Life sciences · 2025
A PBX1-IL7R axis mediates liver fibrosis in non-alcoholic fatty liver disease.
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Yang Zhen, Zhang Jinbo, Wang Qihang, Xu Huihui, Qin Xihu, Lv Fangqiao
Аннотация
AIMS: Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction associated steatotic liver disease (MASLD), represents a spectrum of chronic liver diseases that eventually lead to cirrhosis and hepatocellular carcinoma. Liver fibrosis is both a pathological feature and a contributing factor in NAFLD. In the present study we investigated whether targeting pre-B cell leukemia transcription factor 1 (PBX1) and interleukin 7 receptor (IL7R) might ameliorate liver fibrosis in the context of NAFLD.
METHODS AND MATERIALS: NAFLD was induced in C57/B6j mice by feeding with a choline-deficient amino acid defined high-fat diet (CDAA-HFD).
KEY FINDINGS: Both PBX1 expression and IL7R expression were up-regulated in hepatic stellate cells (HSCs) isolated from the mice fed the CDAA-HFD compared to those isolated from the control mice. Myofibroblast-specific PBX1 depletion, by injecting the mice with AAV6 carrying short-hairpin RNA (shRNA) against PBX1, significantly attenuated liver fibrosis induced by CDAA-HFD feeding. Similarly, myofibroblast-specific IL7R depletion significantly mitigated NAFLD-associated liver fibrosis. Of note, liver injury and steatosis were not influenced by either PBX1 or IL7R depletion. Importantly, IL7R blockade with a neutralizing antibody likewise diminished NAFLD-associated liver fibrosis. Finally, a positive correlation between PBX1 expression, IL7R expression, and myofibroblast activation was identified in liver specimens from NAFLD patients.
SIGNIFICANCE: Our data demonstrate the feasibility of targeting the PBX1-IL7R axis for the intervention of NAFLD-associated liver fibrosis.
METHODS AND MATERIALS: NAFLD was induced in C57/B6j mice by feeding with a choline-deficient amino acid defined high-fat diet (CDAA-HFD).
KEY FINDINGS: Both PBX1 expression and IL7R expression were up-regulated in hepatic stellate cells (HSCs) isolated from the mice fed the CDAA-HFD compared to those isolated from the control mice. Myofibroblast-specific PBX1 depletion, by injecting the mice with AAV6 carrying short-hairpin RNA (shRNA) against PBX1, significantly attenuated liver fibrosis induced by CDAA-HFD feeding. Similarly, myofibroblast-specific IL7R depletion significantly mitigated NAFLD-associated liver fibrosis. Of note, liver injury and steatosis were not influenced by either PBX1 or IL7R depletion. Importantly, IL7R blockade with a neutralizing antibody likewise diminished NAFLD-associated liver fibrosis. Finally, a positive correlation between PBX1 expression, IL7R expression, and myofibroblast activation was identified in liver specimens from NAFLD patients.
SIGNIFICANCE: Our data demonstrate the feasibility of targeting the PBX1-IL7R axis for the intervention of NAFLD-associated liver fibrosis.