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Zhou X, Yue Z, He S, Yuan F, He X, Wang J, Wang R, Luo Y, Yi Q. Relationship between serum uric acid levels and metabolism associated fatty liver disease in postmenopausal women based on NHANES 2017-2020. Sci Rep 2025; 15:8944. [PMID: 40089555 PMCID: PMC11910611 DOI: 10.1038/s41598-025-93738-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 03/10/2025] [Indexed: 03/17/2025] Open
Abstract
Studies have shown that postmenopausal women have more metabolic abnormalities than premenopausal women. No consensus exists on how serum uric acid (sUA) affects metabolism-associated fatty liver disease (MAFLD) in postmenopausal women.This prospective observational study examined this link using National Health and Nutrition Examination Survey (NHANES) 2017 to 2020 data. We divided women's sUA levels into four quartiles and used logistic regression, subgroup analyses, and restricted triple spline methods to compare the prevalence of MAFLD in postmenopausal and non-menopausal women. We also used histograms to analyze the effect of BMI-based indices. This population-based study involved 4477 women, including 1139 postmenopausal women aged 55-73 years. Multivariate logistic regression showed that, in the fully adjusted model, we found that participants in the highest quartile of sUA had a statistically significant 254% increased risk of MAFLD compared with participants in the lowest quartile (OR: 3.54; 95% CI 3.54 1.47-8.55; P < 0.001). Subgroup analyses showed no significant interaction between sUA levels and specific subgroups P( > 0.05 for all interactions). Additionally, RCS and threshold analysis showed a linear correlation (P = 0.186) and an ideal inflection point of 4.6 (P = 0.818) to the left. Right of the inflection point, the effect size was 1.524 (95% CI 1.291-1.814; P < 0.01). Histograms demonstrated that postmenopausal BMI increased sUA's influence on MAFLD and higher sUA levels and BMI may enhance the prevalence of MAFLA in US postmenopausal women. The results of this study suggest that monitoring sUA levels in the postmenopausal period is critical in determining the occurrence of and interventions for MAFLD.
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Affiliation(s)
- Xiaoding Zhou
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Zongxiang Yue
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Shuming He
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Fengjuan Yuan
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Xingrui He
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Jiaqi Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Rong Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Ya Luo
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China
| | - Qiong Yi
- Center for Reproductive Medicine, Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China.
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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Ashiqueali SA, Zhu X, Wiesenborn DS, Gesing A, Schneider A, Noureddine SA, Correa-Garcia CG, Masternak MM, Siddiqi SA. Calorie restriction and life-extending mutation downregulate miR-34a to facilitate lipid metabolism in the liver. Exp Gerontol 2024; 194:112506. [PMID: 38945410 PMCID: PMC11418173 DOI: 10.1016/j.exger.2024.112506] [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: 02/17/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that enable these organisms to have extended lifespan is useful for the development of interventions to slow aging and deter age-related disease. Nonalcoholic fatty liver disease (NAFLD) is a condition that is characterized by the accumulation of excess adipose tissue in the liver. Previous studies highlight the potential of calorie restriction (CR) in promoting longevity, but little is known about its effects on the biomolecular processes that govern NAFLD. In this study, we examined the role of 6-month CR on genes regulating lipid metabolism in the livers of long-living df/df mice and their N littermates. Importantly, our findings showed significant downregulation of miR-34a-5p in N-CR mice and df/df mice regardless of dietary regimen. Alongside, our RT-PCR results indicated that downregulation of miR-34a-5p is correlated with the expression of metabolism-associated mRNAs involved in modulating the processes of de novo lipogenesis (DNL), fatty acid oxidation (FAO), very-low density lipoprotein transport (VLDL-T), and reverse cholesterol transport (RCT). To further verify the role of miR-34a-5p in regulating metabolic processes, we transfected the human liver cancer (HepG2) cell line with miR-34a mimic, and studied its effect on direct targets Sirt1, Ampk, and Ppara as well as downstream lipid transport regulating genes. Our findings suggest that CR and df/df life extending mutation are robust drivers of the miR-34a-5p signaling pathway and prevent the pathogenesis of age-related diseases by improving overall lipid homeostasis.
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Affiliation(s)
- Sarah A Ashiqueali
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Xiang Zhu
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Denise S Wiesenborn
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA; Department of Biotechnology, University of Applied Sciences Kaiserslautern, Zweibrücken, Germany
| | - Adam Gesing
- Department of Endocrinology of Ageing, Medical University of Lodz, Poland
| | - Augusto Schneider
- Department of Nutrition, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Sarah A Noureddine
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Christian G Correa-Garcia
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA; Department of Medicine, San Juan Bautista School of Medicine, Caguas, Puerto Rico
| | - Michal M Masternak
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA; Department of Head and Neck Surgery, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Shadab A Siddiqi
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
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Zhou J, Liang T, Xing F, Li X. Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease. Clin Res Hepatol Gastroenterol 2024; 48:102365. [PMID: 38703816 DOI: 10.1016/j.clinre.2024.102365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by dysregulated carbohydrate and lipid metabolism, which are its primary features. However, traditional biochemical markers pose challenges for accurate quantification and visualization of metabolic states. This study introduces a novel states-based approach for accurate NAFLD assessment. METHODS Joint probabilistic distributions of triglycerides and glycemia were constructed using dual-indicator Probabilistic Scatter Plots based on clinical data (healthy controls: n = 1978; NAFLD patients: n = 471). Patterns of metabolic dysregulation were revealed through comparison against healthy profiles. Self-organizing feature mapping (SOFM) clustered the distributions into four dominant states. RESULTS Healthy scatter plots demonstrated a distinct progression of sub-states ranging from very healthy to sub-healthy. In contrast, NAFLD plots exhibited shifted probability centers and outward divergence. SOFM clustering classified the states into: mild; moderate and severe lipid metabolism disorders; and carbohydrate metabolism disorders. CONCLUSIONS Probabilistic Scatter Plots, when combined with SOFM clustering, facilitate a states-based quantification of NAFLD metabolic dysregulation. This method integrates multi-dimensional biochemical indicators and their distributions into a cohesive framework, enabling precise and intuitive visualization for personalized diagnosis and monitoring of prognostic developments.
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Affiliation(s)
- Jialin Zhou
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tengxiao Liang
- Fever Clinics, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Fangliang Xing
- Beijing Intelligent Entropy Science & Technology Co Ltd., Beijing, China
| | - Xinyuan Li
- Intensive Care Medicine Department, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
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Vacca M, Kamzolas I, Harder LM, Oakley F, Trautwein C, Hatting M, Ross T, Bernardo B, Oldenburger A, Hjuler ST, Ksiazek I, Lindén D, Schuppan D, Rodriguez-Cuenca S, Tonini MM, Castañeda TR, Kannt A, Rodrigues CMP, Cockell S, Govaere O, Daly AK, Allison M, Honnens de Lichtenberg K, Kim YO, Lindblom A, Oldham S, Andréasson AC, Schlerman F, Marioneaux J, Sanyal A, Afonso MB, Younes R, Amano Y, Friedman SL, Wang S, Bhattacharya D, Simon E, Paradis V, Burt A, Grypari IM, Davies S, Driessen A, Yashiro H, Pors S, Worm Andersen M, Feigh M, Yunis C, Bedossa P, Stewart M, Cater HL, Wells S, Schattenberg JM, Anstee QM, Tiniakos D, Perfield JW, Petsalaki E, Davidsen P, Vidal-Puig A. An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD). Nat Metab 2024; 6:1178-1196. [PMID: 38867022 PMCID: PMC11199145 DOI: 10.1038/s42255-024-01043-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 04/08/2024] [Indexed: 06/14/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.
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Affiliation(s)
- Michele Vacca
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy.
- Laboratory of Liver Metabolism and MASLD, Roger Williams Institute of Hepatology, London, UK.
| | - Ioannis Kamzolas
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Lea Mørch Harder
- Research and Early Development, Novo Nordisk A/S, Måløv, Copenhagen, Denmark
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Maximilian Hatting
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Trenton Ross
- Internal Medicine research Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA
| | - Barbara Bernardo
- Internal Medicine research Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA
| | - Anouk Oldenburger
- CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | | | - Iwona Ksiazek
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), AstraZeneca BioPharmaceuticals R&D, Gothenburg, Sweden
- Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany
| | | | - Maria Manuela Tonini
- Luxembourg Institute of Health, Translational Medicine Operations Hub, Dudelange, Luxembourg
| | - Tamara R Castañeda
- R&D Diabetes & Portfolio Innovation and Excellence, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt, Germany
| | - Aimo Kannt
- R&D Diabetes, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Fraunhofer Innovation Center TheraNova and Goethe University, Frankfurt, Germany
| | - Cecília M P Rodrigues
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Simon Cockell
- Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Olivier Govaere
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ann K Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Michael Allison
- Liver Unit, Cambridge University Hospitals NHS Foundation Trust & Cambridge NIHR Biomedical Research Centre, Cambridge, UK
| | | | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Anna Lindblom
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), AstraZeneca BioPharmaceuticals R&D, Gothenburg, Sweden
| | - Stephanie Oldham
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), AstraZeneca BioPharmaceuticals R&D, Gaithersburg, MD, USA
| | - Anne-Christine Andréasson
- Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), AstraZeneca BioPharmaceuticals R&D, Gothenburg, Sweden
| | - Franklin Schlerman
- Inflammation and Immunology Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA
| | | | - Arun Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Marta B Afonso
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Ramy Younes
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Yuichiro Amano
- Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dipankar Bhattacharya
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric Simon
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
| | - Valérie Paradis
- Department of Imaging and Pathology, Université Paris Diderot and Hôpital Beaujon, Paris, France
| | - Alastair Burt
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Ioanna Maria Grypari
- Department of Pathology, Aretaeion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Susan Davies
- Department of Cellular Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ann Driessen
- Department of Pathology, Antwerp University Hospital, Edegem, Belgium
- Department of Molecular Imaging, Pathology, Radiotherapy, Oncology. Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Hiroaki Yashiro
- Research, Takeda Pharmaceuticals Company Limited, Cambridge, MA, USA
| | | | | | | | - Carla Yunis
- Pfizer, Inc.; Internal Medicine and Hospital, Pfizer Research and Development, Lake Mary, FL, USA
| | - Pierre Bedossa
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- LiverPat, Paris, France
| | | | | | - Sara Wells
- Mary Lyon Centre, MRC Harwell, Harwell Campus, Oxford, UK
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Centre, Homburg, Germany
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Department of Pathology, Aretaeion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| | - James W Perfield
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
| | - Peter Davidsen
- Research and Early Development, Novo Nordisk A/S, Måløv, Copenhagen, Denmark.
- Ferring Pharmaceuticals A/S, International PharmaScience Center, Copenhagen, Denmark.
| | - Antonio Vidal-Puig
- TVP Lab, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
- Centro de Investigacion Principe Felipe, Valencia, Spain.
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Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab 2024; 36:947-968. [PMID: 38718757 DOI: 10.1016/j.cmet.2024.04.006] [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: 10/03/2023] [Revised: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/26/2024]
Abstract
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
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Affiliation(s)
- Tao Bo
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Zhenyu Yao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Shanshan Shao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Xuemin Wang
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia
| | - Christopher G Proud
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia.
| | - Jiajun Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
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7
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Calcaterra V, Degrassi I, Taranto S, Porro C, Bianchi A, L’assainato S, Silvestro GS, Quatrale A, Zuccotti G. Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Thyroid Function in Childhood Obesity: A Vicious Circle? CHILDREN (BASEL, SWITZERLAND) 2024; 11:244. [PMID: 38397356 PMCID: PMC10887660 DOI: 10.3390/children11020244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a multisystem disorder characterized by the presence of fatty liver degeneration associated with excess adiposity or prediabetes/type 2 diabetes or metabolic dysregulation. An intricate relationship between the liver and thyroid has been reported in both health and disease. Simultaneously, there is a strong correlation between obesity and both MAFLD and thyroid dysfunction. In this narrative review, we highlighted the relationship between MAFLD and thyroid function in children and adolescents with obesity in order to explore how thyroid hormones (THs) act as predisposing factors in the onset, progression, and sustainability of MAFLD. THs are integral to the intricate balance of metabolic activities, ensuring energy homeostasis, and are indispensable for growth and development. Regarding liver homeostasis, THs have been suggested to interact with liver lipid homeostasis through a series of processes, including stimulating the entry of free fatty acids into the liver for esterification into triglycerides and increasing mitochondrial β-oxidation of fatty acids to impact hepatic lipid accumulation. The literature supports a correlation between MAFLD and obesity, THs and obesity, and MAFLD and THs; however, results in the pediatric population are very limited. Even though the underlying pathogenic mechanism involved in the relationship between MAFLD and thyroid function remains not fully elucidated, the role of THs as predisposing factors of MAFLD could be postulated. A potential vicious circle among these three conditions cannot be excluded. Identifying novel elements that may contribute to MAFLD could offer a practical approach to assessing children at risk of developing the condition.
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Affiliation(s)
- Valeria Calcaterra
- Pediatric and Adolescent Unit, Department of Internal Medicine, University of Pavia, 27100 Pavia, Italy
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Irene Degrassi
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Silvia Taranto
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Cecilia Porro
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Alice Bianchi
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Sara L’assainato
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Giustino Simone Silvestro
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Antonia Quatrale
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
| | - Gianvincenzo Zuccotti
- Pediatric Department, Buzzi Children’s Hospital, 20154 Milan, Italy; (I.D.); (S.T.); (C.P.); (A.B.); (S.L.); (G.S.S.); (A.Q.); (G.Z.)
- Department of Biomedical and Clinical Science “L. Sacco”, University of Milan, 20157 Milan, Italy
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8
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Yang J, Li CW, Zhang JR, Qiu H, Guo XL, Wang W. Perirenal Fat Thickness is Associated with Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2023; 16:1953-1965. [PMID: 37405319 PMCID: PMC10315154 DOI: 10.2147/dmso.s415477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 06/26/2023] [Indexed: 07/06/2023] Open
Abstract
Objective Recent advances in perirenal adipose tissue (PAT) highlighted that PAT might involve in the pathogenesis of chronic inflammatory and dysfunctional metabolic diseases. This study assessed the association between perirenal fat thickness (PrFT) and metabolic dysfunction-associated fatty liver disease (MALFD) in type 2 diabetes mellitus (T2DM). Methods This study comprised 867 eligible participants with T2DM. Trained reviewers collected anthropometric and biochemical measurements. The diagnosis of MAFLD was based on the latest international expert consensus statement. PrFT and fatty liver were evaluated by computed tomography. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by bioelectrical impedance analysis. The non-alcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 (FIB-4) index were used to assess progressive liver fibrosis in MAFLD. Results Overall, the prevalence of MAFLD was 62.3% in T2DM. The PrFT in the MAFLD group was statistically increased than in the non-MAFLD group (P < 0.05). Correlation analysis showed that PrFT was significantly correlated with dysfunctional metabolic factors like body mass index, waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, uric acid, and insulin resistance. Multiple regression analysis revealed that PrFT was positively correlated with NFS (β=0.146, P<0.001) and FIB-4 (β=0.082, P=0.025) in the MAFLD. In contrast, PrFT was negatively correlated with CTL-S (β=-0.188, P<0.001). Furthermore, PrFT was also significantly associated with MAFLD independent of VFA and SFA, the OR (95% CI) was 1.279 (1.191-1.374). Meanwhile, PrFT also had a good identifying value for MAFLD as VFA. The area under the curve (95% CI) value of PrFT identifying MAFLD was 0.782 (0.751-0.812). The optimal cut-off value of PrFT was 12.6mm, with a sensitivity of 77.8% and specificity of 70.8%. Conclusion PrFT was independently associated with MAFLD, NFS, and FIB-4 and showed a similar identifying value for MAFLD as VFA, which suggested that PrFT can be used as an alternative index to VFA.
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Affiliation(s)
- Jian Yang
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
| | - Chuan Wang Li
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
| | - Jing Ru Zhang
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
| | - Honglin Qiu
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
| | - Xiu Li Guo
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
| | - Wei Wang
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian, 364000, People’s Republic of China
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9
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Sun Q, Zhang T, Manji L, Liu Y, Chang Q, Zhao Y, Ding Y, Xia Y. Association Between Serum Uric Acid and Non-Alcoholic Fatty Liver Disease: An Updated Systematic Review and Meta-Analysis. Clin Epidemiol 2023; 15:683-693. [PMID: 37305378 PMCID: PMC10252946 DOI: 10.2147/clep.s403314] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 05/24/2023] [Indexed: 06/13/2023] Open
Abstract
Objective Recent epidemiological evidence shows that there is an association between serum uric acid (SUA) levels and nonalcoholic fatty liver disease (NAFLD). The purpose of this meta-analysis is to summarize all available evidence and assess the associations between SUA levels and NAFLD. Methods Using two databases, Web of Science and PubMed, observational studies were applied from the establishment of the databases to June 2022. We used a random effect model to construct the pooled odds ratio (OR) and 95% confidence interval (CI) to appraise the association between SUA levels and NAFLD. The Begg's test was conducted to appraise publication bias. Results A total of 50 studies were included, involving 2,079,710 participants (719,013 NAFLD patients). The prevalence and incidence rates (95% CIs) of NAFLD in the patients with hyperuricemia were 65% (57-73%) and 31% (20-41%), respectively. Compared to participants with lower levels of SUA, the pooled OR (95% CI) of NAFLD in those with higher levels of SUA was 1.88 (95% CI: 1.76-2.00). In the subgroup analyses, we found that SUA levels were positively associated with NAFLD in all subgroups, according to study design, study quality, sample size, sex, comparison, age, or country. Conclusion This meta-analysis shows that increased SUA levels are positively associated with NAFLD. The results suggested that reducing SUA levels can be a potential strategy for the prevention of NAFLD. Registration Number PROSPERO-CRD42022358431.
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Affiliation(s)
- Qianjia Sun
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China
| | - Tingjing Zhang
- School of Public Health, Wannan Medical College, Wuhu, People’s Republic of China
| | - Laeeqa Manji
- International Educational School, China Medical University, Shenyang, People’s Republic of China
| | - Yashu Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China
| | - Qing Chang
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China
| | - Yuhong Zhao
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Diagnosis and Treatment Centre for Liver Diseases of Liaoning Province, Shenyang, People’s Republic of China
| | - Yang Xia
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China
- Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China
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10
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Jiang Z, Sun H, Miao J, Sheng Q, Xu J, Gao Z, Zhang X, Song Y, Chen K. The natural flavone acacetin protects against high-fat diet-induced lipid accumulation in the liver via the endoplasmic reticulum stress/ferroptosis pathway. Biochem Biophys Res Commun 2023; 640:183-191. [PMID: 36516527 DOI: 10.1016/j.bbrc.2022.12.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. To date, no medication has been approved to treat NAFLD. In this study, we evaluated the therapeutic effect of the natural flavone acacetin on high-fat diet (HFD)-induced NAFLD in mice and the underlying mechanisms. We found that acacetin (10, 20, 50 mg/kg/day) suppressed the increase in body weight, serum total cholesterol, triglycerides, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in mice fed with HFD with a dose-dependent manner. Hepatic lipid accumulation, iron overload, and lipid peroxidation were significantly alleviated by acacetin. Quantitative PCR and western blotting revealed that acacetin inhibited endoplasmic reticulum (ER) stress, ferroptosis, and expressions of lipid acid synthesis-related genes in the livers of HFD mice. Similar results were observed in HepG2 cells treated with oleic acid and lipopolysaccharide. The suppressive effects of acacetin on triglycerides and expression of lipid acid synthesis genes were abolished by ER stress and the ferroptosis activators, erastin or TU. Interestingly, the action of TU was more potent than that of erastin. Treatment with the ER stress inhibitor GSK and the ferroptosis inhibitor Fer-1 revealed that ER stress was the upstream signal of ferroptosis for hepatic lipid accumulation. These findings suggest the protective effect of acacetin against lipid accumulation via suppressing ER stress and ferroptosis and provide evidence that ER stress is an upstream signal of ferroptosis in lipid accumulation. Acacetin may be a promising candidate agent for NAFLD treatment.
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Affiliation(s)
- Zhe Jiang
- Department of Gastroenterology, The Affiliated Li Huili Hospital of Ningbo University, Ningbo, Zhejiang, China; Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Hao Sun
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jiaen Miao
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Qiyu Sheng
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Jia Xu
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China
| | - Zhe Gao
- Ningbo Institute of Medical Sciences, 42 Yangshan Rd, Ningbo, China
| | - Xie Zhang
- Department of Gastroenterology, The Affiliated Li Huili Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Yufei Song
- Department of Gastroenterology, The Affiliated Li Huili Hospital of Ningbo University, Ningbo, Zhejiang, China.
| | - Kuihao Chen
- Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, China; School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
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11
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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12
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Li RY, Qin Q, Yang HC, Wang YY, Mi YX, Yin YS, Wang M, Yu CJ, Tang Y. TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target. Mol Neurodegener 2022; 17:40. [PMID: 35658903 PMCID: PMC9166437 DOI: 10.1186/s13024-022-00542-y] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer’s disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood–brain barrier, and we introduce potential pathways by which TREM2 affects the blood–brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.
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Affiliation(s)
- Rui-Yang Li
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Qi Qin
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Han-Chen Yang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Ying-Ying Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Ying-Xin Mi
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Yun-Si Yin
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Meng Wang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Chao-Ji Yu
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China
| | - Yi Tang
- Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China.
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13
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Xu C, Li H, Tang CK. Sterol carrier protein 2 in lipid metabolism and non-alcoholic fatty liver disease: Pathophysiology, molecular biology, and potential clinical implications. Metabolism 2022; 131:155180. [PMID: 35311663 DOI: 10.1016/j.metabol.2022.155180] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/03/2022] [Accepted: 03/13/2022] [Indexed: 11/29/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered as the most common chronic liver disease and has become a rapidly global public health problem. Sterol carrier protein 2 (SCP-2), also called non-specific lipid-transfer protein, is predominantly expressed by the liver. SCP-2 plays a key role in intracellular lipid transport and metabolism. SCP-2 has been closely implicated in the development of NAFLD-related metabolic disorders, such as obesity, atherosclerosis, Type 2 diabetes mellitus (T2DM), and gallstones. Recent studies indicate that SCP-2 plays a beneficial role in NAFLD by regulating cholesterol-, endocannabinoid-, and fatty acid-related aspects of lipid metabolism. Hence, in this paper, we summarize the latest findings about the roles of SCP-2 in hepatic steatosis and further describe its molecular function in the pathogenesis of NAFLD.
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Affiliation(s)
- Can Xu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, The First Affiliated Hospital of University of South China, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Heng Li
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, The First Affiliated Hospital of University of South China, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China.
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, The First Affiliated Hospital of University of South China, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China.
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14
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Liver Steatosis: A Marker of Metabolic Risk in Children. Int J Mol Sci 2022; 23:ijms23094822. [PMID: 35563210 PMCID: PMC9100068 DOI: 10.3390/ijms23094822] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as 'Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)', supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD's therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis.
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15
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Mitochondrial Dysfunction and Acute Fatty Liver of Pregnancy. Int J Mol Sci 2022; 23:ijms23073595. [PMID: 35408956 PMCID: PMC8999031 DOI: 10.3390/ijms23073595] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 01/27/2023] Open
Abstract
The liver is one of the richest organs in mitochondria, serving as a hub for key metabolic pathways such as β-oxidation, the tricarboxylic acid (TCA) cycle, ketogenesis, respiratory activity, and adenosine triphosphate (ATP) synthesis, all of which provide metabolic energy for the entire body. Mitochondrial dysfunction has been linked to subcellular organelle dysfunction in liver diseases, particularly fatty liver disease. Acute fatty liver of pregnancy (AFLP) is a life-threatening liver disorder unique to pregnancy, which can result in serious maternal and fetal complications, including death. Pregnant mothers with this disease require early detection, prompt delivery, and supportive maternal care. AFLP was considered a mysterious illness and though its pathogenesis has not been fully elucidated, molecular research over the past two decades has linked AFLP to mitochondrial dysfunction and defects in fetal fatty-acid oxidation (FAO). Due to deficient placental and fetal FAO, harmful 3-hydroxy fatty acid metabolites accumulate in the maternal circulation, causing oxidative stress and microvesicular fatty infiltration of the liver, resulting in AFLP. In this review, we provide an overview of AFLP and mitochondrial FAO followed by discussion of how altered mitochondrial function plays an important role in the pathogenesis of AFLP.
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16
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Jain D, Murti Y, Khan WU, Hossain R, Hossain MN, Agrawal KK, Ashraf RA, Islam MT, Janmeda P, Taheri Y, Alshehri MM, Daştan SD, Yeskaliyeva B, Kipchakbayeva A, Sharifi-Rad J, Cho WC. Roles of Therapeutic Bioactive Compounds in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9068850. [PMID: 34754365 PMCID: PMC8572616 DOI: 10.1155/2021/9068850] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/06/2021] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is due to poor prognosis and lack of availability of effective treatment. Novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells of ROS-induced tumor-promoting events. This review discusses the generation of ROS, the major signaling their modulation in therapeutics. We explore some of the major pathways involved in HCC, which include the VEGF, MAPK/ERK, mTOR, FGF, and Ser/Thr kinase pathways. In this review, we study cornerstone on natural bioactive compounds with their effect on hepatocarcinomas. Furthermore, we focus on oxidative stress and FDA-approved signaling pathway inhibitors, along with chemotherapy and radiotherapy enhancers which with early evidence of success. While more in vivo testing is required to confirm the findings presented here, our findings will aid future nonclinical, preclinical, and clinical studies with these compounds, as well as inspire medicinal chemistry scientists to conduct appropriate research on this promising natural compound and their derivatives.
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Affiliation(s)
- Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan, India
| | - Yogesh Murti
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Wasi Ullah Khan
- Key Laboratory for Sustainable Utilization of Tropical Bioresource, College of Tropical Crops Hainan University, Haikou, China
| | - Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Dhaka, Bangladesh
| | - Mohammad Nabil Hossain
- College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China
| | | | - Rana Azeem Ashraf
- School of Pharmaceutical Science and Technology (SPST), Tianjin University, China
| | - Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Dhaka, Bangladesh
| | - Pracheta Janmeda
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan, India
| | - Yasaman Taheri
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammed M. Alshehri
- Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
- Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
| | - Balakyz Yeskaliyeva
- Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, 050040 Almaty, Kazakhstan
| | - Aliya Kipchakbayeva
- Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, 050040 Almaty, Kazakhstan
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, SAR, China
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Wang M, Ma H, Guan S, Luo T, Zhao C, Cai G, Zheng Y, Jia X, Di J, Li R, Cui H. Astaxanthin from Haematococcus pluvialis alleviates obesity by modulating lipid metabolism and gut microbiota in mice fed a high-fat diet. Food Funct 2021; 12:9719-9738. [PMID: 34664590 DOI: 10.1039/d1fo01495a] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Obesity is a global chronic disease epidemic that is attributed to the abnormal accumulation of lipids in adipose tissue. Astaxanthin (AST) from Haematococcus pluvialis, a natural carotenoid, exhibits antioxidant, anti-lipogenic, anti-diabetic and other potent effects. Herein, we evaluated the effect of AST to illuminate its efficacy and mechanisms in high-fat diet-fed mice. AST supplementation not only significantly decreased body weight and lipid droplet accumulation in the liver but also modulated liver function and serum lipid levels. Lipidomic analysis revealed that 13 lipids might be potential biomarkers responsible for the effects of AST in lipid reduction, such as total free fatty acids (FFAs), triacylglycerols (TGs) and cholesterol esters (CEs). The gut microbiota sequencing results indicated that AST alleviated HFD-induced gut microbiota dysbiosis by optimizing the ratio of Firmicutes to Bacteroides and inhibiting the abundance of obesity-related pathogenic microbiota while promoting the abundance of probiotics related to glucose and lipid metabolism. In addition, qRT-PCR demonstrated that AST could regulate the gene expressions of the AMPK/SREBP1c pathway by downregulating lipogenesis correlated-genes and upregulating the lipid oxidant related-gene. The present study revealed the new function of AST in regulating lipid metabolism, which provided a theoretical basis for the development of high-quality AST functional food and the application of diet active substances in obesity, as demonstrated in mice.
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Affiliation(s)
- Meng Wang
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Haotian Ma
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Siyu Guan
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Tao Luo
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Chunchao Zhao
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Guiping Cai
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Yubin Zheng
- Shandong Jinjing Biotechnology Co., Ltd, Weifang 261000, China.
| | - Xiaoyun Jia
- College of Life Sciences, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Jianbing Di
- College of Food Science and Engineering, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Runzhi Li
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
| | - Hongli Cui
- College of Agriculture, Institute of Molecular Agriculture and Bioenergy, Shanxi Agricultural University, Taigu 030801, Shanxi, China.
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18
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Gao Y, Shi W, Yao H, Ai Y, Li R, Wang Z, Liu T, Dai W, Xiao X, Zhao J, Niu M, Bai Z. An Integrative Pharmacology Based Analysis of Refined Liuweiwuling Against Liver Injury: A Novel Component Combination and Hepaprotective Mechanism. Front Pharmacol 2021; 12:747010. [PMID: 34630116 PMCID: PMC8493075 DOI: 10.3389/fphar.2021.747010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 09/08/2021] [Indexed: 12/15/2022] Open
Abstract
Liver disease is a major cause of illness and death worldwide. In China, liver diseases, primarily alcoholic and nonalcoholic fatty liver disease, and viral hepatitis, affect approximately 300 million people, resulting in a major impact on the global burden of liver diseases. The use of Liuweiwuling (LWWL), a traditional Chinese medicine formula, approved by the Chinese Food and Drug Administration for decreasing aminotransferase levels induced by different liver diseases. Our previous study indicated a part of the material basis and mechanisms of LWWL in the treatment of hepatic fibrosis. However, knowledge of the materials and molecular mechanisms of LWWL in the treatment of liver diseases remains limited. Using pharmacokinetic and network pharmacology methods, this study demonstrated that the active components of LWWL were involved in the treatment mechanism against liver diseases and exerted anti-apoptosis and anti-inflammatory effects. Furthermore, esculetin, luteolin, schisandrin A and schisandrin B may play an important role by exerting anti-inflammatory and hepatoprotective effects in vitro. Esculeti and luteolin dose-dependently inhibited H2O2-induced cell apoptosis, and luteolin also inhibited the NF-κB signaling pathway in bone marrow-derived macrophages. schisandrin A and B inhibited the release of ROS in acetaminophen (APAP)-induced acute liver injury in vitro. Moreover, LWWL active ingredients protect against APAP-induced acute liver injury in mice. The four active ingredients may inhibit oxidative stress or inflammation to exert hepatoprotective effect. In conclusion, our results showed that the novel component combination of LWWL can protect against APAP-induced acute liver injury by inhibiting cell apoptosis and exerting anti-inflammatory effects.
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Affiliation(s)
- Yuan Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wei Shi
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongyu Yao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yongqiang Ai
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ruisheng Li
- Department of Infectious Disease Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhilei Wang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Tingting Liu
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Wenzhang Dai
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Xiaohe Xiao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jun Zhao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ming Niu
- Department of Poisoning Treatment, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhaofang Bai
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.,China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China
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19
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Le TNH, Choi HJ, Jun HS. Ethanol Extract of Liriope platyphylla Root Attenuates Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice via Regulation of Lipogenesis and Lipid Uptake. Nutrients 2021; 13:3338. [PMID: 34684339 PMCID: PMC8538311 DOI: 10.3390/nu13103338] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/18/2021] [Accepted: 09/21/2021] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder that causes excess lipid accumulation in the liver and is the leading cause of end-stage liver disease. Liriope platyphylla is a medicinal herb that has long been used to treat cough, obesity, and diabetes. However, the effect of Liriope platyphylla on NAFLD has not been studied. The aim of this study was to investigate the effect of Liriope platyphylla root ethanolic extract (LPE) on hepatic lipid accumulation in high-fat diet (HFD)-induced obese mice. Six-week-old C57BL/6 male mice were fed a HFD for 8 weeks and then treated with LPE (100 or 250 mg/kg/day) by oral gavage for another 8 weeks. Body weight gain and liver weight were significantly lower in the 250 mg/kg LPE-treated HFD group than in the vehicle-treated HFD group. Histological analysis of liver sections demonstrated that LPE treatment reduced lipid accumulation compared to the vehicle treatment. The serum total cholesterol, AST, and ALT levels significantly decreased in the LPE-treated HFD group compared to those in the vehicle-treated HFD group. The LPE significantly decreases the protein expression levels of SREBP1, ACC, p-ACC, FAS, and SCD1, which are involved in lipogenesis, and PPARγ, CD36/FAT, and FATP5, which are involved in fatty acid uptake, both in vivo and in vitro. Thus, LPE may attenuate HFD-induced NAFLD by decreasing lipid accumulation by inhibiting lipogenesis and fatty acid uptake.
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Affiliation(s)
- Trang Nu Huyen Le
- Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea; (T.N.H.L.); (H.-J.C.)
| | - Ho-Jung Choi
- Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea; (T.N.H.L.); (H.-J.C.)
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Korea
| | - Hee-Sook Jun
- Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea; (T.N.H.L.); (H.-J.C.)
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Korea
- Gachon Medical Research Institute, Gil Hospital, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea
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20
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de Alvarenga JFR, Genaro B, Costa BL, Purgatto E, Manach C, Fiamoncini J. Monoterpenes: current knowledge on food source, metabolism, and health effects. Crit Rev Food Sci Nutr 2021; 63:1352-1389. [PMID: 34387521 DOI: 10.1080/10408398.2021.1963945] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Monoterpenes, volatile metabolites produced by plants, are involved in the taste and aroma perception of fruits and vegetables and have been used for centuries in gastronomy, as food preservatives and for therapeutic purposes. Biological activities such as antimicrobial, analgesic and anti-inflammatory are well-established for some of these molecules. More recently, the ability of monoterpenes to regulate energy metabolism, and exert antidiabetic, anti-obesity and gut microbiota modulation activities have been described. Despite their promising health effects, the lack of reliable quantification of monoterpenes in food, hindered the investigation of their role as dietary bioactive compounds in epidemiological studies. Moreover, only few studies have documented the biotransformation of these compounds and identified the monoterpene metabolites with biological activity. This review presents up-to-date knowledge about the occurrence of monoterpenes in food, their bioavailability and potential role in the modulation of intermediate metabolism and inflammation, focusing on novel findings of molecular mechanisms, underlining research gaps and new avenues to be explored.
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Affiliation(s)
- José Fernando Rinaldi de Alvarenga
- Department of Food and Experimental Nutrition. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Food Research Center (FoRC), University of São Paulo, São Paulo, Brazil
| | - Brunna Genaro
- Department of Food and Experimental Nutrition. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Bruna Lamesa Costa
- Department of Food and Experimental Nutrition. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Eduardo Purgatto
- Department of Food and Experimental Nutrition. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Food Research Center (FoRC), University of São Paulo, São Paulo, Brazil
| | - Claudine Manach
- Université Clermont Auvergne, INRAE, UNH, Clermont-Ferrand, France
| | - Jarlei Fiamoncini
- Department of Food and Experimental Nutrition. Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.,Food Research Center (FoRC), University of São Paulo, São Paulo, Brazil
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21
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Zhang X, Zhang Y, Gao W, Guo Z, Wang K, Liu S, Duan Z, Chen Y. Naringin improves lipid metabolism in a tissue-engineered liver model of NAFLD and the underlying mechanisms. Life Sci 2021; 277:119487. [PMID: 33862107 DOI: 10.1016/j.lfs.2021.119487] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
AIMS Nonalcoholic fatty liver disease (NAFLD) is a lipid metabolism disorder. Naringin (a main active ingredient in Ganshuang granules) is a flavanone that has been demonstrated to exert hepatoprotective and antifibrotic effects. The present study aimed to use a novel tissue-engineered fatty liver model to assess the effects and mechanisms of naringin on NAFLD. MAIN METHODS Intracellular triglyceride (TG) was examined by oil red O staining and commercial kits. The proteins associated with lipid metabolism were measured by western blotting and/or qPCR. Very low-density lipoprotein (VLDL) was measured by ELISA. A CCK8 assay was used to assess the cytotoxicity of naringin. Molecular docking was used to predict the interactions and binding patterns between naringin and target proteins. KEY FINDINGS Naringin significantly reduced intracellular TG accumulation by 52.7% in tissue-engineered fatty (TEF) livers, and also the level of pyruvate dehydrogenase kinase 4. Naringin downregulated CD36 and proliferator activated-receptor γ expression, reducing the uptake of FFAs; naringin also downregulated de novo liposynthetases by reducing acetyl CoA carboxylase, fatty acid synthetase etc. in TEF livers. Moreover, naringin increased the expression of proliferator activated-receptor α (PPAR-α) and carnitine palmitoyltransferase 1 to improve the oxidation of fatty acids. The levels of VLDL secreted from TEF livers were reduced by 24.7% after naringin treatment. Molecular docking analyses determined the bioactivity of naringin through its specific binding to CD36 and PPAR-α. SIGNIFICANCE Naringin improved lipid metabolism disorders in TEF livers by reducing fatty acid uptake and de novo lipogenesis and increasing fatty acid oxidation. CD36 and PPAR-α might be specific targets of naringin.
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Affiliation(s)
- Xiaohui Zhang
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yizhi Zhang
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Wen Gao
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhihao Guo
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kun Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuang Liu
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
| | - Yu Chen
- Difficult & Complicated Liver Diseases and Artificial Liver Center & Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
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22
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:1569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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23
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Azzu V, Vacca M, Kamzolas I, Hall Z, Leslie J, Carobbio S, Virtue S, Davies SE, Lukasik A, Dale M, Bohlooly-Y M, Acharjee A, Lindén D, Bidault G, Petsalaki E, Griffin JL, Oakley F, Allison MED, Vidal-Puig A. Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression. Mol Metab 2021; 48:101210. [PMID: 33722690 PMCID: PMC8094910 DOI: 10.1016/j.molmet.2021.101210] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/19/2021] [Accepted: 03/06/2021] [Indexed: 01/22/2023] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.
Human NASH biopsies’ transcriptomics analysis features metabolic pathway rewiring. SCAP/SREBP/INSIG1 modulation promotes lipid/cholesterol synthesis/remodelling in NASH. Loss of Insig1 promotes lipid remodelling, preventing hepatic lipotoxicity in NASH. Loss of Insig1 improves liver damage and wound healing and restrains NASH progression.
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Affiliation(s)
- Vian Azzu
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Liver Unit, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Gastroenterology and Hepatology, Norfolk and Norwich University Hospitals, Norwich, UK
| | - Michele Vacca
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Clinica Medica Cesare Frugoni, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Bari, Italy
| | - Ioannis Kamzolas
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
| | - Zoe Hall
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, 5 Newcastle University, Newcastle upon Tyne, UK
| | - Stefania Carobbio
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Samuel Virtue
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Susan E Davies
- Department of Pathology, Cambridge University Hospitals, Cambridge, UK
| | - Agnes Lukasik
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Martin Dale
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Mohammad Bohlooly-Y
- Translational Genomics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Animesh Acharjee
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; College of Medical and Dental Sciences, Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, UK
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Division of Endocrinology, Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Guillaume Bidault
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Evangelia Petsalaki
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
| | - Julian L Griffin
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK; Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, 5 Newcastle University, Newcastle upon Tyne, UK
| | - Michael E D Allison
- Liver Unit, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Antonio Vidal-Puig
- Wellcome Trust/MRC Institute of Metabolic Science, Metabolic Research Laboratories, University of Cambridge, Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK; Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei, Nanjing, China.
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24
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Hall Z, Chiarugi D, Charidemou E, Leslie J, Scott E, Pellegrinet L, Allison M, Mocciaro G, Anstee QM, Evan GI, Hoare M, Vidal-Puig A, Oakley F, Vacca M, Griffin JL. Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma. Hepatology 2021; 73:1028-1044. [PMID: 32460431 DOI: 10.1002/hep.31391] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/08/2020] [Accepted: 04/27/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state-of-the-art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC. APPROACH AND RESULTS Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis. CONCLUSIONS Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
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Affiliation(s)
- Zoe Hall
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- Biomolecular MedicineDivision of Systems MedicineDepartment of Metabolism, Digestion and ReproductionImperial College LondonLondonUnited Kingdom
| | - Davide Chiarugi
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic ScienceCambridgeUnited Kingdom
| | - Evelina Charidemou
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | - Jack Leslie
- Institute of Cellular MedicineFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Emma Scott
- Institute of Cellular MedicineFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Luca Pellegrinet
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | - Michael Allison
- Department of MedicineAddenbrooke's HospitalCambridge Biomedical Research CentreCambridgeUnited Kingdom
| | - Gabriele Mocciaro
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | - Quentin M Anstee
- Institute of Cellular MedicineFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUnited Kingdom
- Newcastle NIHR Biomedical Research CentreNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUnited Kingdom
| | - Gerard I Evan
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | - Matthew Hoare
- Department of MedicineAddenbrooke's HospitalCambridge Biomedical Research CentreCambridgeUnited Kingdom
- CRUK Cambridge InstituteRobinson WayCambridgeUnited Kingdom
| | - Antonio Vidal-Puig
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic ScienceCambridgeUnited Kingdom
| | - Fiona Oakley
- Institute of Cellular MedicineFaculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Michele Vacca
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic ScienceCambridgeUnited Kingdom
| | - Julian L Griffin
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- Biomolecular MedicineDivision of Systems MedicineDepartment of Metabolism, Digestion and ReproductionImperial College LondonLondonUnited Kingdom
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25
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Discovery of Quality Markers in Hugan Qingzhi Formula by Integrating a Lipid-Lowering Bioassay with UHPLC-QQQ-MS/MS. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:1594350. [PMID: 35198030 PMCID: PMC8860508 DOI: 10.1155/2020/1594350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/18/2020] [Accepted: 10/24/2020] [Indexed: 11/30/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The Hugan Qingzhi formula (HGQZ) has been proven effective in treating NAFLD through clinical and pharmacological mechanism studies. A screening study of the chemical components was carried out to better control the quality of this formula. Current research has combined biological activity assessment with chemical analysis to screen and identify the bioactive compounds in HGQZ for use as potential quality markers (Q-markers) to control the quality of this herbal product. The HGQZ extracted by three different solvents was evaluated in a free fatty acid-induced hepatic steatosis LO2 cell model. Simultaneously, the twelve major chemical constituents of these extracts were quantitatively measured by ultrahigh-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS). Extraction with 50% ethanol showed the most potent lipid-lowering effect in steatosis LO2 cells and the highest extraction rate of major chemical constituents. Correlation analysis was used to establish the relationship between the biological activities and chemical characteristics of these extracts. The results showed that the contents of typhaneoside, hyperoside, isoquercitrin, isorhamnetin-3-O-neohesperidoside, notoginsenoside R1, and alisol B 23-acetate were positively correlated to the lipid-lowering effect. The subsequent bioassay confirmed that typhaneoside, isoquercitrin, and alisol B 23-acetate played the role of reducing the lipid effect. In conclusion, 50% of ethanol extraction produced the most active extract of HGQZ. Typhaneoside, isoquercitrin, and alisol B 23-acetate could be considered potential Q-markers for the quality control of HGQZ.
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26
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Crudele A, Panera N, Braghini MR, Balsano C, Alisi A. The pharmacological treatment of nonalcoholic fatty liver disease in children. Expert Rev Clin Pharmacol 2020; 13:1219-1227. [PMID: 32981386 DOI: 10.1080/17512433.2020.1829468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in childhood/adolescence. It comprises a broad spectrum of liver disease severity ranging from simple steatosis to steatohepatitis and fibrosis. To date lifestyle modifications, diet and physical activity represent the main option for the management of pediatric NAFLD, but numerous treatments classified depending on the mechanism of action, have been introduced. In keeping with, bariatric surgery, insulin sensitizers, antioxidants, probiotic and dietary supplementations have been evaluated in pediatric clinical trials. AREAS COVERED This review describes, after a search in PubMed/MEDLINE database, the current pediatric NAFLD non-pharmacological and pharmacological treatments and their effects on biochemical and histological features. We report not only the efficacy of the diet coupled with regular exercise but also advantages of the pharmacological treatments used in combination with lifestyle interventions in pediatric NAFLD. EXPERT OPINION Since pharmacological and non-pharmacological interventions have demonstrated variable effects in pediatric NAFLD, it is clear that safe and specific and efficient therapeutic strategies have not yet been identified. Therefore, large and long-term clinical trials in children are needed to find a way to reverse the liver tissue damage and the NAFLD-related long-term morbidity and mortality.
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Affiliation(s)
- Annalisa Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Nadia Panera
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Maria Rita Braghini
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
| | - Clara Balsano
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila , L'Aquila, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS , Rome, Italy
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High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms. Chem Biol Interact 2020; 330:109199. [DOI: 10.1016/j.cbi.2020.109199] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023]
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Simard JC, Thibodeau JF, Leduc M, Tremblay M, Laverdure A, Sarra-Bournet F, Gagnon W, Ouboudinar J, Gervais L, Felton A, Letourneau S, Geerts L, Cloutier MP, Hince K, Corpuz R, Blais A, Quintela VM, Duceppe JS, Abbott SD, Blais A, Zacharie B, Laurin P, Laplante SR, Kennedy CRJ, Hébert RL, Leblond FA, Grouix B, Gagnon L. Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease. Sci Rep 2020; 10:12778. [PMID: 32728158 PMCID: PMC7391726 DOI: 10.1038/s41598-020-69675-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84−/− mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.
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Affiliation(s)
- Jean-Christophe Simard
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Jean-François Thibodeau
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada. .,Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
| | - Martin Leduc
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Mikael Tremblay
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Alexandre Laverdure
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - François Sarra-Bournet
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - William Gagnon
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Jugurtha Ouboudinar
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Liette Gervais
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Alexandra Felton
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Sylvie Letourneau
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Lilianne Geerts
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Marie-Pier Cloutier
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Kathy Hince
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Ramon Corpuz
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Alexandra Blais
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Vanessa Marques Quintela
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Jean-Simon Duceppe
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Shaun D Abbott
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Amélie Blais
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Boulos Zacharie
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Pierre Laurin
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Steven R Laplante
- Institut National de La Recherche Scientifique, Institut Armand-Frappier, 531 Boul. Des Prairies, Laval, QC, H7V 5B7, Canada
| | - Christopher R J Kennedy
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - Richard L Hébert
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada
| | - François A Leblond
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Brigitte Grouix
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
| | - Lyne Gagnon
- Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada
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Vacca M, Leslie J, Virtue S, Lam BYH, Govaere O, Tiniakos D, Snow S, Davies S, Petkevicius K, Tong Z, Peirce V, Nielsen MJ, Ament Z, Li W, Kostrzewski T, Leeming DJ, Ratziu V, Allison MED, Anstee QM, Griffin JL, Oakley F, Vidal-Puig A. Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis. Nat Metab 2020; 2:514-531. [PMID: 32694734 PMCID: PMC7617436 DOI: 10.1038/s42255-020-0214-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/24/2020] [Indexed: 12/15/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.
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Affiliation(s)
- Michele Vacca
- TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK.
| | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Samuel Virtue
- TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Brian Y H Lam
- Yeo Group and Genomics and Transcriptomics Core, WT/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Olivier Govaere
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | | | - Susan Davies
- Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge, UK
| | - Kasparas Petkevicius
- TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Zhen Tong
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Vivian Peirce
- TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | | | - Zsuzsanna Ament
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | - Wei Li
- Department of Medicine, University of Cambridge, Cambridge, UK
| | | | | | - Vlad Ratziu
- Sorbonne Université, Institute for Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, Paris, France
| | - Michael E D Allison
- Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge, UK
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Julian L Griffin
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
- Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Antonio Vidal-Puig
- TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
- Welcome Trust Sanger Institute, Hinxton, UK.
- Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, P R China.
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Key CCC, Bishop AC, Wang X, Zhao Q, Chen GY, Quinn MA, Zhu X, Zhang Q, Parks JS. Human GDPD3 overexpression promotes liver steatosis by increasing lysophosphatidic acid production and fatty acid uptake. J Lipid Res 2020; 61:1075-1086. [PMID: 32430316 DOI: 10.1194/jlr.ra120000760] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
The glycerol phosphate pathway produces more than 90% of the liver triacylglycerol (TAG). LysoPA, an intermediate in this pathway, is produced by glycerol-3-phosphate acyltransferase. Glycerophosphodiester phosphodiesterase domain containing 3 (GDPD3), whose gene was recently cloned, contains lysophospholipase D activity, which produces LysoPA from lysophospholipids. Whether human GDPD3 plays a role in hepatic TAG homeostasis is unknown. We hypothesized that human GDPD3 increases LysoPA production and availability in the glycerol phosphate pathway, promoting TAG biosynthesis. To test our hypothesis, we infected C57BL/6J mice with adeno-associated virus encoding a hepatocyte-specific albumin promoter that drives GFP (control) or FLAG-tagged human GDPD3 overexpression and fed the mice chow or a Western diet to induce hepatosteatosis. Hepatic human GDPD3 overexpression induced LysoPA production and increased FA uptake and incorporation into TAG in mouse hepatocytes and livers, ultimately exacerbating Western diet-induced liver steatosis. Our results also showed that individuals with hepatic steatosis have increased GDPD3 mRNA levels compared with individuals without steatosis. Collectively, these findings indicate that upregulation of GDPD3 expression may play a key role in hepatic TAG accumulation and may represent a molecular target for managing hepatic steatosis.
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Affiliation(s)
- Chia-Chi C Key
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157. mailto:
| | - Andrew C Bishop
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Xianfeng Wang
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Qingxia Zhao
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Guan-Yuan Chen
- Department of Chemistry and Center for Translational Biomedical Research, University of North Carolina at Greensboro, Greensboro, NC 27402
| | - Matthew A Quinn
- Section on Comparative Medicine, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Xuewei Zhu
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157
| | - Qibin Zhang
- Department of Chemistry and Center for Translational Biomedical Research, University of North Carolina at Greensboro, Greensboro, NC 27402
| | - John S Parks
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157
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Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease. Gastroenterology 2020; 158:1899-1912. [PMID: 32061598 DOI: 10.1053/j.gastro.2019.12.054] [Citation(s) in RCA: 224] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/20/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023]
Abstract
Adipose tissue and the liver play significant roles in the regulation of whole-body energy homeostasis, but they have not evolved to cope with the continuous, chronic, nutrient surplus seen in obesity. In this review, we detail how prolonged metabolic stress leads to adipose tissue dysfunction, inflammation, and adipokine release that results in increased lipid flux to the liver. Overall, the upshot of hepatic fat accumulation alongside an insulin-resistant state is that hepatic lipid enzymatic pathways are modulated and overwhelmed, resulting in the selective buildup of toxic lipid species, which worsens the pro-inflammatory and pro-fibrotic shift observed in nonalcoholic steatohepatitis.
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Affiliation(s)
- Vian Azzu
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital; The Liver Unit, Department of Medicine, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge.
| | - Michele Vacca
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital
| | - Samuel Virtue
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital
| | - Michael Allison
- The Liver Unit, Department of Medicine, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge
| | - Antonio Vidal-Puig
- Wellcome Trust-Medical Research Council Institute of Metabolic Science-Metabolic Research Laboratories, Addenbrooke's Hospital; Wellcome Trust Sanger Institute, Hinxton, United Kingdom
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32
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Galmés-Pascual BM, Martínez-Cignoni MR, Morán-Costoya A, Bauza-Thorbrügge M, Sbert-Roig M, Valle A, Proenza AM, Lladó I, Gianotti M. 17β-estradiol ameliorates lipotoxicity-induced hepatic mitochondrial oxidative stress and insulin resistance. Free Radic Biol Med 2020; 150:148-160. [PMID: 32105829 DOI: 10.1016/j.freeradbiomed.2020.02.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/11/2020] [Accepted: 02/19/2020] [Indexed: 02/08/2023]
Abstract
The prevalence and severity of nonalcoholic fatty liver disease (NAFLD) is higher in men and postmenopausal women compared to premenopausal women, suggesting a protective role for ovarian hormones. Diet-induced obesity and fatty acids surplus promote mitochondrial dysfunction in liver, triggering oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis, the main hallmarks of NAFLD. Considering that estrogen, in particular 17β-estradiol (E2), have been reported to improve mitochondrial biogenesis and function in liver, our aim was to elucidate the role of E2 in preventing fatty acid-induced insulin resistance in hepatocytes through modulation of mitochondrial function, oxidative stress and JNK activation. An in vivo study was conducted in Wistar rats of both sexes (n = 7) fed control diet and high-fat diet (HFD), and in vitro studies were carried out in HepG2 cells treated with palmitate (PA) and E2 for 24 h. Our HFD-fed male rats showed a prediabetic state characterized by greater systemic and hepatic insulin resistance, as well as higher lipid content in liver, compared to females. JNK activation rose markedly in males in response to HFD feeding, in parallel with mitochondrial dysfunction and oxidative stress. Consistently, in PA-exposed HepG2 cells, E2 treatment prevented JNK activation, insulin resistance and fatty acid accumulation. Altogether, our data highlights the importance of E2 as a mitigating factor of fatty acid-insulin resistance in hepatocytes through downregulation of JNK activation, by means of mitochondrial function improvement.
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Affiliation(s)
- Bel M Galmés-Pascual
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain
| | - Melanie Raquel Martínez-Cignoni
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain
| | - Andrea Morán-Costoya
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain
| | - Marco Bauza-Thorbrügge
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain
| | - Miquel Sbert-Roig
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain
| | - Adamo Valle
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, E- 28029, Madrid, Spain.
| | - Ana M Proenza
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, E- 28029, Madrid, Spain
| | - Isabel Lladó
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, E- 28029, Madrid, Spain
| | - Magdalena Gianotti
- Grup Metabolisme Energètic i Nutrició, Departament de Biologia Fonamental i Ciències de la Salut, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, km 7.5, E-07122, Palma de Mallorca, Illes Balears, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Hospital Universitari Son Espases, E-07120, Palma de Mallorca, Illes Balears, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0043), Instituto de Salud Carlos III, E- 28029, Madrid, Spain
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Kim JC, Jeon JY, Yang WS, Kim CH, Eom DW. Combined Amelioration of Ginsenoside (Rg1, Rb1, and Rg3)-enriched Korean Red Ginseng and Probiotic Lactobacillus on Non-alcoholic Fatty Liver Disease. Curr Pharm Biotechnol 2019; 20:222-231. [PMID: 30854954 DOI: 10.2174/1389201020666190311143554] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 11/15/2018] [Accepted: 02/15/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Red ginseng is a traditional medicine that has been used to treat numerous metabolic and inflammatory diseases. Probiotic administration has been established to have beneficial effects in non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to determine whether a combination of Korean red ginseng (KRG) and probiotics could synergistically reduce NAFLD and liver inflammation compared with the effects reported for each individual product. METHOD db/db and C57BL/6 mice were fed a normal chow diet and high-fat diet (HFD), respectively, and were treated with KRG, probiotics, or both. Samples were examined for lipid content, kinase protein phosphorylation, and gene expression patterns. RESULTS KRG- and probiotic-treated HFD-fed mice exhibited a reduction in body weight and a decrease in inflammatory cytokine secretion compared with the non-treated control mice. The same treatment was less successful in improving NAFLD parameters in the db/db mice while the combination of both products did not enhance their therapeutic potential. CONCLUSION The results of this study indicate that KRG and probiotics administration ameliorated NAFLD symptoms in a mouse model of dyslipidemia by reducing weight gain and liver inflammation. Coadministration of both products did not enhance their efficacy, and further research should be conducted to clarify their mechanisms of action.
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Affiliation(s)
- Jin-Chul Kim
- Natural Product Research Institute, Korea Institute of Science and Technology, Gangneung, Korea
| | - Joo-Yeong Jeon
- Natural Product Research Institute, Korea Institute of Science and Technology, Gangneung, Korea
| | | | - Cheorl-Ho Kim
- Department of Biological Sciences, SungKyunKwan University, Suwon, Kyungki-do, Korea
| | - Dae-Woon Eom
- Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
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Cheng C, Zhuo S, Zhang B, Zhao X, Liu Y, Liao C, Quan J, Li Z, Bode AM, Cao Y, Luo X. Treatment implications of natural compounds targeting lipid metabolism in nonalcoholic fatty liver disease, obesity and cancer. Int J Biol Sci 2019; 15:1654-1663. [PMID: 31360108 PMCID: PMC6643217 DOI: 10.7150/ijbs.33837] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/19/2019] [Indexed: 01/23/2023] Open
Abstract
Metabolic disorders can lead to a scarcity or excess of certain metabolites such as glucose, lipids, proteins, purines, and metal ions, which provide the biochemical foundation and directly contribute to the etiology of metabolic diseases. Nonalcoholic fatty liver disease, obesity, and cancer are common metabolic disorders closely associated with abnormal lipid metabolism. In this review, we first describe the regulatory machinery of lipid metabolism and its deregulation in metabolic diseases. Next, we enumerate and integrate the mechanism of action of some natural compounds, including terpenoids and flavonoids, to ameliorate the development of metabolic diseases by targeting lipid metabolism. Medicinal natural products have an established history of use in health care and therapy. Natural compounds might provide a good source of potential therapeutic agents for treating or preventing metabolic diseases with lipid metabolic abnormalities.
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Affiliation(s)
- Can Cheng
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China
| | - Songming Zhuo
- Department of Respiratory Medicine, Shenzhen Longgang Center Hospital, Shenzhen, Guangdong 518116, PR China
| | - Bo Zhang
- Department of Ultrasound Imaging,Xiangya Hospital,Central South University, Changsha, Hunan 410078, PR China
| | - Xu Zhao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China
| | - Ying Liu
- Department of Medicine, Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China
| | - Chaoliang Liao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China
| | - Jing Quan
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China
| | - Zhenzhen Li
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Ya Cao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China.,Molecular Imaging Research Center of Central South University, Changsha, Hunan 410078, China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China.,Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, Hunan 410078, PR China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, Hunan 410078,PR China.,Molecular Imaging Research Center of Central South University, Changsha, Hunan 410078, China
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Liu Y, Liao L, Chen Y, Han F. Effects of daphnetin on lipid metabolism, insulin resistance and oxidative stress in OA‑treated HepG2 cells. Mol Med Rep 2019; 19:4673-4684. [PMID: 30957185 PMCID: PMC6522799 DOI: 10.3892/mmr.2019.10139] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 03/27/2019] [Indexed: 01/07/2023] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, and has high rates of morbidity and mortality worldwide. Daphnetin (DAP) possesses notable antioxidative, anti‑inflammatory and anticoagulant activities; DAP is an active ingredient extracted from Daphne Koreana Nakai. To investigate the effects and the underlying mechanism of DAP on NAFLD, we treated HepG2 cells with oleic acid (OA) and DAP simultaneously and non‑simultaneously. In the simultaneous treatment condition, HepG2 cells were co‑treated with 0.5 mM OA and DAP (5, 20, and 50 µM) for 24 h. In the non‑simultaneous treatment conditions, HepG2 cells were pretreated with 0.5 mM OA for 24 h, and then treated with DAP (5, 20 and 50 µM) for 24 h. Following the aforementioned treatments, the biochemical indexes associated with NAFLD were measured as follows: i) The intracellular contents of triglyceride (TG), reactive oxygen species (ROS) and fluorescent glucose 2‑[N‑(7‑nitrobenz‑2‑oxa‑1,3‑diazol‑4‑yl) amino]‑2‑deoxyglucose were analyzed with corresponding detection kits; and ii) the cellular expression levels of glycolipid metabolism‑ and oxidative stress‑related genes, including 5'AMP‑activated protein kinase (AMPK), sterol regulatory element‑binding protein‑1C (SREBP‑1C), patatin‑like phospholipase domain‑containing protein 3 (PNPLA3), peroxisome proliferator‑activated receptor α (PPARα), phosphoinositide 3‑kinase (PI3K), protein kinase B (AKT), nuclear factor‑like 2 (Nrf2), cytochrome P450 (CYP) 2E1 and CYP4A were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. The results revealed the potential mechanism underlying the effects of DAP on NAFLD in vitro: i) By increasing the phosphorylation of AMPK, DAP inhibited the expression of SREBP‑1C and PNPLA3, and induced that of PPARα. Lipid accumulation within hepatocytes was reduced; ii) by upregulating PI3K expression and pAKT/AKT levels, DAP may alleviate insulin resistance and promote hepatocellular glucose uptake; and iii) by upregulating the expression of Nrf2, DAP downregulated the expression of CYP2E1 and CYP4A, and the levels of reactive oxygen species in hepatocytes.
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Affiliation(s)
- Yayun Liu
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Lu Liao
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Yong Chen
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
| | - Fengmei Han
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National and Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan, Hubei 430062, P.R. China
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36
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Lee C, Kim J, Wang S, Sung S, Kim N, Lee HH, Seo YS, Jung Y. Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Int J Mol Sci 2019; 20:2369. [PMID: 31086120 PMCID: PMC6539514 DOI: 10.3390/ijms20092369] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/03/2019] [Accepted: 05/08/2019] [Indexed: 12/15/2022] Open
Abstract
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD.
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Affiliation(s)
- Chanbin Lee
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Jieun Kim
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Sihyung Wang
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Sumi Sung
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Namgyu Kim
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Hyun-Hee Lee
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Young-Su Seo
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
- Department of Microbiological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
| | - Youngmi Jung
- Department of Integrated Biological Science, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
- Department of Biological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Geumjeong-gu, Pusan 46241, Korea.
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D'Adamo E, Castorani V, Nobili V. The Liver in Children With Metabolic Syndrome. Front Endocrinol (Lausanne) 2019; 10:514. [PMID: 31428049 PMCID: PMC6687849 DOI: 10.3389/fendo.2019.00514] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as an emerging health risk in obese children and adolescents. NAFLD represents a wide spectrum of liver conditions, ranging from asymptomatic steatosis to steatohepatitis. The growing prevalence of fatty liver disease in children is associated with an increased risk of metabolic and cardiovascular complications. NAFLD is considered the hepatic manifestation of Metabolic Syndrome (MetS) and several lines of evidence have reported that children with NAFLD present one or more features of MetS. The pathogenetic mechanisms explaining the interrelationships between fatty liver disease and MetS are not clearly understood. Altough central obesity and insulin resistance seem to represent the core of the pathophysiology in both diseases, genetic susceptibility and enviromental triggers are emerging as crucial components promoting the development of NAFLD and MetS in children. In the present review we have identified and summarizied studies discussing current pathogenetic data of the association between NAFLD and MetS in children.
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Affiliation(s)
- Ebe D'Adamo
- Department of Neonatology, University of Chieti, Chieti, Italy
- *Correspondence: Ebe D'Adamo
| | | | - Valerio Nobili
- Department of Pediatrics, University “La Sapienza”, Rome, Italy
- Hepatology, Gastroenterology and Nutrition Unit, IRCCS “Bambino Gesù” Children's Hospital, Rome, Italy
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38
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Oriquat GA. Therapeutic effects of Spirulina against experimentally-induced non-alcoholic fatty liver in rats may involve miR-21, -34a and -122. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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39
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Mansouri A, Gattolliat CH, Asselah T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology 2018; 155:629-647. [PMID: 30012333 DOI: 10.1053/j.gastro.2018.06.083] [Citation(s) in RCA: 534] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 05/23/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022]
Abstract
Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol-associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid β-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug-associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically.
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Affiliation(s)
- Abdellah Mansouri
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France
| | - Charles-Henry Gattolliat
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France
| | - Tarik Asselah
- Centre de Recherche sur l'Inflammation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1149, Université Paris Diderot, PRES Paris Sorbonne Cité, Paris, France; Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Clichy, France.
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40
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Örd T, Örd D, Örd T. TRIB3 limits FGF21 induction during in vitro and in vivo nutrient deficiencies by inhibiting C/EBP-ATF response elements in the Fgf21 promoter. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018; 1861:271-281. [PMID: 29378327 DOI: 10.1016/j.bbagrm.2018.01.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/21/2018] [Accepted: 01/22/2018] [Indexed: 12/11/2022]
Abstract
Mammals must be able to endure periods of limited food availability, and the liver plays a central role in the adaptation to nutritional stresses. TRIB3 (Tribbles homolog 3) is a cellular stress-inducible gene with a liver-centric expression pattern and it has been implicated in stress response regulation and metabolic control. In the current article, we study the involvement of TRIB3 in responses to nutrient deficiencies, including fasting for up to 48 h in mice. We show that hepatic expression of Trib3 is increased after 48 h of fasting and mice with a targeted deletion of the Trib3 gene present elevated hepatic triglyceride content and liver weight at 48 h, along with an upregulation of lipid utilization genes in the liver. Further, hepatic and serum levels of the metabolic stress hormone FGF21 are considerably increased in 48-h-fasted Trib3 knockout mice compared to wild type. Trib3 deficiency also leads to elevated FGF21 levels in the mouse liver during essential amino acid deficiency and in cultured mouse embryonic fibroblasts during glucose starvation. Reporter assays reveal that TRIB3 regulates FGF21 by inhibiting ATF4-mediated, C/EBP-ATF site-dependent activation of Fgf21 transcription. Based on chromatin immunoprecipitation from mouse liver, the binding of TRIB3 and ATF4, a transcription factor known to physically interact with TRIB3, is significantly increased at the Fgf21 promoter following 48 h of fasting. Thus, under nutrient-limiting conditions that stimulate ATF4 activity, TRIB3 is implicated in the regulation of metabolic adaptation by restraining the transcription of Fgf21.
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Affiliation(s)
- Tiit Örd
- Estonian Biocentre, Institute of Genomics, University of Tartu, Riia 23b, 51010 Tartu, Estonia
| | - Daima Örd
- Estonian Biocentre, Institute of Genomics, University of Tartu, Riia 23b, 51010 Tartu, Estonia
| | - Tõnis Örd
- Estonian Biocentre, Institute of Genomics, University of Tartu, Riia 23b, 51010 Tartu, Estonia.
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Nagy L. Mechanisms of Hepatic Steatosis. COMPREHENSIVE TOXICOLOGY 2018:296-309. [DOI: 10.1016/b978-0-12-801238-3.95662-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Papandreou C, Bullò M, Tinahones FJ, Martínez-González MÁ, Corella D, Fragkiadakis GA, López-Miranda J, Estruch R, Fitó M, Salas-Salvadó J. Serum metabolites in non-alcoholic fatty-liver disease development or reversion; a targeted metabolomic approach within the PREDIMED trial. Nutr Metab (Lond) 2017; 14:58. [PMID: 28878811 PMCID: PMC5581927 DOI: 10.1186/s12986-017-0213-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 08/16/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Limited prospective studies have examined changes in non-alcoholic fatty-liver disease (NAFLD) related serum-metabolites and none the effects of NAFLD-reversion. We aimed to evaluate whether perturbations in metabolites indicate predisposition to NAFLD development and to assess the effects of NAFLD reversion on metabolite profiles. METHODS A targeted liquid-chromatography tandem mass-spectrometry metabolic profiling (n = 453 metabolites) approach was applied, using serum from 45 subjects of the PREDIMED study, at baseline and after a median 3.8-year follow-up. NAFLD was determined using the hepatic steatosis index; with three groups classified and studied: Group 1, not characterized as NAFLD cases during the follow-up (n = 15); Group 2, characterized as NAFLD during the follow-up (n = 15); Group 3, characterized as NAFLD-reversion during the follow-up (n = 15). RESULTS At baseline, significantly lower storage and transport lipids (triacylglycerols and cholesteryl esters), several monoetherglycerophosphocholines, acylglycerophosphocholines, ceramides and ceramide to sphingomyelin ratio (P < 0.05), were found; whereas a higher L-cystine to L-glutamate ratio (P < 0.05) was observed, in group 2 as compared to group 1.P-ether acylglycerophosphocholines, ceramides and sphingolipids were significantly different betweengroup 3 and group 1 (P < 0.05). Higher 16:1n-7 to 16:0, and 18:0 to16:0 ratio (P < 0.05), while lower 18:1n-9 to 18:0, 16:0 to 18:2n-6, and 18:3n-6 to 18:2n-6 ratio (P < 0.05) were observed in the final, compared to baseline values, in groups 2 and 3. CONCLUSION The rearrangement of lipid biosynthesis and serum transport may indicate predisposition to NAFLD development. Despite an expected reduction of hepatic lipotoxicity and improved hepatic function in the participants of the study characterized as NAFLD-reversing, the side effects of NAFLD in serum metabolic profiles remained present. TRIAL REGISTRATION The trial is registered at ISRCTN35739639. Registration date: 5th October 2005.
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Affiliation(s)
- Christopher Papandreou
- Human Nutrition Department, Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Mònica Bullò
- Human Nutrition Department, Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
| | - Francisco José Tinahones
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Clínico Virgen de la Victoria/Universidad de Málaga, Malaga, Spain
| | - Miguel Ángel Martínez-González
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain
| | - Dolores Corella
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Preventive Medicine, University of Valencia, Valencia, Spain
| | | | - José López-Miranda
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Lipid and Atherosclerosis Unit, Department of Internal Medicine, Reina Sofia University Hospital, IMIBIC, University of Cordoba, Cordoba, Spain
| | - Ramon Estruch
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Department of Internal Medicine, Hospital Clínic, IDIBAPS, Barcelona, Spain
| | - Montserrat Fitó
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Human Nutrition Unit, Faculty of Medicine and Health Sciences, Universitat Rovira i Virgili, St/Sant Llorenç 21, 43201 Reus, Spain
| | - Jordi Salas-Salvadó
- Human Nutrition Department, Hospital Universitari Sant Joan, Institut d’Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain
- Ciber Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar, Barcelona, Spain
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Hall Z, Bond NJ, Ashmore T, Sanders F, Ament Z, Wang X, Murray AJ, Bellafante E, Virtue S, Vidal‐Puig A, Allison M, Davies SE, Koulman A, Vacca M, Griffin JL. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology 2017; 65:1165-1180. [PMID: 27863448 PMCID: PMC5396354 DOI: 10.1002/hep.28953] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 11/11/2016] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. CONCLUSION NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180).
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Affiliation(s)
- Zoe Hall
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- MRC Human Nutrition ResearchCambridgeUnited Kingdom
| | | | - Tom Ashmore
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | | | | | - Xinzhu Wang
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
| | - Andrew J. Murray
- Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUnited Kingdom
| | | | - Sam Virtue
- Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke's HospitalUniversity of CambridgeCambridgeUnited Kingdom
| | - Antonio Vidal‐Puig
- Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke's HospitalUniversity of CambridgeCambridgeUnited Kingdom
| | - Michael Allison
- Liver Unit, Department of MedicineCambridge University Hospitals NHS Foundation TrustCambridgeUnited Kingdom
| | - Susan E. Davies
- Department of HistopathologyCambridge University Hospitals NHS Foundation TrustCambridgeUnited Kingdom
| | | | - Michele Vacca
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- MRC Human Nutrition ResearchCambridgeUnited Kingdom
- Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke's HospitalUniversity of CambridgeCambridgeUnited Kingdom
| | - Julian L. Griffin
- Department of Biochemistry and Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUnited Kingdom
- MRC Human Nutrition ResearchCambridgeUnited Kingdom
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Does Nutrition Matter in Liver Disease? LIVER PATHOPHYSIOLOGY 2017. [DOI: 10.1016/b978-0-12-804274-8.00053-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Nonalcoholic steatohepatitis (NASH) has become a major cause of cirrhosis and liver-related deaths worldwide. NASH is strongly associated with obesity and the metabolic syndrome, conditions that cause lipid accumulation in hepatocytes (hepatic steatosis). It is not well understood why some, but not other, individuals with hepatic steatosis develop NASH. The factors that determine whether or not NASH progresses to cirrhosis are also unclear. This review summarizes key components of NASH pathogenesis and discusses how inherent and acquired variations in regulation of these processes impact the risk for NASH and NASH cirrhosis.
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Affiliation(s)
- Ayako Suzuki
- Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
| | - Anna Mae Diehl
- Division of Gastroenterology, School of Medicine, Duke University, Durham, North Carolina 27710;
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Clemente MG, Mandato C, Poeta M, Vajro P. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions. World J Gastroenterol 2016; 22:8078-8093. [PMID: 27688650 PMCID: PMC5037077 DOI: 10.3748/wjg.v22.i36.8078] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/04/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.
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Salvia R, D'Amore S, Graziano G, Capobianco C, Sangineto M, Paparella D, de Bonfils P, Palasciano G, Vacca M. Short-term benefits of an unrestricted-calorie traditional Mediterranean diet, modified with a reduced consumption of carbohydrates at evening, in overweight-obese patients. Int J Food Sci Nutr 2016; 68:234-248. [PMID: 27615385 DOI: 10.1080/09637486.2016.1228100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The Mediterranean diet (MeD) is believed to promote health; nevertheless, changes in the nutritional patterns in the Mediterranean area (increased intake of refined carbohydrates/saturated fats; reduced fibers intake; main calorie load shifted to dinner) led to reduced MeD benefits in recent decades. We retrospectively investigated the effects of a MeD with a low intake of refined carbohydrates in the evening ("MeDLowC") on body weight (BW) and metabolic profile of overweight/obese subjects. According to their adherence to MeDLowC, subjects were classified into 44 (41%) individuals with "excellent" adherence and 63 (59%) with "poor" adherence. Nutritional counseling induced an improvement in BW, glucose metabolism and liver transaminases in both groups, with an increased magnitude of these effects in the "Excellent" adherence group. "Excellent" adherence to MeDLowC improved insulin sensitivity and lipid metabolism. In conclusion, MeD with a restriction of carbohydrates in the evening significantly ameliorates obesity and associated metabolic complications.
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Affiliation(s)
- Roberto Salvia
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy.,b Dipartimento Interdisciplinare di Medicina , University of Bari "Aldo Moro" , Bari , Italy
| | - Simona D'Amore
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy.,c National Cancer Research Centre , IRCCS Istituto Oncologico Giovanni Paolo II , Bari , Italy
| | - Giusi Graziano
- c National Cancer Research Centre , IRCCS Istituto Oncologico Giovanni Paolo II , Bari , Italy
| | - Caterina Capobianco
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy
| | - Moris Sangineto
- b Dipartimento Interdisciplinare di Medicina , University of Bari "Aldo Moro" , Bari , Italy
| | - Domenico Paparella
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy
| | - Paola de Bonfils
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy
| | - Giuseppe Palasciano
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy
| | - Michele Vacca
- a Clinica Medica "Augusto Murri", University of Bari "Aldo Moro" , Bari , Italy.,b Dipartimento Interdisciplinare di Medicina , University of Bari "Aldo Moro" , Bari , Italy
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