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Selective genetic inactivation of Caspase 8 in hepatocytes ameliorates progression of MASH following Jnk deficiency

氧化应激 细胞凋亡 肝损伤 癌症研究 肝细胞 小干扰RNA 半胱氨酸蛋白酶3 激酶 生物 医学 程序性细胞死亡 细胞生物学 内分泌学 生物化学 基因 核糖核酸 体外
作者
Ines Volkert,Julia Grube,Marius Maximilian Woitok,Mohamed Ramadan Mohamed,Karolina Edlund,Julia Duda,Jana Dietrich,Ursula Schneider,Guo Nan Yin,Cheng Lin,Stephanie Erschfeld,Hilmar Berger,Lena Candels,Roger J. Davis,Matthias Bartneck,Mark Kühnel,Adrien Guillot,Kai Markus Schneider,Carolin V. Schneider,Danny Jonigk
出处
期刊:Hepatology [Wiley]
被引量:1
标识
DOI:10.1097/hep.0000000000001286
摘要

Background and Aims: Metabolic dysfunction–associated steatohepatitis (MASH) is associated with c-Jun N-terminal kinase (JNK) activation across various cell types, but its hepatocyte-specific function in steatotic liver disease remains unclear. Our study investigates the role of JNK1/JNK2 during MASH progression and dissects its hepatocyte-specific function. Approach and Results: We showed that UK Biobank patients with a predicted loss-of-function variant of JNK1 presented an increased prevalence of metabolic dysfunction–associated steatotic liver disease and liver damage. Analysis of a pathology cohort of patients with steatotic liver disease revealed increased oxidative stress response and apoptosis. After subjecting mice deficient for Jnk1 and Jnk2 in hepatocytes ( Jnk1/2 Δhepa ) to 2 different MASH models, we observed enhanced liver injury, fibrosis, and oxidative stress. RNA sequencing revealed highly upregulated pathways in Jnk1/2 Δhepa livers, including inflammatory signals and apoptotic pathways. Additional blocking of Caspase 8 signaling improved high-fat diet–induced liver damage, fibrogenesis, and oxidative stress. Ultimately, a therapeutic approach using lipid nanoparticles containing small interfering RNA targeting Caspase 8 during MASH progression attenuated liver injury and cell death in mice. Conclusions: Our findings define a protective role of JNK1/JNK2 in hepatocytes during the oxidative stress response driving the progression of MASH. This process is mainly mediated by Caspase 8-dependent apoptosis, thereby discovering that Caspase 8 is a downstream target of JNK1/2. Caspase 8-directed therapy in hepatocytes might be a promising treatment for patients with an increased oxidative stress response and MASH.
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