B02
Circadiane Desynchronisation und epigenetische Veränderung: Wechselwirkungen bei der Entwicklung und Auflösung von mit metabolischer Dysfunktion assoziierter Steatohepatitis
Ein koordiniertes circadian-epigenetisches Netzwerk ist entscheidend die metabolische Homöostase der Leber. Störungen der circadianen Rhythmen oder der epigenetischen Regulation verändern Stoffwechsel und Entzündungsprozesse und tragen so zur Entstehung einer Steatohepatitis bei. Dieses Projekt untersucht das Zusammenspiel dieser Mechanismen.
Die Wechselwirkung zwischen circadianer Störung und epigenetischen Veränderungen, die zur metabolischen Dysfunktion und Steatohepatitis beitragen, ist bislang unzureichend verstanden.
Circadiane und epigenetische Signalwege steuern gemeinsam metabolische und entzündliche Programme der Leber; ihre Störung verändert zelluläre Signalübertragung, DNA-Methylierung und Proteinnetzwerke.
Wir werden die Interaktion zwischen circadianer Funktion und DNA-Methylierung im Leberstoffwechsel anhand von Mausmodellen, Hepatozytenkulturen, Organoiden und klinischen Kohorten untersuchen und Interventionen zur Wiederherstellung der Homöostase evaluieren.
Das Team für
B02
Die Publikationen von
B02
Lack of GPNMB Is Associated With Altered Lipid and Glucose Metabolism and Disrupted Diurnal Hepatic Glycogen Regulation
March 9, 2026
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The FASEB Journal
Higher serum levels of GPNMB are linked to type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD). Disruption of circadian rhythms also influences the development and progression of MASLD. In this study, we investigated how GPNMB modulates hepatic glycogen metabolism and its potential interaction with the hepatic circadian clock. Male DBA/2 J mice, either wild-type (GP+) or carrying an inactivating Gpnmb mutation (GP−), were fed a high-fat diet (48.4% fat) supplemented with 30% fructose in drinking water for 12 weeks. Despite similar weight gain, GP− mice displayed greater global fat mass accumulation and elevated serum triglyceride and cholesterol levels. Surprisingly, GP− mice showed improved glucose tolerance, whereas GP+ mice developed impaired glycemic control. Indirect calorimetry under thermoneutral conditions (30°C) revealed loss of diurnal rhythmicity in energy expenditure (EE) in GP− mice, which was independent of food intake. Despite its preserved rhythms, hepatic clock gene expression in GP− mice showed increased MESOR (e.g., Per1, Per2, and Nr1d1) and increased amplitude (e.g., Nr1d1), indicating higher expression levels throughout the day. GPNMB deficiency further impaired hepatic glycogen storage dynamics, which was attributed to reduced AKT phosphorylation (indicative of defective insulin signaling), reduced FOXO1 phosphorylation, and increased PEPCK-M. Translating our findings to human MASLD patients, GPNMB expression obtained from liver biopsies showed a clear increase across MASLD progression. Importantly, patients with metabolic dysfunction-associated steatohepatitis (MASH) and diabetes who received anti-diabetic treatment showed a reduction in hepatic GPNMB expression. Collectively, our findings suggest that GPNMB plays a role in metabolic adaptation to obesogenic diets, as a Gpnmb loss-of-function model reveals an association with impaired hepatic insulin signaling and glycogen metabolism despite improved systemic glucose tolerance in mice, whereas hepatic GPNMB upregulation correlates with MASLD progression in humans.
