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Ye J, Shi R, Wu X, Fan H, Zhao Y, Hu X, Wang L, Bo X, Li D, Ge Y, Wang D, Xia B, Zhao Z, Xiao C, Zhao B, Wang Y, Liu X. Stevioside mitigates metabolic dysregulation in offspring induced by maternal high-fat diet: the role of gut microbiota-driven thermogenesis. Gut Microbes 2025; 17:2452241. [PMID: 39838262 DOI: 10.1080/19490976.2025.2452241] [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: 08/15/2024] [Revised: 12/08/2024] [Accepted: 01/07/2025] [Indexed: 01/23/2025] Open
Abstract
Maternal obesity poses a significant threat to the metabolic profiles of offspring. Microorganisms acquired from the mother early in life critically affect the host's metabolic functions. Natural non-nutritive sweeteners, particularly stevioside (STV), play a crucial role in reducing obesity and affecting gut microbiota composition. Based on this, we hypothesized that maternal STV supplementation could improve the health of mothers and offspring by altering their gut microbiota. Our study found that maternal STV supplementation reduced obesity during pregnancy, decreased abnormal lipid accumulation in offspring mice caused by maternal obesity, and modified the gut microbiota of both dams and offspring, notably increasing the abundance of Lactobacillus apodemi (L. apodemi). Co-housing and fecal microbiota transplant experiments confirmed that gut microbiota mediated the effects of STV on metabolic disorders. Furthermore, treatment with L. apodemi alone replicated the beneficial effects of STV, which were associated with increased thermogenesis. In summary, maternal STV supplementation could alleviate lipid metabolic disorders in offspring by enhancing L. apodemi levels and promoting thermogenic activity, potentially involving changes in bile acid metabolism pathways.
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Affiliation(s)
- Jin Ye
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
- Institute of Biology, Gansu Academy of Sciences, Lanzhou, China
| | - Renjie Shi
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Xiaoning Wu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Hua Fan
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Yapei Zhao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Xinyun Hu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Lulu Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Xiaowei Bo
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Dongning Li
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Yunshu Ge
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Danna Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Bing Xia
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Zhenting Zhao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Chunxia Xiao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Beita Zhao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Yutang Wang
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Xuebo Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
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Allen AM, Younossi ZM, Diehl AM, Charlton MR, Lazarus JV. Envisioning how to advance the MASH field. Nat Rev Gastroenterol Hepatol 2024; 21:726-738. [PMID: 38834817 DOI: 10.1038/s41575-024-00938-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2024] [Indexed: 06/06/2024]
Abstract
Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.
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Affiliation(s)
- Alina M Allen
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, VA, USA
- The Global NASH Council, Washington DC, USA
| | | | - Michael R Charlton
- Center for Liver Diseases, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Jeffrey V Lazarus
- The Global NASH Council, Washington DC, USA.
- CUNY Graduate School of Public Health and Health Policy (CUNY SPH), New York, NY, USA.
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain.
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
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Zhang L, El-Shabrawi M, Baur LA, Byrne CD, Targher G, Kehar M, Porta G, Lee WS, Lefere S, Turan S, Alisi A, Weiss R, Faienza MF, Ashraf A, Sundaram SS, Srivastava A, De Bruyne R, Kang Y, Bacopoulou F, Zhou YH, Darma A, Lupsor-Platon M, Hamaguchi M, Misra A, Méndez-Sánchez N, Ng NBH, Marcus C, Staiano AE, Waheed N, Alqahtani SA, Giannini C, Ocama P, Nguyen MH, Arias-Loste MT, Ahmed MR, Sebastiani G, Poovorawan Y, Al Mahtab M, Pericàs JM, Reverbel da Silveira T, Hegyi P, Azaz A, Isa HM, Lertudomphonwanit C, Farrag MI, Nugud AAA, Du HW, Qi KM, Mouane N, Cheng XR, Al Lawati T, Fagundes EDT, Ghazinyan H, Hadjipanayis A, Fan JG, Gimiga N, Kamal NM, Ștefănescu G, Hong L, Diaconescu S, Li M, George J, Zheng MH. An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease. MED 2024; 5:797-815.e2. [PMID: 38677287 DOI: 10.1016/j.medj.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/20/2024] [Accepted: 03/26/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).
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Affiliation(s)
- Le Zhang
- Department of Paediatrics, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, China
| | - Mortada El-Shabrawi
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Louise A Baur
- Children's Hospital Westmead Clinical School, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; National Institute for Health and Care Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy; Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Gilda Porta
- Pediatric Hepatology, Transplant Unit, Hospital Sírio-Libanês, Hospital Municipal Infantil Menino Jesus, Sau Paulo, Brazil
| | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Sander Lefere
- Hepatology Research Unit, Department Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Serap Turan
- Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Turkey
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Ram Weiss
- Department of Pediatrics, Ruth Children's Hospital, Rambam Medical Center and the Bruce Rappaport School of Medicine, Technion, Haifa, Israel
| | - Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", Bari, Italy
| | - Ambika Ashraf
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shikha S Sundaram
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Pediatric Liver Center, Children's Hospital Colorado, University of Colorado School of Medicine and Anschutz Medical Campus, Aurora, CO, USA
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ruth De Bruyne
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Yunkoo Kang
- Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Flora Bacopoulou
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, Aghia Sophia Children's Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; University Research Institute of Maternal and Child Health & Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Yong-Hai Zhou
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Andy Darma
- Department of Pediatrics, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Monica Lupsor-Platon
- Department of Medical Imaging, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; "Prof. Dr. O. Fodor" Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Anoop Misra
- Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation, New Delhi, India
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Nicholas Beng Hui Ng
- Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, National University Hospital, Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Claude Marcus
- Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | | | - Nadia Waheed
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Saleh A Alqahtani
- Organ Transplantation Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | - Ponsiano Ocama
- Department of Internal Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA; Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
| | - Maria Teresa Arias-Loste
- Hospital Universitario Marqués de Valdecilla, Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Mohamed Rabea Ahmed
- Department of Pediatrics, Jahra Hospital, Kuwait and Department of Pediatrics, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology and Division of Infectious Diseases, McGill University Health Centre, Montreal, QC, Canada
| | - Yong Poovorawan
- Centre of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Juan M Pericàs
- Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | | | - Peter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Center for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Amer Azaz
- Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Hasan M Isa
- Pediatric Department, Salmaniya Medical Complex and Pediatric Department, Arabian Gulf University, Manama, Bahrain
| | - Chatmanee Lertudomphonwanit
- Division of Gastroenterology, Department of Paediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Mona Issa Farrag
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Abd Alwahab Nugud
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hong-Wei Du
- Department of Paediatrics, First Hospital of Jilin University, Changchun, China
| | - Ke-Min Qi
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Nezha Mouane
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Academic Children's Hospital Ibn Sina, Mohammed V University, Rabat, Morocco
| | - Xin-Ran Cheng
- Department of Paediatric Genetics, Endocrinology and Metabolism, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | | | - Eleonora D T Fagundes
- Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Hasmik Ghazinyan
- Department of Hepatology, Nikomed Medical Center, Yerevan, Armenia
| | | | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Nicoleta Gimiga
- Clinical Department of Pediatric Gastroenterology, "St. Mary" Emergency Children's Hospital, Iași, Romania; Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iași, Romania
| | - Naglaa M Kamal
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt; Pediatric Hepatology and Gastroenterology, Alhada Armed Forces Hospital, Taif, Saudi Arabia
| | - Gabriela Ștefănescu
- Department of Gastroenterology, "Grigore T. Popa" University of Medicine and Pharmacy, Iași, Romania
| | - Li Hong
- Department of Clinical Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Smaranda Diaconescu
- Medical-Surgical Department, Faculty of Medicine, University "Titu Maiorescu", Bucuresti, Romania
| | - Ming Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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Leca BM, Lagojda L, Kite C, Karteris E, Kassi E, Randeva HS, Kyrou I. Maternal obesity and metabolic (dysfunction) associated fatty liver disease in pregnancy: a comprehensive narrative review. Expert Rev Endocrinol Metab 2024; 19:335-348. [PMID: 38860684 DOI: 10.1080/17446651.2024.2365791] [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: 01/11/2024] [Accepted: 06/05/2024] [Indexed: 06/12/2024]
Abstract
INTRODUCTION Obesity and metabolic-associated fatty liver disease (MAFLD) during pregnancy constitute significant problems for routine antenatal care, with increasing prevalence globally. Similar to obesity, MAFLD is associated with a higher risk for maternal complications (e.g. pre-eclampsia and gestational diabetes) and long-term adverse health outcomes for the offspring. However, MAFLD during pregnancy is often under-recognized, with limited management/treatment options. AREAS COVERED PubMed/MEDLINE, EMBASE, and Scopus were searched based on a search strategy for obesity and/or MAFLD in pregnancy to identify relevant papers up to 2024. This review summarizes the pertinent evidence on the relationship between maternal obesity and MAFLD during pregnancy. Key mechanisms implicated in the underlying pathophysiology linking obesity and MAFLD during pregnancy (e.g. insulin resistance and dysregulated adipokine secretion) are highlighted. Moreover, a diagnostic approach for MAFLD diagnosis during pregnancy and its complications are presented. Finally, promising relevant areas for future research are covered. EXPERT OPINION Research progress regarding maternal obesity, MAFLD, and their impact on maternal and fetal/offspring health is expected to improve the relevant diagnostic methods and lead to novel treatments. Thus, routine practice could apply more personalized management strategies, incorporating individualized algorithms with genetic and/or multi-biomarker profiling to guide prevention, early diagnosis, and treatment.
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Affiliation(s)
- Bianca M Leca
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Lukasz Lagojda
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Clinical Evidence-Based Information Service (CEBIS), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Chris Kite
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, UK
- Chester Medical School, University of Chester, Shrewsbury, UK
| | - Emmanouil Karteris
- College of Health, Medicine and Life Sciences, Division of Biosciences, Brunel University London, Uxbridge, UK
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Warwick Medical School, University of Warwick, Coventry, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, UK
- Institute of Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Warwick Medical School, University of Warwick, Coventry, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, UK
- Institute of Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, UK
- College of Health, Psychology and Social Care, University of Derby, Derby, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece
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Sugino KY, Janssen RC, McMahan RH, Zimmerman C, Friedman JE, Jonscher KR. Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response. Nutrients 2024; 16:1808. [PMID: 38931163 PMCID: PMC11206590 DOI: 10.3390/nu16121808] [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: 05/09/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of Il10 (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of Lactobacillus in GF offspring. Further, the expression of Il10 was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of Il10. Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways.
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Affiliation(s)
- Kameron Y. Sugino
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.Y.S.); (R.C.J.); (J.E.F.)
| | - Rachel C. Janssen
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.Y.S.); (R.C.J.); (J.E.F.)
| | - Rachel H. McMahan
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Chelsea Zimmerman
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Jacob E. Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.Y.S.); (R.C.J.); (J.E.F.)
- Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Karen R. Jonscher
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.Y.S.); (R.C.J.); (J.E.F.)
- Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Chen H, Wu Q, Chen X, Yu X, Zhao H, Huang Q, Huang Y, Wang J, Huang X, Wei J, Wu F, Xiao X, Wang L. Gestational supplementation of Bifidobacterium, Lactobacillus, and Streptococcus thermophilus attenuates hepatic steatosis in offspring mice through promoting fatty acid β-oxidation. J Food Sci 2024; 89:3064-3077. [PMID: 38578136 DOI: 10.1111/1750-3841.17056] [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: 10/11/2023] [Revised: 03/03/2024] [Accepted: 03/15/2024] [Indexed: 04/06/2024]
Abstract
Currently, Bifidobacterium, Lactobacillus, and Streptococcus thermophilus (BLS) are widely recognized as the crucially beneficial bacteria in the gut. Many preclinical and clinical studies have shown their protective effects against non-alcoholic fatty liver disease (NAFLD). However, whether gestational BLS supplementation could alleviate NAFLD in the offspring is still unknown. Kunming mice were given a high-fat diet (HFD) for 4 weeks before mating. They received BLS supplementation by gavage during pregnancy. After weaning, offspring mice were fed with a regular diet up to 5 weeks old. Gestational BLS supplementation significantly increased the abundance of Actinobacteriota, Bifidobacterium, and Faecalibaculum in the gut of dams exposed to HFD. In offspring mice exposed to maternal HFD, maternal BLS intake significantly decreased the ratio of Firmicutes to Bacteroidetes as well as the relative abundance of Prevotella and Streptococcus, but increased the relative abundance of Parabacteroides. In offspring mice, maternal BLS supplementation significantly decreased the hepatic triglyceride content and mitigated hepatic steatosis. Furthermore, maternal BLS supplementation increased the glutathione content and reduced malondialdehyde content in the liver. In addition, mRNA and protein expression levels of key rate-limiting enzymes in mitochondrial β-oxidation (CPT1α, PPARα, and PGC1α) in the livers of offspring mice were significantly increased after gestational BLS supplementation. Thus, gestational BLS supplementation may ameliorate maternal HFD-induced steatosis and oxidative stress in the livers of offspring mice by modulating fatty acid β-oxidation.
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Affiliation(s)
- Hangjun Chen
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Qiongmei Wu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Xingyi Chen
- Liwan District Maternal and Child Health Hospital, Guangzhou, People's Republic of China
| | - Xinxue Yu
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Hanqing Zhao
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Qiaoli Huang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Yurong Huang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Jinting Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Xueyi Huang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
| | - Jun Wei
- Department of Science and Technology, Guangzhou Customs, Guangzhou, People's Republic of China
| | - Feng Wu
- Department of Science and Technology, Guangzhou Customs, Guangzhou, People's Republic of China
| | - Xiaomin Xiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Lijun Wang
- Department of Nutrition, School of Medicine, Jinan University, Guangzhou, People's Republic of China
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Choudhary D, Andreani GA, Mahmood S, Wen X, Patel MS, Rideout TC. Postnatal Consumption of Black Bean Powder Protects against Obesity and Dyslipidemia in Male Adult Rat Offspring from Obese Pregnancies. Nutrients 2024; 16:1029. [PMID: 38613062 PMCID: PMC11013182 DOI: 10.3390/nu16071029] [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: 02/27/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The adverse influence of maternal obesity on offspring metabolic health throughout the life-course is a significant public health challenge with few effective interventions. We examined if black bean powder (BBP) supplementation to a high-calorie maternal pregnancy diet or a postnatal offspring diet could offer protection against the metabolic programming of metabolic disease risk in adult offspring. Female Sprague Dawley rats were randomly assigned to one of three diets (n = 10/group) for a 3-week pre-pregnancy period and throughout gestation and lactation: (i) a low-caloric control diet (CON); (ii) a high-caloric obesity-inducing diet (HC); or (iii) the HC diet with 20% black bean powder (HC-BBP). At weaning [postnatal day (PND) 21], one male pup from each dam was weaned onto the CON diet throughout the postnatal period until adulthood (PND120). In addition, a second male from the HC group only was weaned onto the CON diet supplemented with BBP (CON-BBP). Thus, based on the maternal diet exposure and offspring postnatal diet, four experimental adult offspring groups were compared: CON/CON, HC/CON, HC-BPP/CON, and HC/CON-BBP. On PND120, blood was collected for biochemical analysis (e.g., lipids, glycemic control endpoints, etc.), and livers were excised for lipid analysis (triglycerides [TG] and cholesterol) and the mRNA/protein expression of lipid-regulatory targets. Compared with the CON/CON group, adult offspring from the HC/CON group exhibited a higher (p < 0.05) body weight (BW) (682.88 ± 10.67 vs. 628.02 ± 16.61 g) and hepatic TG (29.55 ± 1.31 vs. 22.86 ± 1.85 mmol/g). Although maternal BBP supplementation (HC-BBP/CON) had little influence on metabolic outcomes, the consumption of BBP in the postnatal period (HC/CON-BBP) lowered hepatic TG and cholesterol compared with the other treatment groups. Reduced hepatic TG in the HC/CON-BBP was likely associated with lower postnatal BW gain (vs. HC/CON), lower mRNA and protein expression of hepatic Fasn (vs. HC/CON), and lower serum leptin concentration (vs. CON/CON and HC groups). Our results suggest that the postnatal consumption of a black-bean-powder-supplemented diet may protect male rat offspring against the programming of obesity and dyslipidemia associated with maternal obesity. Future work should investigate the bioactive fraction of BBP responsible for the observed effect.
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Affiliation(s)
- Divya Choudhary
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY 14214, USA; (D.C.); (G.A.A.); (S.M.)
- Department of Pediatrics, Division of Behavioral Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA;
| | - Gabriella A. Andreani
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY 14214, USA; (D.C.); (G.A.A.); (S.M.)
| | - Saleh Mahmood
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY 14214, USA; (D.C.); (G.A.A.); (S.M.)
| | - Xiaozhong Wen
- Department of Pediatrics, Division of Behavioral Medicine, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA;
| | - Mulchand S. Patel
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA;
| | - Todd C. Rideout
- Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY 14214, USA; (D.C.); (G.A.A.); (S.M.)
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Fernandez CJ, Nagendra L, Pappachan JM. Metabolic Dysfunction-associated Fatty Liver Disease: An Urgent Call for Global Action. TOUCHREVIEWS IN ENDOCRINOLOGY 2024; 20:5-9. [PMID: 38812662 PMCID: PMC11132654 DOI: 10.17925/ee.2023.20.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/13/2023] [Indexed: 05/31/2024]
Abstract
There has been an exponential increase in the global prevalence of fatty liver disease in recent years in association with the obesity pandemic worldwide. 'Metabolic dysfunction-associated fatty liver disease', the new terminology adopted by an international panel of experts in 2020 to largely replace the old term 'non-alcoholic fatty liver disease', has now been accepted by most hepatologists and diabetologists across the globe. The term metabolic dysfunction-associated fatty liver disease was created to better reflect the metabolicand liver-specific manifestations and complications of fatty liver disease. It is important to disseminate our current understanding of this enigmatic disease among the global scientific fraternity. Recent publications, including articles from the latest issue of Endocrinology & Metabolism Clinics of North America, are attempting to fill this knowledge gap.
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Affiliation(s)
- Cornelius J Fernandez
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston, UK
| | - Lakshmi Nagendra
- Department of Endocrinology, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK
- Faculty of Science, Manchester Metropolitan University, Manchester, UK
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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Nairz J, Messner A, Kiechl SJ, Winder B, Hochmayr C, Egger AE, Griesmacher A, Geiger R, Griesmaier E, Pechlaner R, Knoflach M, Kiechl-Kohlendorfer U. Determinants of non-alcoholic fatty liver disease in young people: Maternal, neonatal, and adolescent factors. PLoS One 2024; 19:e0298800. [PMID: 38386674 PMCID: PMC10883560 DOI: 10.1371/journal.pone.0298800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 01/30/2024] [Indexed: 02/24/2024] Open
Abstract
AIM To assess the impact of maternal, neonatal, and adolescent factors on the development of non-alcoholic fatty liver disease (NAFLD) in a cohort of 14- to 19-year-old adolescents. METHODS This study is part of the Early Vascular Ageing in the YOUth study, a single-center cross-sectional study conducted in western Austria. Maternal and neonatal factors were extracted from the mother-child booklet, adolescent factors were evaluated by a face-to-face interview, physical examination, and fasting blood analyses. Liver fat content was assessed by controlled attenuation parameter (CAP) using signals acquired by FibroScan® (Echosense, Paris, France). The association of maternal, neonatal, and adolescent factors with CAP values was analyzed using linear regression models. RESULTS In total, 595 adolescents (27.2% male) aged 17.0 ± 1.3 years were included. 4.9% (n = 29) showed manifest NAFLD with CAP values above the 90th percentile. Male sex (p < 0.001), adolescent triglyceride levels (p = 0.021), Homeostatic Model Assessment for Insulin Resistance index and BMI z-score (p < 0.001, each) showed a significant association with liver fat content in the multivariable analysis. Maternal pre-pregnancy BMI was associated with CAP values after adjustment for sex, age, and birth weight for gestational age (p < 0.001), but this association was predominantly mediated by adolescent BMI (indirect effect b = 1.18, 95% CI [0.69, 1.77]). CONCLUSION Components of the metabolic syndrome were the most important predictors of adolescent liver fat content. Therefore, prevention of NAFLD should focus on lifestyle modification in childhood and adolescence.
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Affiliation(s)
- Johannes Nairz
- VASCage Research Centre on Vascular Ageing and Stroke, Innsbruck, Tyrol, Austria
- Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
- Department of Pediatrics III, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Alex Messner
- VASCage Research Centre on Vascular Ageing and Stroke, Innsbruck, Tyrol, Austria
- Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Sophia J. Kiechl
- VASCage Research Centre on Vascular Ageing and Stroke, Innsbruck, Tyrol, Austria
- Department of Neurology, Hochzirl Hospital, Zirl, Tyrol, Austria
| | - Bernhard Winder
- VASCage Research Centre on Vascular Ageing and Stroke, Innsbruck, Tyrol, Austria
- Department of Vascular Surgery, Feldkirch Hospital, Feldkirch, Vorarlberg, Austria
| | - Christoph Hochmayr
- Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Alexander E. Egger
- Central Institute of Medical and Chemical Laboratory Diagnostics (ZIMCL), University Hospital of Innsbruck, Innsbruck, Tyrol, Austria
| | - Andrea Griesmacher
- Central Institute of Medical and Chemical Laboratory Diagnostics (ZIMCL), University Hospital of Innsbruck, Innsbruck, Tyrol, Austria
| | - Ralf Geiger
- Department of Pediatrics III, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Elke Griesmaier
- Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Raimund Pechlaner
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
| | - Michael Knoflach
- VASCage Research Centre on Vascular Ageing and Stroke, Innsbruck, Tyrol, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
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10
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Lian V, Hinrichs H, Young M, Faerber A, Özler O, Xie Y, Ballentine SJ, Tarr PI, Davidson NO, Thompson MD. Maternal Obesogenic Diet Attenuates Microbiome-Dependent Offspring Weaning Reaction with Worsening of Steatotic Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:209-224. [PMID: 38029921 PMCID: PMC10835466 DOI: 10.1016/j.ajpath.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/15/2023] [Accepted: 11/07/2023] [Indexed: 12/01/2023]
Abstract
The mechanisms by which maternal obesity increases the susceptibility to steatotic liver disease in offspring are incompletely understood. Models using different maternal obesogenic diets (MODEs) display phenotypic variability, likely reflecting the influence of timing and diet composition. This study compared three maternal obesogenic diets using standardized exposure times to identify differences in offspring disease progression. This study found that the severity of hepatic inflammation and fibrosis in the offspring depends on the composition of the maternal obesogenic diet. Offspring cecal microbiome composition was shifted in all MODE groups relative to control. Decreased α-diversity in some MODE offspring with shifts in abundance of multiple genera were suggestive of delayed maturation of the microbiome. The weaning reaction typically characterized by a spike in intestinal expression of Tnfa and Ifng was attenuated in MODE offspring in an early microbiome-dependent manner using cross-fostering. Cross-fostering also switched the severity of disease progression in offspring dependent on the diet of the fostering dam. These results identify maternal diet composition and timing of exposure as modifiers in mediating transmissible changes in the microbiome. These changes in the early microbiome alter a critical window during weaning that drives susceptibility to progressive liver disease in the offspring.
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Affiliation(s)
- Vung Lian
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Holly Hinrichs
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Monica Young
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Austin Faerber
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Oğuz Özler
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Yan Xie
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Samuel J Ballentine
- Department of Pathology, Washington University School of Medicine, St. Louis, Missouri
| | - Phillip I Tarr
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Nicholas O Davidson
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Michael D Thompson
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
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11
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Karachaliou GS, Suzuki A, Patel VA, Bastian LA, Diehl AM, Abdelmalek MF. Longer Breastfeeding Duration Is Associated With Decreased Risk of Hepatic Fibrosis Among Young Women With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2024; 22:413-415.e3. [PMID: 37302447 DOI: 10.1016/j.cgh.2023.05.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/03/2023] [Accepted: 05/22/2023] [Indexed: 06/13/2023]
Affiliation(s)
- Georgia Sofia Karachaliou
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Ayako Suzuki
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
| | - Vaishali A Patel
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Lori A Bastian
- Department of Medicine, Yale University, New Haven, Connecticut; General Internal Medicine, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Manal F Abdelmalek
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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12
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Butt AS, Devi J. Polycystic ovary syndrome and nonalcoholic fatty liver disease. POLYCYSTIC OVARY SYNDROME 2024:92-99. [DOI: 10.1016/b978-0-323-87932-3.00021-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Manzhalii E, Tatarchuk T, Tutchenko T, Kosei N, Mnevets R. Relationships between nonalcoholic fatty liver disease and polycystic ovary syndrome. REPRODUCTIVE ENDOCRINOLOGY 2023:40-45. [DOI: 10.18370/2309-4117.2023.70.40-45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD) are two common non-infectious pathologies. Their frequency and medico-social significance have increased significantly over the past decades and reflect the effects of radical changes in human lifestyle on human health in a transgenerational aspect. Due to absence a complete understanding of the etiology and pathogenesis of PCOS and NAFLD, modern medicine still does not have etiopathogenetic methods of treating these frequent diseases. Considering epidemiological and pathogenetic data PCOS and NAFLD can be regarded as related pathologies, which creates the prospect of improving the effectiveness of their management if the joint approach to scientific research and implementation of their results in medical practice is applied.The purpose of the review is to summarize the current scientific data on the common pathophysiological and clinical relationships between PCOS and NAFLD, which can contribute to improving the effectiveness management of both diseases.Pathogenetic relationships between PCOS and NAFLD are bidirectional. According to current data, it seems possible to consider PCOS as a significant risk factor for the development of NAFLD in women of reproductive age both in the presence of excess weight and with normal body weight.As is known, that liver is involved in the clearance of androgens by the formation of sex steroid-binding globulin, as well as in the inactivation of insulin. Disruption of these metabolic processes due to liver pathology can lead to the development or strengthening of biochemical and clinical hyperandrogenism and the development of hyperinsulinemia and insulin resistance (IR).Conclusions. The presence of fatty liver and especially steatohepatitis deepens the hormonal disorders inherent in PCOS (primarily, an increase of free androgens, IR and ovulatory dysfunction), as well as potentiates and accelerates the development of cardiometabolic complications, including atherogenic dyslipidemia, dysglycemia, metabolic syndrome and cardiovascular complications. Early detection of NAFLD in women with PCOS, regardless of the presence of obesity, may improve the effectiveness of PCOS management and prevention of its cardiometabolic risks.
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Affiliation(s)
- E.H. Manzhalii
- O.O. Bogomolets National Medical University; Ukrainian Liver Foundation; Global Longevity Institute; Clinic Verum Expert, Kyiv
| | - T.F. Tatarchuk
- SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”;State Scientific Institution “Center for Innovative Medical Technologies of the NAS of Ukraine”, Kyiv
| | - T.M. Tutchenko
- SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”; SSI “Center for Innovative Medical Technologies of the NAS of Ukraine”; “Dila” Medical Laboratory, Kyiv
| | - N.V. Kosei
- SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”; SSI “Center for Innovative Medical Technologies of the NAS of Ukraine”, Kyiv
| | - R.O. Mnevets
- ESC “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv; SI “O.M. Lukyanova Institute of Pediatrics, Obstetrics and Gynecology of the NAMS of Ukraine”, Kyiv, Ukraine
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14
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Wayland JL, Doll JR, Lawson MJ, Stankiewicz TE, Oates JR, Sawada K, Damen MSMA, Alarcon PC, Haslam DB, Trout AT, DeFranco EA, Klepper CM, Woo JG, Moreno-Fernandez ME, Mouzaki M, Divanovic S. Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases. Nutrients 2023; 15:4958. [PMID: 38068816 PMCID: PMC10708424 DOI: 10.3390/nu15234958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/19/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.
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Affiliation(s)
- Jennifer L. Wayland
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jessica R. Doll
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Matthew J. Lawson
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Traci E. Stankiewicz
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jarren R. Oates
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Keisuke Sawada
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Michelle S. M. A. Damen
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Pablo C. Alarcon
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - David B. Haslam
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Andrew T. Trout
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Emily A. DeFranco
- Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Corie M. Klepper
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jessica G. Woo
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Maria E. Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Marialena Mouzaki
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Senad Divanovic
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
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15
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Scheidl T, Wager J, Baker L, Brightwell A, Melan K, Larion S, Sarr O, Regnault T, Urbanski S, Thompson J. High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring. Biosci Rep 2023; 43:BSR20231060. [PMID: 37706282 PMCID: PMC10550783 DOI: 10.1042/bsr20231060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.
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Affiliation(s)
- Taylor B. Scheidl
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Jessica L. Wager
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
| | - Larissa G. Baker
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Katrina M. Melan
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Sebastian Larion
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, U.S.A
| | - Ousseynou Sarr
- Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, Western University, London, ON, Canada
| | - Timothy RH. Regnault
- Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, Western University, London, ON, Canada
| | - Stefan J. Urbanski
- Department of Pathology, University of Calgary, Calgary, Alberta, Canada
| | - Jennifer A. Thompson
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
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Lonardo A, Suzuki A. Concise review: Breastfeeding, lactation, and NAFLD. An updated view of cross-generational disease transmission and prevention. METABOLISM AND TARGET ORGAN DAMAGE 2023; 3. [DOI: 10.20517/mtod.2023.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Evidence suggests that breastfeeding protects the mother-infant dyad against the development and progression of nonalcoholic fatty liver disease (NAFLD). In this context, we aim to provide insight into the most notable and representative epidemiological studies published in the literature. Furthermore, we will delve into the potential underlying pathomechanisms that might be involved in this relationship. The current definitions of breastfeeding, lactation, mother-infant dyad, and nonalcoholic fatty liver disease (NAFLD) are provided. Next, the epidemiological evidence supporting potential benefits for the (long-term) lactating mother in terms of protection from the development and progression of NAFLD is reviewed. The putative mechanisms underlying this protection are also analyzed. Similarly, clinical and epidemiological studies evaluating the benefits of breastfeeding for the offspring are examined, together with a discussion of the putative underlying mechanisms. In conclusion, our understanding of breastfeeding (for the offspring) and lactation (for the mother) as protective factors from NAFLD development and fibrotic progression will provide further insight into unprecedented disease mechanisms shared by the mother-infant dyad promising to interrupt the vicious cycle of NAFLD transmission across generations.
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17
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Wong VWS, Ekstedt M, Wong GLH, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol 2023; 79:842-852. [PMID: 37169151 DOI: 10.1016/j.jhep.2023.04.036] [Citation(s) in RCA: 222] [Impact Index Per Article: 111.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/29/2023] [Accepted: 04/25/2023] [Indexed: 05/13/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common liver disease globally and is currently estimated to affect 38% of the global population. Only a minority of patients with NAFLD will progress to cirrhosis or hepatocellular carcinoma, but from this vast population the total number of patients who are at risk of such severe outcomes is increasing. Worryingly, individuals are increasingly being affected by NAFLD at an earlier age, meaning there is more time for them to develop severe complications. With considerable changes in dietary composition and urbanisation, alongside the growth in obesity and type 2 diabetes in the global population, in particular in developing countries, the global proportion of persons affected by NAFLD is projected to increase further. Yet, there are large geographical discrepancies in the prevalence rates of NAFLD and its inflammatory component non-alcoholic steatohepatitis (NASH). Such differences are partly related to differing socio-economic milieus, but also to genetic predisposition. In this narrative review, we discuss recent changes in the epidemiology of NAFLD and NASH from regional and global perspectives, as well as in special populations. We also discuss the potential consequences of these changes on hepatic and extrahepatic events.
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Affiliation(s)
- Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.
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18
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Williamson C, Nana M, Poon L, Kupcinskas L, Painter R, Taliani G, Heneghan M, Marschall HU, Beuers U. EASL Clinical Practice Guidelines on the management of liver diseases in pregnancy. J Hepatol 2023; 79:768-828. [PMID: 37394016 DOI: 10.1016/j.jhep.2023.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 07/04/2023]
Abstract
Liver diseases in pregnancy comprise both gestational liver disorders and acute and chronic hepatic disorders occurring coincidentally in pregnancy. Whether related to pregnancy or pre-existing, liver diseases in pregnancy are associated with a significant risk of maternal and fetal morbidity and mortality. Thus, the European Association for the Study of Liver Disease invited a panel of experts to develop clinical practice guidelines aimed at providing recommendations, based on the best available evidence, for the management of liver disease in pregnancy for hepatologists, gastroenterologists, obstetric physicians, general physicians, obstetricians, specialists in training and other healthcare professionals who provide care for this patient population.
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19
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Wang L, O'Kane AM, Zhang Y, Ren J. Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy. Obes Rev 2023:e13567. [PMID: 37055041 DOI: 10.1111/obr.13567] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/08/2022] [Accepted: 03/25/2023] [Indexed: 04/15/2023]
Abstract
Maternal obesity leads to obstetric complications and a high prevalence of metabolic anomalies in the offspring. Among various contributing factors for maternal obesity-evoked health sequelae, developmental programming is considered as one of the leading culprit factors for maternal obesity-associated chronic comorbidities. Although a unified theory is still lacking to systematically address multiple unfavorable postnatal health sequelae, a cadre of etiological machineries have been put forward, including lipotoxicity, inflammation, oxidative stress, autophagy/mitophagy defect, and cell death. Hereinto, autophagy and mitophagy play an essential housekeeping role in the clearance of long-lived, damaged, and unnecessary cell components to maintain and restore cellular homeostasis. Defective autophagy/mitophagy has been reported in maternal obesity and negatively impacts fetal development and postnatal health. This review will provide an update on metabolic disorders in fetal development and postnatal health issues evoked by maternal obesity and/or intrauterine overnutrition and discuss the possible contribution of autophagy/mitophagy in metabolic diseases. Moreover, relevant mechanisms and potential therapeutic strategies will be discussed in an effort to target autophagy/mitophagy and metabolic disturbances in maternal obesity.
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Affiliation(s)
- Litao Wang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Aislinn M O'Kane
- Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA
| | - Yingmei Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
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20
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Mandato C, Panera N, Alisi A. Pregnancy and Metabolic-Associated Fatty Liver Disease. Endocrinol Metab Clin North Am 2023. [PMID: 37495342 DOI: 10.1016/j.ecl.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
Abstract
Metabolic-associated fatty liver disease (MAFLD), the term proposed to substitute nonalcoholic fatty liver disease, comprises not only liver features but also potentially associated metabolic dysfunctions. Since experimental studies in mice and retrospective clinical studies in humans investigated the association between nonalcoholic fatty liver disease during pregnancy and the adverse clinical outcomes in mothers and offspring, it is plausible that MAFLD may cause similar or worse effects on mother and the offspring. Only a few studies have investigated the possible association of maternal MAFLD with more severe pregnancy-related complications. This article provides an overview of the evidence for this dangerous liaison.
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21
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Jiang X, Wu Y, Zhong H, Zhang X, Sun X, Liu L, Cui X, Chi X, Ji C. Human milk-derived extracellular vesicles alleviate high fat diet-induced non-alcoholic fatty liver disease in mice. Mol Biol Rep 2023; 50:2257-2268. [PMID: 36575319 DOI: 10.1007/s11033-022-08206-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/13/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic lipid accumulation, imposes serious challenges on public health worldwide. Breastfeeding has been reported to reduce the risk of NAFLD. Extracellular vesicles (EVs) are bilayer membrane vesicles released from various cells into the extracellular space, participating in multiple life processes. Whether EVs from human milk exert metabolic benefits against NAFLD is worth investigating. METHODS AND RESULTS In this study, the EVs were isolated from human milk collected from healthy mothers and quantified. Functional analyses were performed using the NAFLD mouse model and free fatty acid (FFA)-stimulated mouse primary hepatocytes. The results showed that human milk-derived EVs could effectively alleviate high fat diet-induced hepatic steatosis and insulin resistance in mice with NAFLD via inhibiting lipogenesis and increasing lipolysis. The FFA-induced lipid accumulation was also inhibited in hepatocytes after treatment with human milk-derived EVs. Mechanistically, the human milk derived-EVs cargo (proteins and miRNAs), which linked to lipid metabolism, may be responsible for these beneficial effects. CONCLUSION The findings of this study highlighted the therapeutic benefits of human milk-derived EVs and provided a new strategy for NAFLD treatment.
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Affiliation(s)
- Xue Jiang
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yangyang Wu
- Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China
| | - Hong Zhong
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoxiao Zhang
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xingzhen Sun
- School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Li Liu
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xianwei Cui
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Xia Chi
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Chenbo Ji
- Department of Children Health Care, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,Nanjing Maternal and Child Health Institute, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China. .,School of Pediatrics, Nanjing Medical University, Nanjing, Jiangsu, China.
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22
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Melton PE, Burton MA, Lillycrop KA, Godfrey KM, Rauschert S, Anderson D, Burdge GC, Mori TA, Beilin LJ, Ayonrinde OT, Craig JM, Olynyk JK, Holbrook JD, Pennell CE, Oddy WH, Moses EK, Adams LA, Huang RC. Differential DNA methylation of steatosis and non-alcoholic fatty liver disease in adolescence. Hepatol Int 2023; 17:584-594. [PMID: 36737504 PMCID: PMC9897882 DOI: 10.1007/s12072-022-10469-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/11/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. APPROACH AND RESULTS We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value < 0.007. EWAS identified dmCpGs related to three genes (ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p < 2.3 × 10-3). CONCLUSIONS We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
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Affiliation(s)
- Phillip E. Melton
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Private Bag 23, Hobart, TAS 7000 Australia ,grid.1012.20000 0004 1936 7910School of Global and Population Health, The University of Western Australia, Crawley, WA Australia
| | - M. A. Burton
- grid.5491.90000 0004 1936 9297School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - K. A. Lillycrop
- grid.5491.90000 0004 1936 9297Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK ,grid.430506.40000 0004 0465 4079NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - K. M. Godfrey
- grid.430506.40000 0004 0465 4079NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK ,grid.5491.90000 0004 1936 9297MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - S. Rauschert
- grid.1012.20000 0004 1936 7910Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - D. Anderson
- grid.1012.20000 0004 1936 7910Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - G. C. Burdge
- grid.5491.90000 0004 1936 9297School of Human Health and Development, Faculty of Medicine, University of Southampton, Southampton, UK
| | - T. A. Mori
- grid.1012.20000 0004 1936 7910Medical School, The University of Western Australia, Perth, Australia
| | - L. J. Beilin
- grid.1012.20000 0004 1936 7910Medical School, The University of Western Australia, Perth, Australia
| | - O. T. Ayonrinde
- grid.1012.20000 0004 1936 7910Medical School, The University of Western Australia, Perth, Australia ,Department of Gastroenterology and Hepatology, Fiona Stanley and Fremantle Hospitals, Murdoch, WA Australia
| | - J. M. Craig
- grid.416107.50000 0004 0614 0346MCRI, Royal Children’s Hospital, Flemington Road, Parkville, VIC Australia ,grid.1021.20000 0001 0526 7079The Institute for Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Deakin University, Geelong, VIC Australia
| | - J. K. Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley and Fremantle Hospitals, Murdoch, WA Australia ,grid.1038.a0000 0004 0389 4302School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA Australia
| | - J. D. Holbrook
- grid.5491.90000 0004 1936 9297MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - C. E. Pennell
- grid.266842.c0000 0000 8831 109XUniversity of Newcastle, Newcastle, NSW Australia
| | - W. H. Oddy
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Private Bag 23, Hobart, TAS 7000 Australia
| | - E. K. Moses
- grid.1009.80000 0004 1936 826XMenzies Institute for Medical Research, University of Tasmania, 17 Liverpool Street, Private Bag 23, Hobart, TAS 7000 Australia ,grid.1012.20000 0004 1936 7910School of Biomedical Sciences, University of Western Australia, Crawley, WA Australia
| | - L. A. Adams
- grid.1012.20000 0004 1936 7910Medical School, The University of Western Australia, Perth, Australia
| | - R. C. Huang
- grid.1012.20000 0004 1936 7910Telethon Kids Institute, The University of Western Australia, Perth, Australia
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23
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Hinrichs H, Faerber A, Young M, Ballentine SJ, Thompson MD. Maternal Exercise Protects Male Offspring From Maternal Diet-Programmed Nonalcoholic Fatty Liver Disease Progression. Endocrinology 2023; 164:6991827. [PMID: 36655378 PMCID: PMC10091505 DOI: 10.1210/endocr/bqad010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/20/2023]
Abstract
Maternal obesity programs the risk for development of nonalcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to a maternal obesogenic diet. Female mice were fed chow (CON) or high fat, fructose, cholesterol (HFFC) and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting the diet to allow for voluntary exercise. The offspring were weaned to the HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed the HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed the HFFC diet had an increase in exercise distance relative to CON during the preconception period. Exercise distance was similar between groups during pregnancy and lactation. CON-active and HFFC-active offspring exhibited decreased inflammation compared with offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared with CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, 1-carbon, histidine, and acylcarnitine metabolism. This study provides preclinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.
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Affiliation(s)
- Holly Hinrichs
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Austin Faerber
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Monica Young
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samuel J Ballentine
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Michael D Thompson
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
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24
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Moylan CA, Mavis AM, Jima D, Maguire R, Bashir M, Hyun J, Cabezas MN, Parish A, Niedzwiecki D, Diehl AM, Murphy SK, Abdelmalek MF, Hoyo C. Alterations in DNA methylation associate with fatty liver and metabolic abnormalities in a multi-ethnic cohort of pre-teenage children. Epigenetics 2022; 17:1446-1461. [PMID: 35188871 PMCID: PMC9586600 DOI: 10.1080/15592294.2022.2039850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 01/09/2022] [Accepted: 02/01/2022] [Indexed: 11/03/2022] Open
Abstract
Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90 mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7-12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3-13.4%) and MRE was 2.5 kPa (range, 1.5-3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR<5%). The top two CpGs, cg25474373 and cg07264203, mapped to or near RFTN2 and PRICKLE2 genes. These two CpG sites were also significantly associated with a NAFLD diagnosis. As higher LFC associates with an adverse cardiometabolic profile already in childhood, altered DNAm may identify these children early in disease course for targeted intervention. Larger, longitudinal studies are needed to validate these findings and determine mechanistic relevance.
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Affiliation(s)
- Cynthia A. Moylan
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alisha M. Mavis
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
| | - Dereje Jima
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Rachel Maguire
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
| | - Mustafa Bashir
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Jeongeun Hyun
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Melanie N. Cabezas
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Alice Parish
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Donna Niedzwiecki
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Anna Mae Diehl
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Susan K. Murphy
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
- Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Manal F. Abdelmalek
- Department of Radiology, Center of Advanced Magnetic Resonance Development, Duke University Medical Center, Durham, NC, United States
| | - Cathrine Hoyo
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, United States
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25
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Fouda S, Vennikandam MM, Pappachan JM, Fernandez CJ. Pregnancy and Metabolic-associated Fatty Liver Disease: A Clinical Update. J Clin Transl Hepatol 2022; 10:947-954. [PMID: 36304500 PMCID: PMC9547252 DOI: 10.14218/jcth.2022.00052] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/15/2022] [Accepted: 04/26/2022] [Indexed: 12/04/2022] Open
Abstract
The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapidly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both mother and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the effects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of pregnancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.
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Affiliation(s)
- Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Madhu Mathew Vennikandam
- Department of Gastroenterology and Hepatology, Sparrow Hospital, Michigan State University College of Human Medicine, Lansing, MI, USA
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK
- Faculty of Science, Manchester Metropolitan University, Manchester, UK
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Correspondence to: Joseph M Pappachan, Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane, Preston PR2 9HT, UK. ORCID: https://orcid.org/0000-0003-0886-5255. Tel/Fax: +44-1-7725-22092, E-Mail:
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26
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Shook LL, Fourman LT, Edlow AG. Immune Responses to SARS-CoV-2 in Pregnancy: Implications for the Health of the Next Generation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1465-1473. [PMID: 36192115 PMCID: PMC9536183 DOI: 10.4049/jimmunol.2200414] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/08/2022] [Indexed: 11/06/2022]
Abstract
Widespread SARS-CoV-2 infection among pregnant individuals has led to a generation of fetuses exposed in utero, but the long-term impact of such exposure remains unknown. Although fetal infection is rare, children born to mothers with SARS-CoV-2 infection may be at increased risk for adverse neurodevelopmental and cardiometabolic outcomes. Fetal programming effects are likely to be mediated at least in part by maternal immune activation. In this review, we discuss recent evidence regarding the effects of prenatal SARS-CoV-2 infection on the maternal, placental, and fetal immune response, as well as the implications for the long-term health of offspring. Extrapolating from what is known about the impact of maternal immune activation in other contexts (e.g., obesity, HIV, influenza), we review the potential for neurodevelopmental and cardiometabolic morbidity in offspring. Based on available data suggesting potential increased neurodevelopmental risk, we highlight the importance of establishing large cohorts to monitor offspring born to SARS-CoV-2-positive mothers for neurodevelopmental and cardiometabolic sequelae.
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Affiliation(s)
- Lydia L Shook
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA; and
| | - Lindsay T Fourman
- Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Andrea G Edlow
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, MA;
- Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA; and
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Lu S, Kuang M, Yue J, Hu C, Sheng G, Zou Y. Utility of traditional and non-traditional lipid indicators in the diagnosis of nonalcoholic fatty liver disease in a Japanese population. Lipids Health Dis 2022; 21:95. [PMID: 36207744 PMCID: PMC9540727 DOI: 10.1186/s12944-022-01712-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/16/2022] [Accepted: 09/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Traditional and non-traditional (TNNT) lipid indicators are known to be closely related to nonalcoholic fatty liver disease (NAFLD). This study's objective was to compare the degree of associations and diagnostic values of TNNT lipid indicators with NAFLD. METHODS Participants were 14,251 Japanese adults who undergoing health checkups, and we measured and calculated 11 lipid indicators, including traditional lipid indicators such as high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG), as well as non-traditional lipid indicators such as TC/HDL-C ratio, LDL-C/HDL-C ratio, TG/HDL-C ratio, non-HDL-C, remnant cholesterol (RC), RC/HDL-C ratio and non-HDL-C/HDL-C ratio. The associations between these lipid indicators and NAFLD were assessed using multivariate logistic regression, and the performance of these lipid indicators in identifying NAFLD was analyzed by receiver operating characteristic (ROC) curves. RESULTS After rigorous adjustment for potential confounders, multivariate logistic regression showed that all TNNT lipid indicators were independently associated with NAFLD, among which the RC/HDL-C ratio and RC had the strongest association with NAFLD. ROC analysis showed that non-traditional lipid indicators were superior to traditional lipid indicators in identifying NAFLD, especially in young adults and females. It is worth mentioning that the RC/HDL-C ratio was the best lipid indicator for identifying NAFLD with an area under the curve (AUC) of 0.82 and an optimal cut-off value of 0.43; in addition, TG/HDL-C ratio also had a high recognition performance for NAFLD. CONCLUSION Overall, in the Japanese population, non-traditional lipid indicators had a higher diagnostic value for NAFLD compared to traditional lipid indicators, and lipid indicators alone had a lower diagnostic value for NAFLD than the ratio of two lipid indicators, with RC/HDL-C and TG/HDL-C being the best lipid indicators for identifying NAFLD.
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Affiliation(s)
- Song Lu
- Medical College of Nanchang University, 330006, Nanchang, Jiangxi Provincial, China.,Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi Provincial, China
| | - Maobin Kuang
- Medical College of Nanchang University, 330006, Nanchang, Jiangxi Provincial, China.,Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi Provincial, China
| | - Jinjing Yue
- Department of Obstetrics and Gynaecology, The Third Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, Henan Provincial, China
| | - Chong Hu
- Department of Gastroenterology, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi Provincial, China
| | - Guotai Sheng
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi Provincial, China
| | - Yang Zou
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, 330006, Nanchang, Jiangxi Provincial, China.
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Savva C, Helguero LA, González-Granillo M, Melo T, Couto D, Angelin B, Domingues MR, Li X, Kutter C, Korach-André M. Molecular programming modulates hepatic lipid metabolism and adult metabolic risk in the offspring of obese mothers in a sex-specific manner. Commun Biol 2022; 5:1057. [PMID: 36195702 PMCID: PMC9532402 DOI: 10.1038/s42003-022-04022-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 09/22/2022] [Indexed: 11/09/2022] Open
Abstract
Male and female offspring of obese mothers are known to differ extensively in their metabolic adaptation and later development of complications. We investigate the sex-dependent responses in obese offspring mice with maternal obesity, focusing on changes in liver glucose and lipid metabolism. Here we show that maternal obesity prior to and during gestation leads to hepatic steatosis and inflammation in male offspring, while female offspring are protected. Females from obese mothers display important changes in hepatic transcriptional activity and triglycerides profile which may prevent the damaging effects of maternal obesity compared to males. These differences are sustained later in life, resulting in a better metabolic balance in female offspring. In conclusion, sex and maternal obesity drive differently transcriptional and posttranscriptional regulation of major metabolic processes in offspring liver, explaining the sexual dimorphism in obesity-associated metabolic risk. Sex and maternal obesity drive differently transcriptional and posttranscriptional regulation of major metabolic processes in the livers of female and male offspring, contributing to the sexual dimorphism in obesity-associated metabolic risk.
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Affiliation(s)
- Christina Savva
- Department of Medicine, Cardiometabolic Unit and Integrated Cardio Metabolic Center, Karolinska Institute, Stockholm, Sweden.,Clinical Department of Endocrinology, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Luisa A Helguero
- Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
| | | | - Tânia Melo
- Mass Spectrometry Centre, Department of Chemistry, University of Aveiro, Aveiro, Portugal.,CESAM, Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Daniela Couto
- Mass Spectrometry Centre, Department of Chemistry, University of Aveiro, Aveiro, Portugal.,CESAM, Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Bo Angelin
- Department of Medicine, Cardiometabolic Unit and Integrated Cardio Metabolic Center, Karolinska Institute, Stockholm, Sweden.,Clinical Department of Endocrinology, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Maria Rosário Domingues
- Mass Spectrometry Centre, Department of Chemistry, University of Aveiro, Aveiro, Portugal.,CESAM, Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Xidan Li
- Department of Medicine, Cardiometabolic Unit and Integrated Cardio Metabolic Center, Karolinska Institute, Stockholm, Sweden
| | - Claudia Kutter
- Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
| | - Marion Korach-André
- Department of Medicine, Cardiometabolic Unit and Integrated Cardio Metabolic Center, Karolinska Institute, Stockholm, Sweden. .,Department of Gene Technology, Science for Life Laboratory, Royal Institute of Technology (KTH), Stockholm, Sweden.
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Association of rs738409 Polymorphism in Adiponutrin Gene with Liver Steatosis and Atherosclerosis Risk Factors in Greek Children and Adolescents. Nutrients 2022; 14:nu14173452. [PMID: 36079710 PMCID: PMC9459993 DOI: 10.3390/nu14173452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/03/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) shares several risk factors with atherosclerosis, as it is associated with components of the metabolic syndrome. However, genetic variations have also been linked to the risk of NAFLD, such as adiponutrin/patatin-like phospholipase domain-containing the protein 3 (PNPLA3) rs738409 polymorphism. The aim of the study was to determine the associations of thePNPLA3 rs738409 polymorphism with NAFLD and atherosclerosis risk factors in children and adolescents from northern Greece. A total of 91 children/adolescents who followed a Mediterranean eating pattern with no particular restrictions were studied. They were divided into three subgroups, according to their body mass index (BMI) and the presence or absence of liver disease. Diagnosis of NAFLD was based on a liver ultrasound, while the distribution of the PNPLA3 rs738409 polymorphism was investigated in all the participants. From the components of metabolic syndrome, only BMI, waist circumference, blood pressure, and the homeostasis model of insulin resistance (HOMA-IR) differed significantly between groups. The rs738409 polymorphism was significantly associated with BMI and NAFLD, while lipid values had no significant association with either NAFLD or gene polymorphism. This study shows that in Greekchildren, there is a significant association between the rs738409polymorphism in the PNPLA3 gene and hepatic steatosis, regardless of bodyweight.
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Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Gastroenterol 2022; 28:2890-2899. [PMID: 35978876 PMCID: PMC9280730 DOI: 10.3748/wjg.v28.i25.2890] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/20/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.
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Affiliation(s)
- Natalia Balassiano Wajsbrot
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Nathalie Carvalho Leite
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Gil F Salles
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
| | - Cristiane A Villela-Nogueira
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
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Cohen CC, Francis EC, Perng W, Sauder KA, Scherzinger A, Sundaram SS, Shankar K, Dabelea D. Exposure to maternal fuels during pregnancy and offspring hepatic fat in early childhood: The healthy start study. Pediatr Obes 2022; 17:e12902. [PMID: 35122420 PMCID: PMC9177565 DOI: 10.1111/ijpo.12902] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/07/2022] [Accepted: 01/20/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Intrauterine overnutrition has been associated with paediatric nonalcoholic fatty liver disease (NAFLD), but the exact mechanisms involved remain unclear. OBJECTIVE To examine whether maternal fuels and metabolic markers during pregnancy are associated with offspring hepatic fat in childhood. METHODS This analysis included 286 mother-child pairs from the Healthy Start Study, a longitudinal pre-birth cohort in Colorado. Fasting blood draws were collected in early pregnancy (~17 weeks) and mid-pregnancy (~27 weeks). Offspring hepatic fat was assessed by magnetic resonance imaging (MRI) at ~5 years. RESULTS In early pregnancy, maternal triglycerides (TGs) and free fatty acids (FFAs) were positively associated with offspring hepatic fat [Back-transformed β (95% CI): 1.15 (1.05, 1.27) per 1 standard deviation (SD) TGs; 1.14 (1.05, 1.23) per 1 SD FFAs]. Maternal total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were also associated with offspring hepatic fat, but only among boys [1.22 (1.08, 1.37) per 1 SD TC; 1.21 (1.07, 1.37) per 1 SD LDL-C]. In mid-pregnancy, only maternal TGs remained associated with offspring hepatic fat. Adjusting for potential confounders or mediators did not affect associations. CONCLUSIONS Maternal lipid concentrations, especially in early pregnancy, are associated with higher offspring hepatic fat, and may, therefore, be targeted in future interventions among pregnant women.
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Affiliation(s)
- Catherine C. Cohen
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ellen C. Francis
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Wei Perng
- Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Katherine A. Sauder
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ann Scherzinger
- Department of Radiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Shikha S. Sundaram
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kartik Shankar
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Dana Dabelea
- Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA,Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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de Groot JM, Geurtsen ML, Santos S, Jaddoe VWV. Ethnic disparities in liver fat accumulation in school-aged children. Obesity (Silver Spring) 2022; 30:1472-1482. [PMID: 35785476 PMCID: PMC9546249 DOI: 10.1002/oby.23478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) has a different prevalence in adults from different ethnic groups. This study examined whether these ethnic differences originate in early life and could be explained by early-life factors. METHODS This observational study was embedded in a population-based prospective cohort study from fetal life onward among 2,570 children born in Rotterdam, the Netherlands. Information about prepregnancy, pregnancy, and childhood factors, as well as childhood BMI, was obtained from questionnaires and physical examinations. Liver fat was assessed by magnetic resonance imaging at age 10 years. RESULTS Median liver fat fraction was 2.0% (95% CI: 1.2%-5.3%), and NAFLD prevalence was 2.8%. Children from a Turkish background had the highest median liver fat percentage (2.5%, 95% CI: 1.2%-10.7%) and NAFLD prevalence (9.1%). Children of Cape Verdean, Dutch Antillean, Surinamese-Creole, or Turkish background had a higher total liver fat fraction compared with children with a Dutch background (p < 0.05). After controlling for early-life factors, these differences persisted only in children with a Turkish background. CONCLUSIONS Prevalence of liver fat accumulation and NAFLD differs between ethnic subgroups living in the Netherlands, especially for those with a Turkish background. Early-life factors have a strong influence on these associations and may hold clues for future preventive strategies.
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Affiliation(s)
- Jasmin M. de Groot
- Generation R Study GroupErasmus University Medical CenterRotterdamThe Netherlands
- Department of PediatricsErasmus University Medical CenterRotterdamThe Netherlands
| | - Madelon L. Geurtsen
- Generation R Study GroupErasmus University Medical CenterRotterdamThe Netherlands
- Department of PediatricsErasmus University Medical CenterRotterdamThe Netherlands
| | - Susana Santos
- Generation R Study GroupErasmus University Medical CenterRotterdamThe Netherlands
- Department of PediatricsErasmus University Medical CenterRotterdamThe Netherlands
| | - Vincent W. V. Jaddoe
- Generation R Study GroupErasmus University Medical CenterRotterdamThe Netherlands
- Department of PediatricsErasmus University Medical CenterRotterdamThe Netherlands
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Quek SXZ, Tan EXX, Ren YP, Muthiah M, Loo EXL, Tham EH, Siah KTH. Factors early in life associated with hepatic steatosis. World J Hepatol 2022; 14:1235-1247. [PMID: 35978672 PMCID: PMC9258263 DOI: 10.4254/wjh.v14.i6.1235] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/01/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) mirrors the obesity epidemic. NAFLD is insidious but may gradually progress from simple steatosis to steatohepatitis, fibrosis and cirrhosis and/or hepatocellular carcinoma. Intervention strategies to ameliorate developmental programming of NAFLD may be more efficacious during critical windows of developmental plasticity.
AIM To review the early developmental factors associated with NAFLD.
METHODS Databases MEDLINE via PubMed, and EMBASE and Reference Citation Analysis were searched and relevant publications up to April 30, 2021 were assessed. Original research studies that included risk factors associated with early development of NAFLD in human subjects were included. These factors include: Maternal factors, intrauterine and prenatal factors, post-natal factors, genetic and ethnic predisposition, childhood and adolescence environmental factors. Studies were excluded if they were review articles or animal studies, case reports or conference abstracts, or if NAFLD was not clearly defined and assessed radiologically.
RESULTS Of 1530 citations identified by electronic search, 420 duplicates were removed. Of the 1110 citations screened from title and abstract, 80 articles were included in the final analysis. Genetic polymorphisms such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) were associated with increased risk of NAFLD. Familial factors such as maternal obesogenic environment and parental history of hepatic steatosis was associated with offspring NAFLD. Longer duration of exclusive breastfeeding in infancy was associated with a lower risk of developing NAFLD later in life while metabolic dysfunction and/or obesity in adolescence was associated with increased risk of NAFLD. Studies relating to socioeconomic factors and its association with NAFLD reported confounding results.
CONCLUSION Maternal metabolic dysfunction during pregnancy, being exclusively breastfed for a longer time postnatally, diet and physical activity in childhood and adolescence are potential areas of intervention to decrease risk of NAFLD.
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Affiliation(s)
- Sabrina Xin Zi Quek
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
| | - Eunice Xiang-Xuan Tan
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Yi Ping Ren
- Department of Medicine, National University Hospital, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Evelyn Xiu Ling Loo
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore 119228, Singapore
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Singapore
| | - Elizabeth Huiwen Tham
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore 119228, Singapore
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore 119228, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
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Thompson MD, Hinrichs H, Faerber A, Tarr PI, Davidson NO. Maternal obesogenic diet enhances cholestatic liver disease in offspring. J Lipid Res 2022; 63:100205. [PMID: 35341737 PMCID: PMC9046959 DOI: 10.1016/j.jlr.2022.100205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 03/08/2022] [Accepted: 03/19/2022] [Indexed: 10/25/2022] Open
Abstract
Human and animal model data show that maternal obesity promotes nonalcoholic fatty liver disease in offspring and alters bile acid (BA) homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS) diet and then bred them with lean males. Offspring were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 2 weeks to induce cholestasis, and a subgroup was then fed CON for an additional 10 days. Additionally, to evaluate the role of the gut microbiome, we fed antibiotic-treated mice cecal contents from CON or HF/HS offspring, followed by DDC for 2 weeks. We found that HF/HS offspring fed DDC exhibited increased fine branching of the bile duct (ductular reaction) and fibrosis but did not differ in BA pool size or intrahepatic BA profile compared to offspring of mice fed CON. We also found that after 10 days recovery, HF/HS offspring exhibited sustained ductular reaction and periportal fibrosis, while lesions in CON offspring were resolved. In addition, cecal microbiome transplant from HF/HS offspring donors worsened ductular reaction, inflammation, and fibrosis in mice fed DDC. Finally, transfer of the microbiome from HF/HS offspring replicated the cholestatic liver injury phenotype. Taken together, we conclude that maternal HF/HS diet predisposes offspring to increased cholestatic injury after DDC feeding and delays recovery after returning to CON diets. These findings highlight the impact of maternal obesogenic diet on hepatobiliary injury and repair pathways during experimental cholestasis.
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Affiliation(s)
- Michael D Thompson
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
| | - Holly Hinrichs
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Austin Faerber
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Phillip I Tarr
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Nicholas O Davidson
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
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Querter I, Pauwels NS, De Bruyne R, Dupont E, Verhelst X, Devisscher L, Van Vlierberghe H, Geerts A, Lefere S. Maternal and Perinatal Risk Factors for Pediatric Nonalcoholic Fatty Liver Disease: A Systematic Review. Clin Gastroenterol Hepatol 2022; 20:740-755. [PMID: 33862225 DOI: 10.1016/j.cgh.2021.04.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) has become the most common pediatric liver disease. The intrauterine and early life environment can have an important impact on long-term metabolic health. We investigated the impact of maternal prepregnancy obesity, (pre)gestational diabetes, breastfeeding, and birth anthropometrics/preterm birth on the development of NAFLD in children and adolescents. METHODS A comprehensive search was performed in MEDLINE, PubMed Central, EMBASE, and grey literature databases through August 2020. The primary outcome was the prevalence of pediatric NAFLD, whereas the histologic severity of steatohepatitis and/or fibrosis were secondary outcomes. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. RESULTS Our systematic review included 33 articles. Study heterogeneity regarding patient populations, diagnostic tools, and overall quality was considerable. Eight studies determined the impact of maternal prepregnancy overweight/obesity and identified this as a possible modifiable risk factor for pediatric NAFLD. Conversely, 8 studies investigated (pre)gestational diabetes, yet the evidence on its impact is conflicting. Breastfeeding was associated with a reduced risk for NAFLD, steatohepatitis, and fibrosis, especially in studies that evaluated longer periods of breastfeeding. Being born preterm or small for gestational age has an unclear impact on the development of NAFLD, although an early catch-up growth might drive NAFLD. CONCLUSIONS In a systematic review, we found that maternal prepregnancy overweight and obesity were associated with an increased risk of pediatric NAFLD. Breastfeeding might be protective against the development of NAFLD when the duration of breastfeeding is sufficiently long (≥6 months).
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Affiliation(s)
- Ilya Querter
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent
| | - Nele S Pauwels
- Knowledge Center for Health Ghent, Ghent University and Ghent University Hospital, Ghent
| | - Ruth De Bruyne
- Pediatric Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine and Pediatrics, Ghent University, Ghent
| | | | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, Ghent; Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent, Ghent University, Ghent, Belgium.
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Gwag T, Ma E, Zhou C, Wang S. Anti-CD47 antibody treatment attenuates liver inflammation and fibrosis in experimental non-alcoholic steatohepatitis models. Liver Int 2022; 42:829-841. [PMID: 35129307 PMCID: PMC9101015 DOI: 10.1111/liv.15182] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 01/07/2022] [Accepted: 02/01/2022] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS With the epidemic burden of obesity and metabolic diseases, nonalcoholic fatty liver disease (NAFLD) including steatohepatitis (NASH) has become the most common chronic liver disease in the western world. NASH may progress to cirrhosis and hepatocellular carcinoma. Currently, no treatment is available for NASH. Therefore, finding a therapy for NAFLD/NASH is in urgent need. Previously we have demonstrated that mice lacking CD47 or its ligand thrombospondin1 (TSP1) are protected from obesity-associated NALFD. This suggests that CD47 blockade might be a novel treatment for obesity-associated metabolic disease. Thus, in this study, the therapeutic potential of an anti-CD47 antibody in NAFLD progression was determined. METHODS Both diet-induced NASH mouse model and human NASH organoid model were utilized in this study. NASH was induced in mice by feeding with diet enriched with fat, fructose and cholesterol (AMLN diet) for 20 weeks and then treated with anti-CD47 antibody or control IgG for 4 weeks. Body weight, body composition and liver phenotype were analysed. RESULTS We found that anti-CD47 antibody treatment did not affect mice body weight, fat mass or liver steatosis. However, liver immune cell infiltration, inflammation and fibrosis were significantly reduced by anti-CD47 antibody treatment. In vitro data further showed that CD47 blockade prevented hepatic stellate cell activation and NASH progression in a human NASH organoid model. CONCLUSION Collectively, these data suggest that anti-CD47 antibody might be a new therapeutic option for obesity-associated NASH and liver fibrosis.
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Affiliation(s)
- Taesik Gwag
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, and Lexington VA Medical Center, Lexington KY 40502
| | - Eric Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, and Lexington VA Medical Center, Lexington KY 40502
| | - Changcheng Zhou
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521
| | - Shuxia Wang
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, and Lexington VA Medical Center, Lexington KY 40502.,To whom correspondence should be addressed: Shuxia Wang, MD, PhD, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Wethington Bldg. Room 583, 900 S. Limestone Street, Lexington, KY 40536. Tel: 859-218-1367, Fax: 859-257-3646,
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Thompson MD, Kang J, Faerber A, Hinrichs H, Özler O, Cowen J, Xie Y, Tarr PI, Davidson NO. Maternal obesogenic diet regulates offspring bile acid homeostasis and hepatic lipid metabolism via the gut microbiome in mice. Am J Physiol Gastrointest Liver Physiol 2022; 322:G295-G309. [PMID: 34984925 PMCID: PMC8816615 DOI: 10.1152/ajpgi.00247.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mice exposed in gestation to maternal high-fat/high-sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 wk and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic-treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses were performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. After CMT was performed, HF/HS-recipient mice had larger BA pools, increased intrahepatic muricholic acid, and decreased deoxycholic acid species. HF/HS-recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS-recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS-recipient mice had larger livers and increased intrahepatic triglyceride versus CON-recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.NEW & NOTEWORTHY We utilized a mouse model of maternal obesogenic diet exposure to evaluate the effect on offspring microbiome and bile acid homeostasis. We identified shifts in the offspring microbiome associated with changes in cecal bile acid levels. Transfer of the microbiome from maternal obesogenic diet-exposed offspring to microbiome-depleted mice altered bile acid homeostasis and increased fructose-induced hepatic steatosis.
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Affiliation(s)
- Michael D. Thompson
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Jisue Kang
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Austin Faerber
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Holly Hinrichs
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Oğuz Özler
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Jamie Cowen
- 1Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Yan Xie
- 2Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Phillip I. Tarr
- 3Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Nicholas O. Davidson
- 2Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
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Valentini F, Rocchi G, Vespasiani-Gentilucci U, Guarino MPL, Altomare A, Carotti S. The Origins of NAFLD: The Potential Implication of Intrauterine Life and Early Postnatal Period. Cells 2022; 11:cells11030562. [PMID: 35159371 PMCID: PMC8834011 DOI: 10.3390/cells11030562] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/30/2022] [Accepted: 02/02/2022] [Indexed: 02/04/2023] Open
Abstract
Fetal life and the first few months after birth represent a plastic age, defined as a “window of opportunity”, as the organism is particularly susceptible to environmental pressures and has to adapt to environmental conditions. Several perturbations in pregnancy, such as excessive weight gain, obesity, gestational diabetes mellitus and an inadequate or high-fat diet, have been associated with long-term metabolic consequences in offspring, even without affecting birth weight. Moreover, great interest has also been focused on the relationship between the gut microbiome of early infants and health status in later life. Consistently, in various epidemiological studies, a condition of dysbiosis has been associated with an increased inflammatory response and metabolic alterations in the host, with important consequences on the intestinal and systemic health of the unborn child. This review aims to summarize the current knowledge on the origins of NAFLD, with particular attention to the potential implications of intrauterine life and the early postnatal period. Due to the well-known association between gut microbiota and the risk of NAFLD, a specific focus will be devoted to factors affecting early microbiota formation/composition.
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Affiliation(s)
- Francesco Valentini
- Pediatric Unit, Sant’Andrea Hospital, Faculty of Medicine and Psychology, “Sapienza” University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;
| | - Giulia Rocchi
- Unit of Food Science and Human Nutrition, Campus Biomedico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy;
| | - Umberto Vespasiani-Gentilucci
- Unit of Internal Medicine and Hepatology, Fondazione Policlinico Campus Biomedico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy;
| | - Michele Pier Luca Guarino
- Gastroenterology Unit, Fondazione Policlinico Campus Biomedico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy;
| | - Annamaria Altomare
- Gastroenterology Unit, Fondazione Policlinico Campus Biomedico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy;
- Correspondence:
| | - Simone Carotti
- Unit of Microscopic and Ultrastructural Anatomy, Campus Biomedico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy;
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Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem. Biomedicines 2021; 9:biomedicines9121915. [PMID: 34944730 PMCID: PMC8698722 DOI: 10.3390/biomedicines9121915] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/24/2022] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum of liver diseases from fatty liver to nonalcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and hepatocellular cancer. Importantly, the growing incidence of overweight and obesity in childhood, 4% in 1975 to 18% in 2016, with persisting obesity complications into adulthood, is likely to be harmful by increasing the incidence of severe MAFLD at an earlier age. Currently, MAFLD is the leading form of chronic liver disease in children and adolescents, with a global prevalence of 3 to 10%, pointing out that early diagnosis is therefore crucial. In this review, we highlight the current knowledge concerning the epidemiology, risk factors and potential pathogenic mechanisms, as well as diagnostic and therapeutic approaches, of pediatric MAFLD.
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Pal P, Palui R, Ray S. Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity. World J Hepatol 2021; 13:1584-1610. [PMID: 34904031 PMCID: PMC8637673 DOI: 10.4254/wjh.v13.i11.1584] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/29/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity. There is also substantial inter-individual variation and variable response to a different therapy. This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history. Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease. Consequently, leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease (MAFLD) which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease (e.g. alcohol, viral hepatitis, etc.). Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.
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Affiliation(s)
- Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 500082, India
| | - Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Sayantan Ray
- Department of Endocrinology, Jagannath Gupta Institute of Medical Sciences and Hospital, Kolkata 700137, West Bengal, India
- Diabetes and Endocrinology, Apollo Clinic, Ballygunge, Kolkata 700019, West Bengal, India
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Abeysekera KWM, Orr JG, Madley-Dowd P, Fernandes GS, Zuccolo L, Gordon FH, Lawlor DA, Heron J, Hickman M. Association of maternal pre-pregnancy BMI and breastfeeding with NAFLD in young adults: a parental negative control study. THE LANCET REGIONAL HEALTH. EUROPE 2021; 10:100206. [PMID: 34806068 PMCID: PMC8589711 DOI: 10.1016/j.lanepe.2021.100206] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
BACKGROUND The importance of the maternal-infant dyad in the genesis of nonalcoholic fatty liver disease (NAFLD) is of increasing interest. The Avon Longitudinal Study of Parents and Children (ALSPAC) showed that at age 24, 1 in 5 had NAFLD measured by transient elastography and controlled attenuation parameter (CAP). Our aim was to investigate the association between breastfeeding duration and maternal pre-pregnancy BMI on offspring NAFLD in young adulthood. METHODS 4021 participants attended clinic for FibroScan and CAP measurement using Echosens 502 Touch®. 440 participants with Alcohol Use Disorders were excluded. Offspring of 100 non-singleton pregnancies were excluded. 2961 valid CAP measurements for NAFLD were analysed. Exposures of interest were breastfeeding of any duration, ≥6months exclusive breastfeeding, and maternal pre-pregnancy BMI. Multivariable regression models estimated the odds of NAFLD at 24 years. We performed a paternal negative control test to explore residual confounding in the analyses of pre-pregnancy BMI. FINDINGS There was a modest inverse association of exclusive and non-exclusive breastfeeding ≥6 months having a protective effect on NAFLD in offspring (OR 0·92 [95%CI 0·66-1·27] and OR 0·90 [0·67-1·21] respectively).The odds of offspring NAFLD in overweight pre-pregnancy maternal BMI and paternal BMI was OR 2·09 [1·62-2·68] and OR 1·33 [95%CI 1·07-1·65] respectively, with the ratio of effect sizes OR 1·57 [1·11-2·22]. Similarly, odds of offspring NAFLD with obese pre-pregnancy maternal BMI and paternal BMI was OR 2·66 [1·71-4·14] and OR 1·35 [0·91-2·00] respectively, with the ratio of effect sizes OR 1·98 [1·05-3·74]. INTERPRETATION Higher maternal pre-pregnancy BMI was associated with offspring NAFLD, having accounted for shared parental confounding. We did not replicate previous work that found a strong association between breastfeeding and NAFLD. FUNDING Medical Research Council UK, Alcohol Research UK, David Telling Charitable Trust.
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Affiliation(s)
- Kushala WM Abeysekera
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, UK
| | - James G Orr
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, UK
| | - Paul Madley-Dowd
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
| | - Gwen S Fernandes
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
| | - Luisa Zuccolo
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
| | - Fiona H Gordon
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, UK
| | - Deborah A Lawlor
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Bristol NIHR Biomedical Research Centre
| | - Jon Heron
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
| | - Matthew Hickman
- Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
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Hagström H, Simon TG, Roelstraete B, Stephansson O, Söderling J, Ludvigsson JF. Maternal obesity increases the risk and severity of NAFLD in offspring. J Hepatol 2021; 75:1042-1048. [PMID: 34289397 DOI: 10.1016/j.jhep.2021.06.045] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Maternal obesity has been linked to the development of cardiovascular disease and diabetes in offspring, but its relationship to non-alcoholic fatty liver disease (NAFLD) is unclear. METHODS Through the nationwide ESPRESSO cohort study we identified all individuals ≤25 years of age in Sweden with biopsy-verified NAFLD diagnosed between 1992 and 2016 (n = 165). These were matched by age, sex, and calendar year with up to 5 controls (n = 717). Through linkage with the nationwide Swedish Medical Birth Register (MBR) we retrieved data on maternal early-pregnancy BMI, and possible confounders, in order to calculate adjusted odds ratios (aORs) for NAFLD in offspring. RESULTS Maternal BMI was associated with NAFLD in offspring: underweight (aOR 0.84; 95% CI 0.14-5.15), normal weight (reference, aOR 1), overweight (aOR 1.51; 0.95-2.40), and obese (aOR 3.26; 1.72-6.19) women. Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was also more common in offspring of overweight (aOR 1.94; 95% CI 0.96-3.90) and obese (aOR 3.67; 95% CI 1.61-8.38) mothers. Associations were similar after adjusting for maternal pre-eclampsia and gestational diabetes. Socio-economic parameters (smoking, mother born outside the Nordic countries and less than 10 years of basic education) were also associated with NAFLD in offspring but did not materially alter the effect size of maternal BMI in a multivariable model. CONCLUSIONS This nationwide study found a strong association between maternal overweight/obesity and future NAFLD in offspring. Adjusting for socio-economic and metabolic parameters in the mother did not affect this finding, suggesting that maternal obesity is an independent risk factor for NAFLD in offspring. LAY SUMMARY In a study of all young persons in Sweden with a liver biopsy consistent with fatty liver, the authors found that compared to matched controls, the risk of fatty liver was much higher in those with obese mothers. This was independent of available confounders and suggests that the high prevalence of obesity in younger persons might lead to a higher risk of fatty liver in their offspring.
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Affiliation(s)
- Hannes Hagström
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden; Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
| | - Tracey G Simon
- Division of Gastroenterology and Hepatology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Olof Stephansson
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; Division of Women's Health, Department of Obstetrics, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Söderling
- Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
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Shapiro WL, Noon SL, Schwimmer JB. Recent advances in the epidemiology of nonalcoholic fatty liver disease in children. Pediatr Obes 2021; 16:e12849. [PMID: 34498413 PMCID: PMC8807003 DOI: 10.1111/ijpo.12849] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/24/2021] [Accepted: 08/14/2021] [Indexed: 12/16/2022]
Abstract
Children with obesity are at risk for numerous health problems, including nonalcoholic fatty liver disease (NAFLD). This review focuses on progress made in the epidemiology of NAFLD in children for the years 2015-2020. The estimated prevalence of NAFLD in children with obesity is 26%. The incidence of NAFLD in children has risen rapidly over the past decade. An understanding of the reasons for this rise is incomplete, but over the past 5 years, many studies have provided additional insight into the complexity of risk factors, diagnostic approaches, and associated comorbidities. Risk factors for NAFLD are wide-ranging, including perinatal factors involving both the mother and newborn, as well as environmental toxin exposure. Progress made in the noninvasive assessment will be critical to improving issues related to variability in approach to screening and diagnosis of NAFLD in children. The list of serious comorbidities observed in children with NAFLD continues to grow. Notably, for many of these conditions, such as diabetes and depression, the rates observed have exceeded the rates reported in children with obesity without NAFLD. Recent advancements reviewed show an increased awareness of this problem, while also calling attention to the need for additional research to guide successful efforts at prevention and treatment.
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Affiliation(s)
- Warren L. Shapiro
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California,Department of Gastroenterology, Rady Children’s Hospital, San Diego, California,Southern California Permanente Medical Group, Pasadena, California
| | - Sheila L. Noon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California
| | - Jeffrey B. Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California,Department of Gastroenterology, Rady Children’s Hospital, San Diego, California
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Sekkarie A, Welsh JA, Northstone K, Stein AD, Ramakrishnan U, Vos MB. Associations of maternal diet and nutritional status with offspring hepatic steatosis in the Avon longitudinal study of parents and children. BMC Nutr 2021; 7:28. [PMID: 34233762 PMCID: PMC8265091 DOI: 10.1186/s40795-021-00433-3] [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] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/22/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Priming for cardiometabolic diseases, including non-alcoholic fatty liver disease (NAFLD), is hypothesized to begin in utero. The primary objective of this study is to determine whether there is an association between maternal nutritional status and offspring NAFLD. METHODS Data come from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK. The analytic sample included 3353 participants who had maternal information on pre-pregnancy BMI, gestational weight gain, diabetes, and free sugar intake as percent of total energy and were assessed for mild-severe hepatic steatosis at 24 years by transient elastography (controlled attenuation parameter score ≥ 248 dB/m). Multiple logistic regression was used to evaluate the association between maternal factors and offspring hepatic steatosis at 24 years. RESULTS In confounder-adjusted models the independent associations for each maternal factor with mild to severe vs low hepatic steatosis at 24 years were: pre-pregnancy overweight (OR: 1.84, 95%CL: 1.43-2.38) or obesity (OR: 2.73, 95%CL: 1.84-4.03), more than recommended gestational weight gain (OR: 1.30, 95%CL: 1.04-1.64), diabetes (OR: 1.39, 95%CI: 0.87, 2.21), and high free sugar intake during pregnancy (OR: 1.04, 95% CI: 0.82, 1.33). These associations were largely mediated by BMI at 24 years, but not by birthweight or breastfeeding. CONCLUSIONS Our results suggest that maternal nutritional status is associated with the development of NAFLD in their adult offspring, although the relationship is largely mediated by offspring BMI in adulthood.
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Affiliation(s)
- Ahlia Sekkarie
- Nutrition and Health Sciences Program, Laney Graduate School, Emory University, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA.
| | - Jean A Welsh
- Nutrition and Health Sciences Program, Laney Graduate School, Emory University, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA
- Department of Pediatrics, Emory School of Medicine, Atlanta, GA, 30322, USA
| | - Kate Northstone
- Population Health Science, Bristol Medical School, Bristol, BS8 2BN, UK
| | - Aryeh D Stein
- Nutrition and Health Sciences Program, Laney Graduate School, Emory University, 1518 Clifton Rd NE, Atlanta, GA, 30322, USA
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Usha Ramakrishnan
- Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Miriam B Vos
- Department of Pediatrics, Emory School of Medicine, Atlanta, GA, 30322, USA
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Jian C, Carpén N, Helve O, de Vos WM, Korpela K, Salonen A. Early-life gut microbiota and its connection to metabolic health in children: Perspective on ecological drivers and need for quantitative approach. EBioMedicine 2021; 69:103475. [PMID: 34256346 PMCID: PMC8324810 DOI: 10.1016/j.ebiom.2021.103475] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/18/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022] Open
Abstract
The colonisation and development of the gut microbiota has been implicated in paediatric metabolic disorders via its powerful effect on host metabolic and immune homeostasis. Here we summarise the evidence from human studies on the early gut microbiota and paediatric overweight and obesity. Manipulation of the early gut microbiota may represent a promising target for countering the burgeoning metabolic disorders in the paediatric population, provided the assembly patterns of microbiota and their health consequences can be decoded. Therefore, in this review, we pay particular attention to the important ecological drivers affecting the community dynamics of the early gut microbiota. We then discuss the knowledge gaps in commonly studied exposures linking the gut microbiota to metabolic disorders, especially regarding maternal factors and antibiotic use. This review also attempts to give directions for future studies aiming to identify predictive and corrective measures for paediatric metabolic disorders based on the gut microbiota. Gut microbiota; Metabolism; Paediatric overweight and obesity; Ecological driver; Dynamics; Infants.
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Affiliation(s)
- Ching Jian
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Noora Carpén
- Children's Hospital, Pediatric Research Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Otto Helve
- Children's Hospital, Pediatric Research Center, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Finnish Institute for Health and Welfare, Department of Health Security, Helsinki, Finland
| | - Willem M de Vos
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Katri Korpela
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Anne Salonen
- Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Kabasakal Çetin A, Alkan Tuğ T, Güleç A, Akyol A. Effects of maternal taurine supplementation on maternal dietary intake, plasma metabolites and fetal growth and development in cafeteria diet fed rats. PeerJ 2021; 9:e11547. [PMID: 34141487 PMCID: PMC8180190 DOI: 10.7717/peerj.11547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/11/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Maternal obesity may disrupt the developmental process of the fetus during gestation in rats. Recent evidence suggests that taurine can exert protective role against detrimental influence of obesogenic diets. This study aimed to examine the effect of maternal cafeteria diet and/or taurine supplementation on maternal dietary intake, plasma metabolites, fetal growth and development. METHODS Female Wistar rats were fed a control diet (CON), CON supplemented with 1.5% taurine in drinking water (CONT), cafeteria diet (CAF) or CAF supplemented with taurine (CAFT) from weaning. After 8 weeks all animals were mated and maintained on the same diets during pregnancy and lactation. RESULTS Dietary intakes were significantly different between the groups. Both CAF and CAFT fed dams consumed less water in comparison to CON and CONT dams. Taurine supplementation only increased plasma taurine concentrations in CONT group. Maternal plasma adiponectin concentrations increased in CAF and CAFT fed dams compared to CON and CONT fed dams and there was no effect of taurine. Hyperleptinemia was observed in CAF fed dams but not in CAFT fed dams. Malondialdehyde was significantly increased only in CAF fed dams. Litter size, sex ratio and birth weight were similar between the groups. There was an increase in neonatal mortality in CONT group. DISCUSSION This study showed that maternal taurine supplementation exerted modest protective effects on cafeteria diet induced maternal obesity. The increased neonatal mortality in CONT neonates indicates possible detrimental effects of taurine supplementation in the setting of normal pregnancy. Therefore, future studies should investigate the optimal dose of taurine supplementation and long term potential effects on the offspring.
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Affiliation(s)
- Arzu Kabasakal Çetin
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
| | - Tuǧba Alkan Tuğ
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
| | - Atila Güleç
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
| | - Aslı Akyol
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Hacettepe University, Ankara, Türkiye
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Zhang X, Wu M, Liu Z, Yuan H, Wu X, Shi T, Chen X, Zhang T. Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study. BMJ Open 2021; 11:e042843. [PMID: 33947727 PMCID: PMC8098935 DOI: 10.1136/bmjopen-2020-042843] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To describe the prevalence and variations of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) among children and adolescents (CADs) and young adults (YADs). DESIGN A population-based observational study. SETTING Annual cases and prevalence of NAFLD/NASH from 1990 to 2017, by sex, region and country were collected from the Global Burden of Disease database. MAIN OUTCOME MEASURES The estimated annual percentage change, which was calculated by a regression line, was used to quantify the temporal trends in NAFLD/NASH burden among young people at the global, regional and national levels. RESULTS Globally, NAFLD/NASH incidence increased from 19.34 million in 1990 to 29.49 million in 2017 among CADs, with an annual increase of 1.35%. Additionally, in YADs, the number of cases and NAFLD/NASH prevalence significantly increased during this period, independent of sex and region. The greatest NAFLD/NASH increase was in North Africa and the Middle East. Almost all countries showed an increasing trend from 1990 to 2017, with the most pronounced increase observed in the developed regions. CONCLUSIONS The epidemiology of NAFLD/NASH in young people has changed considerably over the last three decades. Both the prevalence and number of cases have increased irrespective of sex, age and region. This phenomenon can result in a predictable increase in chronic liver disease burden in the near future. Understanding the prevalence of NAFLD/NASH and its variations is of paramount importance to develop strategies to implement public health policy.
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Affiliation(s)
- Xin Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Mingshan Wu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Zhenqiu Liu
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Huangbo Yuan
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Xuefu Wu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Tingting Shi
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Tiejun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
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48
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Han S, Zhu F, Huang X, Yan P, Xu K, Shen F, Sun J, Yang Z, Jin G, Teng Y. Maternal obesity accelerated non-alcoholic fatty liver disease in offspring mice by reducing autophagy. Exp Ther Med 2021; 22:716. [PMID: 34007325 PMCID: PMC8120514 DOI: 10.3892/etm.2021.10148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by an excessive accumulation of triacylglycerol in the liver. Autophagy is a lysosome-dependent degradation product recovery process, which widely occurs in eukaryotic cells, responsible for the vital maintenance of cellular energy balance. Previously published studies have demonstrated that autophagy is closely related to NAFLD occurrence and maternal obesity increases the susceptibility of offspring to non-alcoholic fatty liver disease, however, the underlying mechanism of this remains unclear. In the present study, NAFLD mouse models (offspring of an obese mother mouse via high-fat feeding) were generated, and the physiological indices of the liver were observed using total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein serum assay kits. The morphological changes of the liver were also observed via HE, Masson and oil red O staining. Reverse transcription-quantitative-PCR and western blotting were performed to detect changes of autophagy-related genes in liver or fibrosis marker proteins (α-smooth muscle actin or TGF-β1). Changes in serum inflammatory cytokine IL-6 levels were determined via ELISA. The results of the present study demonstrated that the offspring of an obese mother were more likely to develop NALFD than the offspring of a chow-fed mother, due to their increased association with liver fibrosis. When feeding continued to 17 weeks, the worst cases of NAFLD were observed and the level of autophagy decreased significantly compared with the offspring of a normal weight mouse. In addition, after 17 weeks of feeding, compared with the offspring of a chow-fed mother, the offspring of an obese mouse mother had reduced adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation levels and increased mammalian target of rapamycin (mTOR) phosphorylation levels. These results suggested that a reduced level of AMPK/mTOR mediated autophagy may be of vital importance for the increased susceptibility of offspring to NAFLD caused by maternal obesity. In conclusion, the current study provided a new direction for the treatment of NAFLD in offspring caused by maternal obesity.
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Affiliation(s)
- Shuguang Han
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Feng Zhu
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Xiaoxia Huang
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China.,The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China
| | - Panpan Yan
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Ke Xu
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Fangfang Shen
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Jiawen Sun
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Zeyu Yang
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Guoxi Jin
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Yiqun Teng
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
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49
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Morrison JL, Ayonrinde OT, Care AS, Clarke GD, Darby JRT, David AL, Dean JM, Hooper SB, Kitchen MJ, Macgowan CK, Melbourne A, McGillick EV, McKenzie CA, Michael N, Mohammed N, Sadananthan SA, Schrauben E, Regnault TRH, Velan SS. Seeing the fetus from a DOHaD perspective: discussion paper from the advanced imaging techniques of DOHaD applications workshop held at the 2019 DOHaD World Congress. J Dev Orig Health Dis 2021; 12:153-167. [PMID: 32955011 DOI: 10.1017/s2040174420000884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
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Affiliation(s)
- Janna L Morrison
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Oyekoya T Ayonrinde
- Fiona Stanley Hospital, Murdoch, WA, Australia
- Medical School, The University of Western Australia, Perth, WA, Australia
| | - Alison S Care
- The Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Geoffrey D Clarke
- Department of Radiology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Jack R T Darby
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - Anna L David
- Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK
| | - Justin M Dean
- Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Stuart B Hooper
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
- The Department of Obstetrics and Gynecology, Monash University, Melbourne, Victoria, Australia
| | - Marcus J Kitchen
- School of Physics and Astronomy, Monash University, Melbourne, Victoria, Australia
| | | | - Andrew Melbourne
- School of Biomedical Engineering and Imaging Sciences, Kings College London, London, UK
| | - Erin V McGillick
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
- The Department of Obstetrics and Gynecology, Monash University, Melbourne, Victoria, Australia
| | - Charles A McKenzie
- Department of Medical Biophysics, Western University, London, ON, Canada
- Lawson Health Research Institute and Children's Health Research Institute, London, ON, Canada
| | - Navin Michael
- Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Nuruddin Mohammed
- Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology, Aga Khan University Hospital, Karachi, Pakistan
| | - Suresh Anand Sadananthan
- Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Eric Schrauben
- Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Timothy R H Regnault
- Lawson Health Research Institute and Children's Health Research Institute, London, ON, Canada
- Department of Obstetrics and Gynecology, Western University, London, ON, Canada
- Department of Physiology and Pharmacology, Western University, London, ON, Canada
| | - S Sendhil Velan
- Singapore Bioimaging Consortium, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
- Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
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50
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Wegermann K, Suzuki A, Mavis AM, Abdelmalek MF, Diehl AM, Moylan CA. Tackling Nonalcoholic Fatty Liver Disease: Three Targeted Populations. Hepatology 2021; 73:1199-1206. [PMID: 32865242 DOI: 10.1002/hep.31533] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/31/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Kara Wegermann
- Division of GastroenterologyDepartment of MedicineDuke University Health SystemDurhamNC
| | - Ayako Suzuki
- Division of GastroenterologyDepartment of MedicineDuke University Health SystemDurhamNC.,Department of MedicineDurham Veterans Affairs Medical CenterDurhamNC
| | - Alisha M Mavis
- Division of Gastroenterology, Hepatology, and NutritionDepartment of PediatricsDuke University Health SystemDurhamNC
| | - Manal F Abdelmalek
- Division of GastroenterologyDepartment of MedicineDuke University Health SystemDurhamNC
| | - Anna Mae Diehl
- Division of GastroenterologyDepartment of MedicineDuke University Health SystemDurhamNC
| | - Cynthia A Moylan
- Division of GastroenterologyDepartment of MedicineDuke University Health SystemDurhamNC.,Department of MedicineDurham Veterans Affairs Medical CenterDurhamNC
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