC, quality control
- SDS, sodium dodecyl sulfate
- SHP, small heterodimer partner
- SREBP1, sterol regulatory element-binding protein 1
- SREBP2, sterol regulatory element-binding protein 2
- SREBPs, sterol regulatory element binding proteins
- TC, total cholesterol
- TG, triglyceride
- TGR5, Takeda G-protein-coupled receptor 5
- Targeted metabolomics
- VLDL, very low-density lipoprotein
- WB, Western blot
- pACC, phosphorylated ACC
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Affiliation(s)
- Songsong Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Feiya Sheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Liang Zou
- School of Medicine, Chengdu University, Chengdu 610106, China
| | - Jianbo Xiao
- Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632, China
- Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo, Vigo, Spain
| | - Peng Li
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
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26
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Siskind D, Russell AW, Suetani S, Flaws D, Kisely S, Moudgil V, Northwood K, Robinson G, Scott JG, Stedman T, Warren N, Winckel K, Cosgrove P, Baker A. CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine. Ther Adv Psychopharmacol 2021; 11:20451253211045248. [PMID: 34671454 PMCID: PMC8521414 DOI: 10.1177/20451253211045248] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/23/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND There is limited evidence on interventions to minimise weight gain at clozapine commencement. We compared the effect of adjunctive metformin versus placebo at clozapine initiation. METHODS People with schizophrenia commencing on clozapine were randomised to either metformin or placebo for 24 weeks. The primary outcome was difference in the change of body weight. Secondary outcomes included comparative rates of weight gain of more than 5%, overall weight gain/loss, and differences in metabolic and psychosis outcomes. RESULTS The study was closed prematurely in March 2020 due to COVID-19 restrictions. Ten participants were randomised to each of the metformin and placebo groups. Eight metformin group and five placebo group participants completed the trial and were included in the analysis. The study was insufficiently powered to detect difference between the metformin and placebo groups for the primary outcome of change in weight (0.09 kg vs 2.88 kg, p = 0.231). In terms of secondary outcomes, people in the metformin group were significantly less likely to gain >5% of their body weight (12.5% vs 80%, p = 0.015) and were more likely to lose weight (37.5% vs 0% p = 0.024) compared to placebo. There was no difference between the groups in terms of adverse drug reactions (ADRs). CONCLUSION While limited by the forced premature closure of the trial due to COVID19, the findings from this randomised controlled trial are promising. Clozapine and metformin co-commencement may be a promising treatment to prevent clozapine-associated weight gain, especially given the low rates of ADRs associated with metformin. This supports the consideration of use of metformin to prevent weight gain in people initiated on clozapine; however, further studies are needed to confirm this finding. TRIAL REGISTRATION ACTRN12617001547336.
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Affiliation(s)
- Dan Siskind
- School of Clinical Medicine, The University of Queensland, c/- MIRT, Level 2 Mental Health, 228 Logan Rd, Woolloongabba, Brisbane, QLD 4102, Australia
- Metro South Addiction and Mental Health Services, Brisbane, QLD, Australia
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Anthony W. Russell
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Shuichi Suetani
- Metro South Addiction and Mental Health Services, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
- Medical School, Griffith University, Brisbane, QLD, Australia
| | - Dylan Flaws
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
- Metro North Mental Health Services, Brisbane, QLD, Australia
| | - Steve Kisely
- Metro South Addiction and Mental Health Services, Brisbane, QLD, Australia
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
| | - Vikas Moudgil
- Metro North Mental Health Services, Brisbane, QLD, Australia
| | - Korinne Northwood
- Metro South Addiction and Mental Health Services, Brisbane, QLD, Australia
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Gail Robinson
- Metro North Mental Health Services, Brisbane, QLD, Australia
- Menzies Health Institute Queensland, Griffith University, Brisbane, QLD, Australia
| | - James G. Scott
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
- Metro North Mental Health Services, Brisbane, QLD, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Terry Stedman
- West Moreton Mental Health Service, Brisbane, QLD, Australia
| | - Nicola Warren
- Metro South Addiction and Mental Health Services, Brisbane, QLD, Australia
- School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
| | - Karl Winckel
- Department of Pharmacy, Princess Alexandra Hospital, Brisbane, QLD, Australia
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Peter Cosgrove
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
- West Moreton Mental Health Service, Brisbane, QLD, Australia
| | - Andrea Baker
- Queensland Centre for Mental Health Research, Brisbane, QLD, Australia
- West Moreton Mental Health Service, Brisbane, QLD, Australia
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27
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Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, Marcus C, Lee WS, Kelly D, Porta G, El-Guindi MA, Alisi A, Mann JP, Mouane N, Baur LA, Dhawan A, George J. Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Lancet Gastroenterol Hepatol 2021; 6:864-873. [PMID: 34364544 DOI: 10.1016/s2468-1253(21)00183-7] [Citation(s) in RCA: 185] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022]
Abstract
The term non-alcoholic fatty liver disease (NAFLD), and its definition, have limitations for both adults and children. The definition is most problematic for children, for whom alcohol consumption is usually not a concern. This problematic definition has prompted a consensus to rename and redefine adult NAFLD associated with metabolic dysregulation to metabolic (dysfunction)-associated fatty liver disease (MAFLD). Similarities, distinctions, and differences exist in the causes, natural history, and prognosis of fatty liver diseases in children compared with adults. In this Viewpoint we, an international panel, propose an overarching framework for paediatric fatty liver diseases and an age-appropriate MAFLD definition based on sex and age percentiles. The framework recognises the possibility of other coexisting systemic fatty liver diseases in children. The new MAFLD diagnostic criteria provide paediatricians with a conceptual scaffold for disease diagnosis, risk stratification, and improved clinical and multidisciplinary care, and they align with a definition that is valid across the lifespan.
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Affiliation(s)
- Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
| | - Naim Alkhouri
- Department of Hepatology, Arizona Liver Health, Chandler, AZ, USA
| | - Pietro Vajro
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Italy
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Ram Weiss
- Department of Pediatrics, Ruth Rappaport Children's Hospital, Rambam Medical Center, Technion School of Medicine, Haifa, Israel
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Claude Marcus
- Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Deirdre Kelly
- The Liver Unit, Birmingham Women's & Children's Hospital, University of Birmingham, Birmingham, UK
| | - Gilda Porta
- Pediatric Hepatology, Transplant Unit, Hospital Sírio-Libanês, Hospital Municipal Infantil Menino Jesus, San Paulo, Brazil
| | - Mohamed A El-Guindi
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Anna Alisi
- Research Unit of Molecular Genetics and Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Jake P Mann
- Metabolic Research Laboratories, Institute of Metabolic Science, and Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Nezha Mouane
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, Academic Children's Hospital, Mohammed V University, Rabat, Morocco; Department of Pediatric Hepatology, Gastroenterology and Nutrition, Children's Hospital of Rabat, Rabat, Morocco
| | - Louise A Baur
- Children's Hospital Westmead Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre, and MowatLabs, King's College Hospital, London, UK
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia
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28
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Junior, Lai YS, Nguyen HT, Salmanida FP, Chang KT. MERTK +/hi M2c Macrophages Induced by Baicalin Alleviate Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2021; 22:10604. [PMID: 34638941 PMCID: PMC8508959 DOI: 10.3390/ijms221910604] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. An accumulation of fat, followed by inflammation, is the major cause of NAFLD progression. During inflammation, macrophages are the most abundant immune cells recruited to the site of injury. Macrophages are classified into "proinflammatory" M1 macrophages, and "anti-inflammatory" M2 macrophages. In NAFLD, M1 macrophages are the most prominent macrophages that lead to an excessive inflammatory response. Previously, we found that baicalin could polarize macrophages into anti-inflammatory M2c subtype macrophages with an increased level of MERTK expression. Several studies have also shown a strong correlation between MERTK expression and cholesterol efflux, efferocytosis, as well as phagocytosis capability. Therefore, in this study, we aim to elucidate the potential and efficacy of mononuclear-cell (MNC)-derived MERTK+/hi M2c macrophages induced by baicalin as a cell-based therapy for NAFLD treatment. In our results, we have demonstrated that a MERTK+/hi M2c macrophage injection to NAFLD mice contributes to an increased level of serum HDL secretion in the liver, a decline in the circulating CD4+CD25- and CD8+CD25- T cells and lowers the total NAFLD pathological score by lessening the inflammation, necrosis, and fibrosis. In the liver, profibrotic COL1A1 and FN, proinflammation TNFα, as well as the regulator of lipid metabolism PPARɣ expression, were also downregulated after injection. In parallel, the transcriptomic profiles of the injected MERTK+/hi M2c macrophages showed that the various genes directly or indirectly involved in NAFLD progression (e.g., SERPINE1, FADS2) were also suppressed. Downregulation of cytokines and inflammation-associated genes, such as CCR5, may promote a pro-resolving milieu in the NAFLD liver. Altogether, cell-based therapy using MERTK+/hi M2c macrophages is promising, as it ameliorates NAFLD in mice.
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Affiliation(s)
- Junior
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (J.); (H.T.N.); (F.P.S.)
| | - Yin-Siew Lai
- Research Center for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
| | - Huyen Thi Nguyen
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (J.); (H.T.N.); (F.P.S.)
| | - Farrah P. Salmanida
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (J.); (H.T.N.); (F.P.S.)
| | - Ko-Tung Chang
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan; (J.); (H.T.N.); (F.P.S.)
- Research Center for Animal Biologics, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan;
- Flow Cytometry Center, Precision Instruments Center, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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Hintikka J, Lensu S, Mäkinen E, Karvinen S, Honkanen M, Lindén J, Garrels T, Pekkala S, Lahti L. Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:4049. [PMID: 33921370 PMCID: PMC8068902 DOI: 10.3390/ijerph18084049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/26/2021] [Accepted: 04/08/2021] [Indexed: 12/15/2022]
Abstract
We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.
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Affiliation(s)
- Jukka Hintikka
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
| | - Sanna Lensu
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
- Department of Psychology, University of Jyväskylä, FI-40014 Jyväskylä, Finland
| | - Elina Mäkinen
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
| | - Sira Karvinen
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
| | - Marjaana Honkanen
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
| | - Jere Lindén
- Veterinary Pathology and Parasitology and Finnish Centre for Laboratory Animal Pathology/HiLIFE, University of Helsinki, FIN-00014 Helsinki, Finland;
| | - Tim Garrels
- Department of Computing, University of Turku, FI-20014 Turku, Finland; (T.G.); (L.L.)
| | - Satu Pekkala
- Faculty of Sport and Health Sciences, University of Jyväskylä, FI-40014 Jyväskylä, Finland; (S.L.); (E.M.); (S.K.); (M.H.); (S.P.)
- Department of Clinical Microbiology, Turku University Hospital, FI-20521 Turku, Finland
| | - Leo Lahti
- Department of Computing, University of Turku, FI-20014 Turku, Finland; (T.G.); (L.L.)
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30
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Zhang Y, Zhao N, Yang L, Hong Z, Cai B, Le Q, Yang T, Shi L, He J, Cui CB. Insoluble dietary fiber derived from brown seaweed Laminaria japonica ameliorate obesity-related features via modulating gut microbiota dysbiosis in high-fat diet-fed mice. Food Funct 2021; 12:587-601. [PMID: 33350422 DOI: 10.1039/d0fo02380a] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Gut microbiota (GM) is considered to play an important role in obesity. Additionally, the impact of dietary fiber (DF) consumption on GM has been well established. Brown seaweeds are known to be a rich source of DF. However, the effect of insoluble DFs (IDFs) alone from brown seaweed on obesity and GM remains to be determined. This study investigated the effect of IDFs prepared from Laminaria japonica Aresch on high-fat diet (HFD)-induced obesity and GM dysbiosis in mice. Although HFD-induced body weight gain was not significantly attenuated by the IDF treatment, HFD-induced liver injury was ameliorated, and the HFD-elevated serum cholesterol concentration and glucose level of obese mice were significantly lowered. IDF treatment significantly modulated the GM composition disturbed by the HFD. It was found that 5% IDFs restored the GM to a very similar composition to that in the normal mice. The relative abundance of Akkermansia genus was decreased by >300-fold in HFD-fed mice, and it was fully restored by 5% IDF administration. Akkermansia muciniphila, a short-chain fatty acid producer, was identified as a marker species in both control and high-dose IDF groups. Furthermore, IDFs significantly restored the HFD-reduced acetate and propionate levels in the cecal content. In conclusion, the beneficial effect of IDFs derived from L. japonica on obesity was confirmed in mice, and the underlying mechanism may be associated with the modulation of GM composition, possibly through the enrichment of Akkermansia.
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Affiliation(s)
- Yiping Zhang
- Technology Innovation Center for Exploitation of Marine Biological Resources, Ministry of Natural Resources; Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, PR China.
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31
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Joo JH, Kim HJ, Park EC, Jang SI. Association between sitting time and non-alcoholic fatty live disease in South Korean population: a cross-sectional study. Lipids Health Dis 2020; 19:212. [PMID: 32967678 PMCID: PMC7513533 DOI: 10.1186/s12944-020-01385-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 09/06/2020] [Indexed: 12/13/2022] Open
Abstract
Background To examine the association between sitting time and non-alcoholic fatty liver disease among South Koreans aged ≥20 years. Methods Data from the 2016–2018 Korea National Health and Nutrition Examination Survey were used for the analysis. Non-alcoholic fatty liver disease was diagnosed according to a hepatic steatosis index of > 36. Sitting time was categorized into as Q1, Q2, Q3, and Q4 using the age-adjusted quartile with Q4 being the longest sitting hour. Multiple logistic regression analysis was used to examine the association between sitting time and non-alcoholic fatty liver disease in South Korean population. Results A total of 13,518 participants were enrolled. The odds for having NAFLD in Q1, Q2, Q3, and Q4 (sitting hours) were 1.07 (CI: 0.88–1.31), 1.16 (CI: 1.96–1.41), and 1.34 (CI: 1.11–1.61), respectively. The odds ratio increased in magnitude with longer hours of sitting time (test for trend: P-value = 0.0002). Conclusion Advising physical exercises and discouraging sedentary activities may help to alleviate NAFLD among the South Korean population.
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Affiliation(s)
- Jae Hong Joo
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea.,Institute of Health Services Research, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hwi Jun Kim
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea.,Institute of Health Services Research, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,27th Infantry Division Medical Dispensary Operation Branch, Hwacheon, Republic of Korea
| | - Eun-Cheol Park
- Institute of Health Services Research, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Department of Preventive Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sung-In Jang
- Institute of Health Services Research, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Department of Preventive Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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32
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Di Ciaula A, Baj J, Garruti G, Celano G, De Angelis M, Wang HH, Di Palo DM, Bonfrate L, Wang DQH, Portincasa P. Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk. J Clin Med 2020; 9:2648. [PMID: 32823983 PMCID: PMC7465294 DOI: 10.3390/jcm9082648] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/07/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Giuseppe Celano
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Domenica Maria Di Palo
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
- Dipartimento di Scienze del Suolo, della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (G.C.); (M.D.A.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
| | - David Q-H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (H.H.W.); (D.Q.-H.W.)
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (D.M.D.P.); (L.B.)
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Kilchoer B, Vils A, Minder B, Muka T, Glisic M, Bally L. Efficacy of Dietary Supplements to Reduce Liver Fat. Nutrients 2020; 12:nu12082302. [PMID: 32751906 PMCID: PMC7469018 DOI: 10.3390/nu12082302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/26/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Liver fat accumulation is an important pathophysiological feature of non-alcoholic fatty liver disease that may be modulated by dietary supplements (DS). A systematic search of the literature was conducted for randomized controlled trials (RCTs) pertaining to the effect of a DS on liver fat as assessed using quantitative tomographic imaging in human adults. Where feasible, data were pooled, and meta-analyses conducted using random-effect model. Quality assessment was done according the Cochrane Collaboration's tool for assessing risk of bias. Twenty RCTs, involving 1171 overweight and obese adults, of which 36% were females, with or without comorbidities, were included. Only RCTs assessing omega-3 fatty acids (n = 4) and resveratrol (n = 4) qualified for meta-analysis. Results did neither favor omega-3 (effect size -1.17; weighted mean difference (WMD) (95% confidence interval (CI)) -3.62, 1.28; p < 0.001) nor resveratrol supplementation (0.18; 95% CI -1.08, 1.43; p = 0.27). The findings of the qualitatively summarized RCTs suggested that catechins (n = 1), Lactobacillus reuteri (n = 1), and carnitine (n = 1) may reduce liver fat. All other DS did not show any influence. The current evidence is scarce, of limited quality and does not support DS use to reduce liver fat. Further well-designed trials are warranted.
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Affiliation(s)
- Brittanie Kilchoer
- Department of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (B.K.); (A.V.)
| | - Anina Vils
- Department of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (B.K.); (A.V.)
| | - Beatrice Minder
- Public Health & Primary Care Library, University Library of Bern, University of Bern, 3012 Bern, Switzerland;
| | - Taulant Muka
- Institute of Social and Preventive Medicine, University of Bern, 2013 Bern, Switzerland; (T.M.); (M.G.)
| | - Marija Glisic
- Institute of Social and Preventive Medicine, University of Bern, 2013 Bern, Switzerland; (T.M.); (M.G.)
- Swiss Paraplegic Research, 6207 Nottwil, Switzerland
| | - Lia Bally
- Department of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (B.K.); (A.V.)
- Correspondence:
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Bae JS, Lee JY, Lee DH, Kim H, Lee Y, Han JK. Quantitative Evaluation of Hepatic Steatosis Using Normalized Local Variance in a Rat Model: Comparison with Histopathology as the Reference Standard. Korean J Radiol 2020; 20:1399-1407. [PMID: 31464118 PMCID: PMC6715566 DOI: 10.3348/kjr.2019.0068] [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: 01/24/2019] [Accepted: 05/02/2019] [Indexed: 12/16/2022] Open
Abstract
Objective To evaluate the diagnostic performance of the normalized local variance (NLV) ultrasound technique in the assessment of hepatic steatosis, and to identify the factors that influence the NLV value using histopathological examination as the reference standard. Materials and Methods Forty male Sprague-Dawley rats were fed a methionine-choline-deficient diet for variable periods (0, 2, 4, 6, 8, 10, or 12 days or 2, 3, or 4 weeks; four rats per group). At the end of each diet duration, magnetic resonance spectroscopy (MRS) and NLV examination were performed. Thereafter, the rats were sacrificed and their livers were histopathologically evaluated. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic capability of the NLV value in the detection of varying degrees of hepatic steatosis. Univariate and multivariate linear regressions were used to determine the factors associated with the NLV value. Results The areas under the ROC curve for the detection of mild, moderate, and severe hepatic steatosis were 0.953, 0.896, and 0.735, respectively. The NLV value showed comparable diagnostic performance to that of MRS in the detection of ≥ mild or ≥ moderate hepatic steatosis. Multivariate linear regression analysis revealed that the degree of hepatic steatosis was the only significant factor affecting the NLV value (p < 0.001). Conclusion The NLV value of ultrasound demonstrated satisfactory diagnostic performance in the assessment of varying degrees of hepatic steatosis. The degree of hepatic steatosis was the only significant factor that affected the NLV value.
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Affiliation(s)
- Jae Seok Bae
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Young Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
| | - Dong Ho Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Youngeun Lee
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Joon Koo Han
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea
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Santos FO, Correia BRO, Marinho TS, Barbosa-da-Silva S, Mandarim-de-Lacerda CA, Souza-Mello V. Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice. Mol Cell Endocrinol 2020; 509:110804. [PMID: 32259637 DOI: 10.1016/j.mce.2020.110804] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 03/30/2020] [Accepted: 03/30/2020] [Indexed: 12/30/2022]
Abstract
AIM To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice. METHODS Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups. RESULTS The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining. CONCLUSION Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.
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Affiliation(s)
- F O Santos
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - B R O Correia
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - T S Marinho
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Sandra Barbosa-da-Silva
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
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Wang J, Wang F, Yuan L, Wu Y, Peng X, Kai G, Zhu S, Liu Y. Aqueous extracts of Lindera aggregate (Sims) Kosterm leaves regulate serum/hepatic lipid and liver function in normal and hypercholesterolemic mice. J Pharmacol Sci 2020; 143:45-51. [PMID: 32169433 DOI: 10.1016/j.jphs.2020.01.009] [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: 06/25/2019] [Revised: 01/01/2020] [Accepted: 01/21/2020] [Indexed: 02/06/2023] Open
Abstract
The leaves of Lindera aggregate (Sims) Kosterm. are traditionally used as healthy tea for the prevention and treatment of hyperlipidemia in Chinese. The aim of this study was to evaluate the antihyperlipidemic effects and potential mechanisms of the aqueous extracts from L. aggregate leaves (AqLA-L) on normal and hypercholesterolemic (HCL) mice. HCL mice were induced by high fat diet (HFD) and orally administrated with or without AqLA-L for ten days. The results showed that AqLA-L (0.3, 0.6, 1.2 g/kg) significantly reduced serum TG, ALT, but elevated fecal TG in normal mice. AqLA-L (0.3, 0.6, 1.2 g/kg) also remarkably lowered serum TC, TG, LDL, N-HDL, ALT, GLU, APOB, hepatic GLU and increased serum HDL, APOA-I, fecal TG levels in HCL mice. These results revealed that AqLA-L treatment regulated the disorders of the serum lipid and liver function, reduced hepatic GLU contents both in normal and HCL mice. The potential mechanisms for cholesterol-lowering effects of AqLA-L might be up-regulation of cholesterol 7-alpha-hydroxylase (CYP7A1) and ATP-binding cassette transporter A1 (ABCA1), as well as down-regulation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). The data indicated that AqLA-L has potential therapeutic value in treatment of hyperlipidemia with great application security.
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Affiliation(s)
- Juan Wang
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
| | - Furong Wang
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
| | - Lixia Yuan
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
| | - Yao Wu
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
| | - Xin Peng
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China.
| | - Guoyin Kai
- Zhejiang Chinese Medical University, Zhejiang Province, Hangzhou 311400, PR China
| | - ShaoFeng Zhu
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
| | - Yugang Liu
- Institute of Biopharmaceutical, Zhejiang Pharmaceutical College, Zhejiang Province, Ningbo 315100, PR China
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Oketch-Rabah HA, Roe AL, Rider CV, Bonkovsky HL, Giancaspro GI, Navarro V, Paine MF, Betz JM, Marles RJ, Casper S, Gurley B, Jordan SA, He K, Kapoor MP, Rao TP, Sherker AH, Fontana RJ, Rossi S, Vuppalanchi R, Seeff LB, Stolz A, Ahmad J, Koh C, Serrano J, Low Dog T, Ko R. United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep 2020; 7:386-402. [PMID: 32140423 PMCID: PMC7044683 DOI: 10.1016/j.toxrep.2020.02.008] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 02/04/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023] Open
Abstract
As part of the United States Pharmacopeia's ongoing review of dietary supplement safety data, a new comprehensive systematic review on green tea extracts (GTE) has been completed. GTEs may contain hepatotoxic solvent residues, pesticide residues, pyrrolizidine alkaloids and elemental impurities, but no evidence of their involvement in GTE-induced liver injury was found during this review. GTE catechin profiles vary significantly with manufacturing processes. Animal and human data indicate that repeated oral administration of bolus doses of GTE during fasting significantly increases bioavailability of catechins, specifically EGCG, possibly involving saturation of first-pass elimination mechanisms. Toxicological studies show a hepatocellular pattern of liver injury. Published adverse event case reports associate hepatotoxicity with EGCG intake amounts from 140 mg to ∼1000 mg/day and substantial inter-individual variability in susceptibility, possibly due to genetic factors. Based on these findings, USP included a cautionary labeling requirement in its Powdered Decaffeinated Green Tea Extract monograph that reads as follows: "Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes)."
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Key Words
- ADME, Absorption, distribution, metabolism, and excretion
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- AUC, area under the curve
- Bw, body weight
- C, Catechin
- CAM, causality assessment method
- CG, (+)‐catechin‐3‐gallate
- CIH, Concanavalin A-induced hepatitis
- CMC, chemistry, manufacturing, and controls
- COMT, catechol‐O‐methyltransferase
- Camellia sinensis
- ConA, Concanavalin A
- DILI, drug‐induced liver injury
- DILIN, Drug‐Induced Liver Injury Network
- DO, Diversity Outbred
- DS, Dietary Supplement
- DSAE, JS3 USP Dietary Supplements Admission Evaluations Joint Standard-Setting Subcommittee
- Dietary supplements
- EC, (–)‐epicatechin
- ECG, (‐)‐epicatechin‐3‐gallate
- EFSA, European Food Safety Authority
- EGC, (–)‐epigallocatechin
- EGCG, (–)‐epigallocatechin‐3‐gallate
- FDA, United States Food and Drug Administration
- GC, (+)‐gallocatechin
- GCG, (–)‐gallocatechin‐3‐gallate
- GT(E), green tea or green tea extract
- GT, green tea
- GTE, green tea extract
- GTEH, EP Green Tea Extract Hepatotoxicity Expert Panel
- Green tea
- Green tea extract
- HDS, herbal dietary supplement
- HPMC, Hydroxypropyl methylcellulose
- Hepatotoxicity
- LD50, lethal dose, median
- LFT(s), liver function test(s)
- LT(s), Liver test(s)
- Liver injury
- MGTT, Minnesota Green Tea Trial
- MIDS, multi-ingredient dietary supplement
- MRL, maximum residue limit
- NAA, N-acetyl aspartate
- NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases
- NIH, National Institutes of Health
- NOAEL, no observed adverse effect level
- NTP, National Toxicology Program
- OSM, online supplementary material
- PAs, Pyrrolizidine Alkaloids
- PD-1, Programmed death domain-1
- PDGTE, powdered decaffeinated green tea extract
- PK/PD, pharmacokinetics and pharmacodynamics
- RUCAM, Roussel Uclaf Causality Assessment Method
- SIDS, single-ingredient dietary supplement
- TGF-beta, Transforming growth factor beta
- USP, United States Pharmacopeia
- γ-GT, Gamma-glutamyl transferase
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Affiliation(s)
- Hellen A. Oketch-Rabah
- U.S. Pharmacopeial Convention, Rockville, MD, USA
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Amy L. Roe
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
- Vice Chair, (USP GTEH EP, 2015-2020 cycle)
| | - Cynthia V. Rider
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Herbert L. Bonkovsky
- U.S. FDA Liaison to the USP GTEH EP (2015-2020 cycle)
- Section on Gastroenterology & Hepatology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Gabriel I. Giancaspro
- U.S. Pharmacopeial Convention, Rockville, MD, USA
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Victor Navarro
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
| | - Mary F. Paine
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - Joseph M. Betz
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Robin J. Marles
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Steven Casper
- U.S. FDA Liaison to the USP GTEH EP (2015-2020 cycle)
| | - Bill Gurley
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Scott A. Jordan
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Kan He
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Mahendra P. Kapoor
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Theertham P. Rao
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Averell H. Sherker
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
- Liver Diseases Research Branch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 6707 Democracy Blvd., Bethesda, MD, USA
| | - Robert J. Fontana
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Simona Rossi
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
| | | | - Leonard B. Seeff
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
| | - Andrew Stolz
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
| | - Jawad Ahmad
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
| | - Christopher Koh
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
- Liver Diseases Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, 10 Center Drive, Building 10, Rm 9B-16, Bethesda, MD, 20892,USA
| | - Jose Serrano
- Expert Members of the Drug Induced Liver Injury Network (DILIN), USA
- Liver Diseases Research Branch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 6707 Democracy Blvd., Bethesda, MD, USA
| | - Tieraona Low Dog
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
| | - Richard Ko
- United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA
- Chair (USP GTEH EP, 2015-2020 cycle)
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He X, Gao J, Hou H, Qi Z, Chen H, Zhang XX. Inhibition of Mitochondrial Fatty Acid Oxidation Contributes to Development of Nonalcoholic Fatty Liver Disease Induced by Environmental Cadmium Exposure. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2019; 53:13992-14000. [PMID: 31682409 DOI: 10.1021/acs.est.9b05131] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) is one of the most prevalent toxic metal pollutants widely distributed in water and soil environments. Epidemiological studies have shown that exposure to Cd is implicated in the prevalence of nonalcoholic fatty liver disease (NAFLD) in middle-aged human population, but biological evidence is lacking and its toxicological mechanism remains unclear for the disease predisposition from environmental Cd exposure. In this study, we established a chronic Cd-exposure mouse model mimicking the liver Cd deposition in middle-aged human population to determine whether the environmental Cd exposure can induce NAFLD. Results showed that hepatic Cd burden at levels of 0.95 and 6.04 μg/g wet weight resulting from 20-week Cd exposure at different doses induced NAFLD and nonalcoholic steatohepatitis-like phenotypes in mice, respectively. The Cd exposure caused marked hepatic mitochondrial dysfunction and fatty acid oxidation deficiency, along with significant suppression of sirtuin 1 (SIRT1) signaling pathway in the liver. In vitro study confirmed that Cd evidently inhibited the mitochondrial fatty acid oxidation in hepatocytes and that SIRT1 signaling was potentially involved in the process. Our findings suggest that exposure to environmental Cd is a tangible risk factor for NAFLD, and the induced public health risks deserve greater attention.
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Pedroso JA, Camporez JP, Belpiede LT, Pinto RS, Cipolla-Neto J, Donato J. Evaluation of Hepatic Steatosis in Rodents by Time-Domain Nuclear Magnetic Resonance. Diagnostics (Basel) 2019; 9:diagnostics9040198. [PMID: 31756971 PMCID: PMC6963644 DOI: 10.3390/diagnostics9040198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 11/11/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022] Open
Abstract
Devices that analyze body composition of rodents by time-domain nuclear magnetic resonance (TD-NMR) are becoming popular in research centers that study metabolism. Theoretically, TD-NMR devices can also evaluate lipid content in isolated tissues. However, the accuracy of TD-NMR to determine hepatic steatosis in the liver of small laboratory animals has not been evaluated in detail. We observed that TD-NMR was able to detect increased lipid content in the liver of rats consuming high-fat diet (HFD) for 12 weeks and in genetically obese (Lepob/ob and Leprdb/db) mice. The lipid content determined by TD-NMR showed a positive correlation with triglyceride content measured by colorimetric assays. In contrast, TD-NMR did not detect hepatic steatosis in C57BL/6 mice consuming HFD for 4 or 12 weeks, despite their obesity and increased liver triglyceride content. These findings indicate that tissue mass and the severity of hepatic steatosis affect the sensitivity of TD-NMR to detect liver lipid content.
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Chen J, Zhuang Y, Sng MK, Tan NS, Wahli W. The Potential of the FSP1cre- Pparb/d-/- Mouse Model for Studying Juvenile NAFLD. Int J Mol Sci 2019; 20:ijms20205115. [PMID: 31618976 PMCID: PMC6830345 DOI: 10.3390/ijms20205115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) can progress from steatosis to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, possibly leading to cirrhosis and hepatocellular carcinoma (HCC). Mice with impaired macrophage activation, when fed a high-fat diet, develop severe NASH. Evidence is mounting that Kupffer cells are implicated. However, it is unknown whether the resident CD68+ or bone marrow-derived CD11b+ Kupffer cells are involved. Characterization of the FSP1cre-Pparb/d-/- mouse liver revealed that FSP1 is expressed in CD11b+ Kupffer cells. Although these cells only constitute a minute fraction of the liver cell population, Pparb/d deletion in these cells led to remarkable hepatic phenotypic changes. We report that a higher lipid content was present in postnatal day 2 (P2) FSP1cre-Pparb/d-/- livers, which diminished after weaning. Quantification of total lipids and triglycerides revealed that P2 and week 4 of age FSP1cre-Pparb/d-/- livers have higher levels of both. qPCR analysis also showed upregulation of genes involved in fatty acid β-oxidation, and fatty acid and triglyceride synthesis pathways. This result is further supported by western blot analysis of proteins in these pathways. Hence, we propose that FSP1cre-Pparb/d-/- mice, which accumulate lipids in their liver in early life, may represent a useful animal model to study juvenile NAFLD.
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Affiliation(s)
- Jiapeng Chen
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Yan Zhuang
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
| | - Ming Keat Sng
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- INRA UMR1331, ToxAlim, 180 Chemin de Tournefeuille, 31300 Toulouse, France
- Center for Integrative Genomics, University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
- Correspondence: ; Tel.: +65-6904-7012
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Current Status in Testing for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH). Cells 2019; 8:cells8080845. [PMID: 31394730 PMCID: PMC6721710 DOI: 10.3390/cells8080845] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis.
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Abstract
Non-alcoholic fatty liver disease encompasses a spectrum of conditions from hepatic steatosis through to cirrhosis; obesity is a known risk factor. The liver plays a major role in regulating fatty acid metabolism and perturbations in intrahepatic processes have potential to impact on metabolic health. It remains unclear why intra-hepatocellular fat starts to accumulate, but it likely involves an imbalance between fatty acid delivery to the liver, fatty acid synthesis and oxidation within the liver and TAG export from the liver. As man spends the majority of the day in a postprandial rather than postabsorptive state, dietary fatty acid intake should be taken into consideration when investigating why intra-hepatic fat starts to accumulate. This review will discuss the impact of the quantity and quality of dietary fatty acids on liver fat accumulation and metabolism, along with some of the potential mechanisms involved. Studies investigating the role of dietary fat in liver fat accumulation, although surprisingly limited, have clearly demonstrated that it is total energy intake, rather than fat intake per se, that is a key mediator of liver fat content; hyperenergetic diets increase liver fat whilst hypoenergetic diets decrease liver fat content irrespective of total fat content. Moreover, there is now, albeit limited evidence emerging to suggest the composition of dietary fat may also play a role in liver fat accumulation, with diets enriched in saturated fat appearing to increase liver fat content to a greater extent when compared with diets enriched in unsaturated fats.
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High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype. Transl Oncol 2018; 12:256-268. [PMID: 30439626 PMCID: PMC6234703 DOI: 10.1016/j.tranon.2018.10.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 10/22/2018] [Accepted: 10/25/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: We analyzed livers of aged Krt18−/− mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18−/− mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18−/− mice with 26 human hepatoma cell lines and with data sets of >300 patients with HCC, where Krt18−/− gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.
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Thota RN, Ferguson JJA, Abbott KA, Dias CB, Garg ML. Science behind the cardio-metabolic benefits of omega-3 polyunsaturated fatty acids: biochemical effects vs. clinical outcomes. Food Funct 2018; 9:3576-3596. [PMID: 29904777 DOI: 10.1039/c8fo00348c] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Lower incidence of cardiovascular disease (CVD) in the Greenland Inuit, Northern Canada and Japan has been attributed to their consumption of seafood rich in long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA). While a large majority of pre-clinical and intervention trials have demonstrated heart health benefits of LCn-3PUFA, some studies have shown no effects or even negative effects. LCn-3PUFA have been shown to favourably modulate blood lipid levels, particularly a reduction in circulating levels of triglycerides. High density lipoprotein-cholesterol (HDL-C) levels are elevated following dietary supplementation with LCn-3PUFA. Although LCn-3PUFA have been shown to increase low-density lipoprotein-cholesterol (LDL-C) levels, the increase is primarily in the large-buoyant particles that are less atherogenic than small-dense LDL particles. The anti-inflammatory effects of LCn-3PUFA have been clearly outlined with inhibition of NFkB mediated cytokine production being the main mechanism. In addition, reduction in adhesion molecules (intercellular adhesion molecule, ICAM and vascular cell adhesion molecule 1, VCAM-1) and leukotriene production have also been demonstrated following LCn-3PUFA supplementation. Anti-aggregatory effects of LCn-3PUFA have been a subject of controversy, however, recent studies showing sex-specific effects on platelet aggregation have helped resolve the effects on hyperactive platelets. Improvements in endothelium function, blood flow and blood pressure after LCn-3PUFA supplementation add to the mechanistic explanation on their cardio-protective effects. Modulation of adipose tissue secretions including pro-inflammatory mediators and adipokines by LCn-3PUFA has re-ignited interest in their cardiovascular health benefits. The aim of this narrative review is to filter out the reasons for possible disparity between cohort, mechanistic, pre-clinical and clinical studies. The focus of the article is to provide possible explanation for the observed controversies surrounding heart health benefits of LCn-3PUFA.
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Affiliation(s)
- Rohith N Thota
- Nutraceuticals Research Program, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
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Silva-Veiga FM, Rachid TL, de Oliveira L, Graus-Nunes F, Mandarim-de-Lacerda CA, Souza-Mello V. GW0742 (PPAR-beta agonist) attenuates hepatic endoplasmic reticulum stress by improving hepatic energy metabolism in high-fat diet fed mice. Mol Cell Endocrinol 2018; 474:227-237. [PMID: 29580823 DOI: 10.1016/j.mce.2018.03.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/10/2018] [Accepted: 03/22/2018] [Indexed: 02/07/2023]
Abstract
Endoplasmic reticulum (ER) stress and hepatic steatosis are intertwined with insulin resistance. PPARs are at the crossroads of these pathways. This study aimed to investigate the effects of GW0742 (PPAR-beta agonist) on hepatic energy metabolism and ER stress in a murine diet-induced obesity model. HF diet caused overweight, hyperinsulinemia, hepatic inflammation (increased NF-kB, TNF-alpha, and IL-6 protein expression) and favored hepatic lipogenesis, leading to ER stress, with ultrastructural and molecular alterations, ending up in proapoptotic stimulus. GW0742 rescued the overweight and the glucose tolerance, tackled hepatic inflammation and favored hepatic beta-oxidation over lipogenesis. These results comply with ER ultrastructure improvement, reducing ER stress and apoptosis in treated animals. Our results indicate that the PPAR-beta/delta activation alleviated the ER stress by improving the insulin sensitivity and maximizing the hepatic energy metabolism with a shift towards beta-oxidation. PPAR-beta/delta activation could be an essential tool to avoid the NAFLD progression and other obesity constraints.
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Affiliation(s)
- Flavia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Tamiris Lima Rachid
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Letícia de Oliveira
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Francielle Graus-Nunes
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.
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Sid V, Siow YL, Shang Y, Woo CW, O K. High-fat diet consumption reduces hepatic folate transporter expression via nuclear respiratory factor-1. J Mol Med (Berl) 2018; 96:1203-1213. [PMID: 30178194 DOI: 10.1007/s00109-018-1688-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 08/03/2018] [Accepted: 08/17/2018] [Indexed: 12/13/2022]
Abstract
Folate is an essential micronutrient for biological function. The liver, a primary organ for folate metabolism and storage, plays an important role in folate homeostasis. Proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC) are the major folate transporters responsible for folate uptake at basolateral membrane of hepatocytes. Low serum folate levels are frequently associated with obesity. We investigated the mechanism that regulated folate status in a mouse model with diet-induced obesity. Mice (C57BL/6J) were fed a high-fat diet (60% kcal fat) for 8 weeks. Mice displayed increased hepatic lipid accumulation and decreased folate levels in the liver and serum compared to mice fed a normal chow diet (10% kcal fat). High-fat diet-fed mice had low expression of PCFT and RFC and decreased nuclear respiratory factor-1 (NRF-1)/DNA-binding activity. Treatment with NRF-1 siRNA or palmitic acid reduced folate transporter expression in hepatocytes. Inhibition of NRF-1 mediated folate transporter expression significantly reduced intracellular folate levels. These results suggest that chronic consumption of high-fat diets impairs folate transporter expression via NRF-1-dependent mechanism, leading to reduced hepatic folate storage. Understanding the regulation of folate homeostasis in obesity may have an important implication in current guideline of folate intake. KEY MESSAGES: Serum and liver folate levels are decreased in diet-induced obese mice. Chronic high-fat diet consumption impairs expression of hepatic PCFT and RFC. NRF-1 regulates hepatic folate transporters expression and folate levels.
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Affiliation(s)
- Victoria Sid
- St. Boniface Hospital Research Centre, Winnipeg, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada
| | - Yaw L Siow
- St. Boniface Hospital Research Centre, Winnipeg, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada
- Agriculture and Agri-Food Canada, Winnipeg, Canada
| | - Yue Shang
- St. Boniface Hospital Research Centre, Winnipeg, Canada
- Department of Animal Science, University of Manitoba, Winnipeg, Canada
| | - Connie W Woo
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, SAR, China.
| | - Karmin O
- St. Boniface Hospital Research Centre, Winnipeg, Canada.
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada.
- Department of Animal Science, University of Manitoba, Winnipeg, Canada.
- Laboratory of Integrative Biology, CCARM, St. Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada.
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Wang D, Cong H, Wang X, Cao Y, Ikuyama S, Fan B, Gu J. Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice. Am J Physiol Endocrinol Metab 2018; 315:E218-E228. [PMID: 29462565 DOI: 10.1152/ajpendo.00009.2017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PycnogenolR (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg-1·day-1 for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).
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Affiliation(s)
- Difei Wang
- Department of Geriatric Endocrinology, The First Hospital of China Medical University , Shenyang , China
| | - Huiying Cong
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University , Shenyang , China
| | - Xiaoli Wang
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University , Shenyang , China
| | - Yanli Cao
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University , Shenyang , China
| | - Shoichiro Ikuyama
- Department of Clinical Investigation, Department of Diabetes, Endocrine and Rheumatic Diseases Oita San-ai Medical Center, Ichi, Oita , Japan
| | - Bin Fan
- Department of Neurology, Shengjing Hospital, China Medical University , Shenyang , China
| | - Jianqiu Gu
- Department of Endocrinology and Metabolism, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University , Shenyang , China
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Chen J, Montagner A, Tan NS, Wahli W. Insights into the Role of PPARβ/δ in NAFLD. Int J Mol Sci 2018; 19:ijms19071893. [PMID: 29954129 PMCID: PMC6073272 DOI: 10.3390/ijms19071893] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/13/2018] [Accepted: 06/23/2018] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue in developed countries. Although usually associated with obesity, NAFLD is also diagnosed in individuals with low body mass index (BMI) values, especially in Asia. NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by liver damage and inflammation, leading to cirrhosis and hepatocellular carcinoma (HCC). NAFLD development can be induced by lipid metabolism alterations; imbalances of pro- and anti-inflammatory molecules; and changes in various other factors, such as gut nutrient-derived signals and adipokines. Obesity-related metabolic disorders may be improved by activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)β/δ, which is involved in metabolic processes and other functions. This review is focused on research findings related to PPARβ/δ-mediated regulation of hepatic lipid and glucose metabolism and NAFLD development. It also discusses the potential use of pharmacological PPARβ/δ activation for NAFLD treatment.
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Affiliation(s)
- Jiapeng Chen
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
| | - Alexandra Montagner
- ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), 180 Chemin de Tournefeuille, 31300 Toulouse, France.
- Institut National de La Santé et de La Recherche Médicale (INSERM), UMR1048, Institute of Metabolic and Cardiovascular Diseases, 31027 Toulouse, France.
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
- KK Research Centre, KK Women's and Children Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
- Institute of Molecular and Cell Biology, Agency for Science Technology & Research, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), 180 Chemin de Tournefeuille, 31300 Toulouse, France.
- Center for Integrative Genomics, University of Lausanne, Génopode, CH-1015 Lausanne, Switzerland.
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49
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Castro RQ, Soto Rodriguez I, Deschamps Lago RA, Pagola PG, Rodriguez Antolin J, Peres Quintal A, Rivera JR, Aguilera AA. Dietary sucrose regulates the expression of the Cd36 gene in hepatic tissue of rats with obesity and Non Alcoholic Fatty Liver Disease (NAFLD). Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:99-106. [DOI: 10.5507/bp.2018.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 04/04/2018] [Indexed: 01/07/2023] Open
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50
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Li J, Sasaki GY, Dey P, Chitchumroonchokchai C, Labyk AN, McDonald JD, Kim JB, Bruno RS. Green tea extract protects against hepatic NFκB activation along the gut-liver axis in diet-induced obese mice with nonalcoholic steatohepatitis by reducing endotoxin and TLR4/MyD88 signaling. J Nutr Biochem 2018; 53:58-65. [PMID: 29190550 DOI: 10.1016/j.jnutbio.2017.10.016] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 10/12/2017] [Accepted: 10/25/2017] [Indexed: 12/12/2022]
Abstract
Green tea extract (GTE) reduces NFκB-mediated inflammation during nonalcoholic steatohepatitis (NASH). We hypothesized that its anti-inflammatory activities would be mediated in a Toll-like receptor 4 (TLR4)-dependent manner. Wild-type (WT) and loss-of-function TLR4-mutant (TLR4m) mice were fed a high-fat diet containing GTE at 0 or 2% for 8 weeks before assessing NASH, NFκB-mediated inflammation, TLR4 and its adaptor proteins MyD88 and TRIF, circulating endotoxin, and intestinal tight junction protein mRNA expression. TLR4m mice had lower (P<.05) body mass compared with WT mice but similar adiposity, whereas body mass and adiposity were lowered by GTE regardless of genotype. Liver steatosis, serum alanine aminotransferase, and hepatic lipid peroxidation were also lowered by GTE in WT mice, and were similarly lowered in TLR4m mice regardless of GTE. Phosphorylation of the NFκB p65 subunit and pro-inflammatory genes (TNFα, iNOS, MCP-1, MPO) were lowered by GTE in WT mice, and did not differ from the lowered levels in TLR4m mice regardless of GTE. TLR4m mice had lower TLR4 mRNA, which was also lowered by GTE in both genotypes. TRIF expression was unaffected by genotype and GTE, whereas MyD88 was lower in mice fed GTE regardless of genotype. Serum endotoxin was similarly lowered by GTE regardless of genotype. Tight junction protein mRNA levels were unaffected by genotype. However, GTE similarly increased claudin-1 mRNA in the duodenum and jejunum and mRNA levels of occludin and zonula occluden-1 in the jejunum and ileum. Thus, GTE protects against inflammation during NASH, likely by limiting gut-derived endotoxin translocation and TLR4/MyD88/NFκB activation.
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Affiliation(s)
- Jinhui Li
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | - Geoffrey Y Sasaki
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | - Priyankar Dey
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | | | - Allison N Labyk
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | - Joshua D McDonald
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | - Joshua B Kim
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
| | - Richard S Bruno
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210, USA.
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