JNKs protect from cholestatic liver disease progression by modulating Apelin signalling

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dc.contributor.authorRamadan Mohamed, Mohamed
dc.contributor.authorWu, Hanghang
dc.contributor.authorCubero Palero, Francisco Javier
dc.contributor.authorTrautwein, Christian
dc.date.accessioned2024-03-08T09:46:54Z
dc.date.available2024-03-08T09:46:54Z
dc.date.issued2023
dc.description.abstractBackground & aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipGerman Research Foundation
dc.description.sponsorshipMinisterio de Ciencia e Inovacción
dc.description.sponsorshipEuropean Research Council
dc.description.sponsorshipFederal Ministry of Education and Research
dc.description.statuspub
dc.identifier.citationMohamed MR, Haybaeck J, Wu H, Su H, Bartneck M, Lin C, Boekschoten MV, Boor P, Goeppert B, Rupp C, Strnad P, Davis RJ, Cubero FJ, Trautwein C. JNKs protect from cholestatic liver disease progression by modulating Apelin signalling. JHEP Rep. 2023 Jul 18;5(11):100854. doi: 10.1016/j.jhepr.2023.100854. PMID: 37791376; PMCID: PMC10543210
dc.identifier.doi10.1016/j.jhepr.2023.100854
dc.identifier.urihttps://hdl.handle.net/20.500.14352/102058
dc.issue.number5
dc.journal.titleJHEP Reports
dc.language.isoeng
dc.page.initial100854
dc.relation.projectIDDFG CRC 1382
dc.relation.projectIDProject-ID 403224013
dc.relation.projectIDTr 285/10-2
dc.relation.projectIDGRK 2375
dc.relation.projectIDPID2020-117941RBI00
dc.relation.projectIDEXOHEP2-CM
dc.relation.projectIDS2022/BMD-7409
dc.relation.projectIDHORIZON-HLTH-2022- STAYHLTH-02
dc.relation.projectIDSTOP-FSGS-01GM2202
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu611.36
dc.subject.keywordc-Jun N-terminal kinases (JNK)
dc.subject.keywordCholestasis
dc.subject.keywordFibrosis
dc.subject.keywordHepatocytes
dc.subject.keywordApelin
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmGastroenterología y hepatología
dc.subject.ucmInmunología
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco2412 Inmunología
dc.titleJNKs protect from cholestatic liver disease progression by modulating Apelin signalling
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number18
dspace.entity.typePublication
relation.isAuthorOfPublication00cd7853-9957-498a-953b-f38d6cc185a9
relation.isAuthorOfPublicationb3877679-0fbd-42e6-8541-1efeb2df768a
relation.isAuthorOfPublication.latestForDiscoveryb3877679-0fbd-42e6-8541-1efeb2df768a
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