E2F2 transcription factor promotes a cholestatic MASH phenotype by regulating hepatobiliary metabolism through miR-34a-5p.
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Apodaka-Biguri Maider, Simão André L, González-Romero Francisco, Mestre Daniela, Rodrigues Pedro M, Aurrekoetxea Igor, Gómez-Santos Beatriz, Buqué Xabier, Nieva-Zuluaga Ane, de Gauna Mikel Ruiz, Fernandez-Puertas Idoia, Gomez-Jauregui Paul, Sainz-Ramirez Natalia, Alfaro-Jiménez Kendall, Ortiz-Palma Ane, Castillero Estibaliz, Iglesias-Ara Ainhoa, Mitxelena Jone, Eriz Ainhoa, Aransay Ana M, Lozano Juan-José, Marin Jose J G, Izquierdo-Sanchez Laura, Perugorria Maria J, Bujanda Luis, Banales Jesus M, Martín César, Mosteiro Lorena, Errazti Gaizka, Syn Wing-Kin, Castaño Luis, Zubiaga Ana M, Castro Rui E, Aspichueta Patricia
Аннотация
APPROACH AND RESULTS: E2f2 -knockout ( E2f2-/- ) and wild-type (WT) mice were fed a choline-deficient high-fat diet (ChD-HFD) or an HFD after injection of diethylnitrosamine (DEN-HFD) to induce metabolic dysfunction-associated steatohepatitis (MASH). E2F2 was overexpressed in the liver by AAV8. Cholestasis was induced by bile duct ligation or by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-enriched diet. microRNA sequencing was performed. Two biopsy-proven MASLD patient cohorts were used. E2F2 deficiency resulted in increased synthesis and excretion of cholesterol, phosphatidylcholine, and bile acids, reducing their storage in the liver while increasing their presence in feces. This was consistent with increased expression of genes involved in biliary lipid metabolism, reduced inflammation and fibrosis, and the generation of a distinct miRNA profile, thereby preventing MASH. Liver-specific induction of E2F2 in vivo hampered the transcriptional program involved in biliary lipid metabolism and upregulated miR-34a-5p, which was downregulated in E2f2-/- mice. The protective effects observed in E2f2-/- mice were lost when a miR-34a-5p mimic was used. Hepatic miR-34a-5p levels were elevated in patients with advanced fibrosis, inflammation, steatosis score, cholelithiasis, and increased serum bile acids and biliary lipids. E2f2 deficiency conferred protection against cholestatic liver injury.
CONCLUSIONS: E2F2 deficiency protects against MASH and cholestasis, preventing cholesterol accumulation, fibrosis, and inflammation through modulation of miR-34a-5p. This could provide therapeutic benefits for patients with cholestatic MASH.