Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation

Schwerbel, Kristin; Kamitz, Anne; Krahmer, Natalie; Hallahan, Nicole; Jähnert, Markus; Gottmann, Pascal; Lebek, Sandra; Schallschmidt, Tanja; Arends, Danny; Schumacher, Fabian; Kleuser, Burkhard; Haltenhof, Tom; Heyd, Florian; Gancheva, Sofiya; Broman, Karl W.; Roden, Michael; Joost, Hans-Georg; Chadt, Alexandra; Al-Hasani, Hadi; Vogel, Heike; Jonas, Wenke; Schürmann, Annette

doi:10.1016/j.jhep.2020.04.031

Cited by 35 publications

(33 citation statements)

References 44 publications

(64 reference statements)

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“…Die Proteine steigern den spezifischen Abbau von Fett in der Leber (Lipophagie). Bei Menschen aber auch bei Mäusen mit einer Fettleber werden die Gene jedoch deutlich weniger abgelesen [7]. Ursache dafür ist bei Mäusen eine kleine genetische Veränderung.…”

Section: Inhibition Der Expression Bestimmter Gene Induziert Eine Fettleberunclassified

Diabetes und nicht-alkoholische Fettleber-Erkrankungen

2021

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ZUSAMMENFASSUNGAdipositas und Typ-2-Diabetes (T2D) erhöhen das Risiko für nicht-alkoholische Fettleber-Erkrankungen (non-alcoholic fatty liver disease, NAFLD) und andere Komorbiditäten. In Deutschland leiden etwa 18 Mio. Menschen an NAFLD, davon haben etwa 3,3 Mio. eine nicht-alkoholische Steatohepatitis (NASH). Zu viel Fett in der Leber hat aber auch einen negativen Einfluss auf den Glukosestoffwechsel und kann zur Entwicklung eines T2D beitragen. Um den Zusammenhang zwischen NAFLD und T2D zielgerichtet zu untersuchen, hat das Deutsche Zentrum für Diabetesforschung (DZD) einen Forschungsschwerpunkt ("Akademie") zu Diabetes und NAFLD aufgebaut. Interdisziplinäre Teams suchen nach Biomarkern zur Verbesserung der Diagnose und Risikostratifizierung sowie nach Mechanismen, die zur Pathogenese und Progression der NAFLD und ihrer Komorbiditäten beitragen. Zudem werden neue Strategien entwickelt, um die NAFLD zu verhindern bzw. besser behandeln zu können. Dabei arbeiten die Forschenden sowohl an medikamentösen Ansätzen als auch an Ernährungsumstellungen.

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Section: Inhibition Der Expression Bestimmter Gene Induziert Eine Fettleberunclassified

Diabetes und nicht-alkoholische Fettleber-Erkrankungen

2021

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“…This genetic association has been replicated in a cohort of obese Italian children (55). A recent murine study revealed liver specific suppression of Ifgga2 (the mice ortholog of human IRGM) increases hepatic fat content in a backcross of obese C57BL/6J New Zealand mice (115).…”

Section: Irgmmentioning

confidence: 99%

New Perspectives on Genetic Prediction for Pediatric Metabolic Associated Fatty Liver Disease

Lin

2020

Front. Pediatr.

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Non-alcoholic or recently re-defined metabolic associated fatty liver disease (MAFLD), a spectrum of progressive hepatic disease, has become a public health issue in obese children and adolescents. MAFLD is a complex metabolic disease strongly associated with obesity and insulin resistance. It is not known why not every obese subject will develop MAFLD. Different ethnic/racial groups display differences in MAFLD prevalence, indicating genetic factor plays a role. In the past two decades, sequence variations in genetic loci, including PNPLA3, TM6SF2, GCKR, MBOAT7, HSD17B13, etc. have been shown to confer susceptibility to MAFLD in children and adults. This review article provides an updated viewpoint of genetic predictors related to pediatric MAFLD. We discuss whether these susceptible genes can be clinically used for risk stratification and personalized care. Understanding human genetics and molecular mechanisms can give important information not only for prediction of risk but also on how to design drugs. In view of current epidemic of MAFLD worldwide, it is necessary to identify which children with MAFLD progress rapidly and need earlier intervention. In the future, a comprehensive analysis of individualized genetic and environmental factors may help assess the risk of children with MAFLD and personalize their treatment.

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“…This strategy addresses the current gaps in the knowledge of the genetic basis for T2D. It confers several advantages, including the ability to use haplotype maps for higher resolution positional cloning ( Schwerbel et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

et al. 2020

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Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL), Nidd/DBA on chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of β-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four ( Kti12 , Osbpl9 , Ttc39a , and Calr4 ) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTL Nidd/DBA . Future studies are necessary to understand the exact role of the different candidates in β-cell function and their contribution in maintaining glycemic control.

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Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation

Cited by 35 publications

References 44 publications

Diabetes und nicht-alkoholische Fettleber-Erkrankungen

Diabetes und nicht-alkoholische Fettleber-Erkrankungen

New Perspectives on Genetic Prediction for Pediatric Metabolic Associated Fatty Liver Disease

Identification of Novel Potential Type 2 Diabetes Genes Mediating β-Cell Loss and Hyperglycemia Using Positional Cloning

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