Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch/osteopontin signaling
Yue Li, … , Qi Wang, Chunjiong Wang
Yue Li, … , Qi Wang, Chunjiong Wang
Published December 8, 2022
Citation Information: JCI Insight. 2022;7(23):e162402. https://doi.org/10.1172/jci.insight.162402.
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Research Article Gastroenterology Hepatology

Increased CHCHD2 expression promotes liver fibrosis in nonalcoholic steatohepatitis via Notch/osteopontin signaling

Abstract

Nonalcoholic steatohepatitis (NASH) is closely related to liver fibrosis. The role of coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) in NASH remains unknown. CHCHD2’s functions as a transcription factor have received much less attention than those in mitochondria. Herein, we systematically characterized the role of CHCHD2 as a transcription factor by chromatin immunoprecipitation sequencing and found its target genes were enriched in nonalcoholic fatty liver disease (NAFLD). Overall, CHCHD2 expression was found to be increased in the livers of patients with NAFLD and those of NASH mice. In line with these findings, CHCHD2 deficiency ameliorated NASH- and thioacetamide-induced liver fibrosis, whereas hepatocyte-specific CHCHD2 overexpression promoted liver fibrosis in NASH mice via Notch signaling. Specifically, CHCHD2-overexpressing hepatocytes activated hepatic stellate cells by upregulating osteopontin levels, a downstream mediator of Notch signals. Moreover, Notch inhibition attenuated CHCHD2 overexpression–induced liver fibrosis in vivo and in vitro. Then we found lipopolysaccharide-induced CHCHD2 expression in hepatocytes was reverted by verteporfin, an inhibitor that disrupts the interaction between Yes-associated protein (YAP) and transcriptional enhanced associate domains (TEADs). In addition, CHCHD2 levels were positively correlated with those of TEAD1 in human samples. In conclusion, CHCHD2 is upregulated via YAP/TAZ-TEAD in NASH livers and consequently promotes liver fibrosis by activating the Notch pathway and enhancing osteopontin production.

Authors

Yue Li, Wenjing Xiu, Jingwen Xu, Xiangmei Chen, Guangyan Wang, Jinjie Duan, Lei Sun, Ben Liu, Wen Xie, Guangyin Pu, Qi Wang, Chunjiong Wang

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Figure 8

CHCHD2 expression is upregulated by palmitate and LPS and is suppressed by verteporfin.

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CHCHD2 expression is upregulated by palmitate and LPS and is suppressed ...
(A–E) Western blot analysis of protein level of CHCHD2: primary murine hepatocytes were treated with 100 μM palmitate for 48 hours (A) or 100 ng/mL LPS for 48 hours (n = 5 independent experiment) (B); (C) primary murine hepatocytes were treated with 100 ng/mL LPS and 50 ng/mL cycloheximide (CHX) for 0, 1, 3, 6, or 9 hours (n = 5 independent experiments); (D) primary murine hepatocytes were treated with 0.5 or 1 nM verteporfin for 48 hours (n = 5 independent experiments); (E) primary murine hepatocytes were treated with LPS for 48 hours with or without pretreatment with 1 nM verteporfin for 0.5 hours (n = 3 independent experiments). (F) Quantitative PCR (qPCR) analysis of mRNA levels of Tead1 in MCD/HFD-fed mouse liver (n = 12–13 per group). (G) Western blot analysis of protein level of TEAD1 in MCD/HFD-fed mouse liver (n = 4 per group). (H) Hepatocytes were transfected with siRNA targeting Tead1 and then treated with LPS. Western blot analysis of protein levels of CHCHD2 and TEAD1 (n = 5 independent experiments). (I) Correlation analysis of CHCHD2 and TEAD1 expression based on the immunohistochemical staining in patient livers (n = 33; compare to Figure 1B, 9 human liver samples were not stained with TEAD1 antibody because the liver sections ran out). *P < 0.05. (A, B, and F–H) P values were from unpaired t test; (C) P values were from a 2-way ANOVA with a post hoc Fisher’s least significant difference (LSD) test; (D and E) P values were from a 1-way ANOVA with a post hoc Fisher’s LSD test. VP, verteporfin; PA, palmitate.