Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease
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Le résumé fourni par la source
Background & Aims Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP , encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions We have identified and characterised a rare causal variant in MTTP , and homozygosity for MTTP p . I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and Implications A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease
- Date Crossref
- 01/08/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Nottingham University Hospitals NHS Trust National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre pays non établi dans la noticeÉtablissement de santé
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University of Nottingham pays non établi dans la noticeUniversité ou école supérieure
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NIHR Nottingham Digestive Diseases Biomedical Research Unit pays non établi dans la noticeOrganisme public
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Nottingham Biomedical Research Centre pays non établi dans la noticeStructure de recherche
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University of Leicester Department of Population Health Sciences pays non établi dans la noticeUniversité ou école supérieure
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University Hospitals of Leicester NHS Trust Department of Chemical Pathology and Metabolic Diseases pays non établi dans la noticeÉtablissement de santé
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Glenfield Hospital pays non établi dans la noticeÉtablissement de santé
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Ulverscroft (United Kingdom) pays non établi dans la noticeEntreprise
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Health Action by People pays non établi dans la noticeOrganisation à but non lucratif
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School of Medicine Translational Medical Sciences pays non établi dans la noticeUniversité ou école supérieure
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University Hospitals Leicester NHS Trust Clinical Genetics Department pays non établi dans la noticeUniversité ou école supérieure
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NIHR Leicester Respiratory Biomedical Research Centre pays non établi dans la noticeStructure de recherche
National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre — Nottingham University Hospitals NHS Trust, University of Nottingham et NIHR Nottingham Digestive Diseases Biomedical Research Unit, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.