Journal of gastroenterology and hepatology · 2023
Hepatic stellate cells activate and avoid death under necroptosis stimuli: Hepatic fibrosis during necroptosis.
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Oh Ju Hee, Saeed Waqar Khalid, Kim Hye Young, Lee Seung Min, Lee A Hyeon, Park Gye Ryeol, Yoon Eileen L, Jun Dae Won
Аннотация
BACKGROUND AND AIM: Necroptosis is an emerging cell death pathway that allows cells to undergo "cellular suicide" in a caspase-independent manner. We investigated the fate of hepatic stellate cells (HSCs) under necroptotic stimuli.
METHODS AND RESULTS: The RNA level of mixed lineage kinase domain-like protein (MLKL) is higher in patients with non-alcoholic fatty liver disease than in healthy controls. Hepatic fibrosis was significantly lower in MLKL-KO bile duct ligation (KO-BDL) mice than in wild-type-BDL mice. Necroptotic stimuli caused the death of HT-29 and U937 cells. However, necroptotic stimuli activate HSCs instead of inducing cell death. MLKL inhibitors attenuated fibrogenic changes in HSCs during necroptosis. Unlike HT-29 and U937 cells, MLKL phosphorylation and oligomerization were not observed during necroptosis in HSCs. RNA sequencing showed that NF-κB signaling-related genes were upregulated in HSCs following necroptotic stimulation. Necroptotic stimuli in HSCs increased the nuclear expression of NF-κB, which decreased after MLKL inhibitor treatment. Induction of necroptosis in HSCs led to autophagosome activation and formation, which were attenuated by MLKL inhibitor treatment.
CONCLUSION: HSCs avoid necroptosis due to the absence of MLKL phosphorylation and oligomerization and are activated through autophagosome and NF-κB pathways.
METHODS AND RESULTS: The RNA level of mixed lineage kinase domain-like protein (MLKL) is higher in patients with non-alcoholic fatty liver disease than in healthy controls. Hepatic fibrosis was significantly lower in MLKL-KO bile duct ligation (KO-BDL) mice than in wild-type-BDL mice. Necroptotic stimuli caused the death of HT-29 and U937 cells. However, necroptotic stimuli activate HSCs instead of inducing cell death. MLKL inhibitors attenuated fibrogenic changes in HSCs during necroptosis. Unlike HT-29 and U937 cells, MLKL phosphorylation and oligomerization were not observed during necroptosis in HSCs. RNA sequencing showed that NF-κB signaling-related genes were upregulated in HSCs following necroptotic stimulation. Necroptotic stimuli in HSCs increased the nuclear expression of NF-κB, which decreased after MLKL inhibitor treatment. Induction of necroptosis in HSCs led to autophagosome activation and formation, which were attenuated by MLKL inhibitor treatment.
CONCLUSION: HSCs avoid necroptosis due to the absence of MLKL phosphorylation and oligomerization and are activated through autophagosome and NF-κB pathways.