THEMIS attenuates MASH by suppressing disease-associated hepatocyte induction and hepatocyte senescence in mice
Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza A.P. Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, Jiandie D. Lin
Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza A.P. Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, Jiandie D. Lin
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Research Article Hepatology Metabolism

THEMIS attenuates MASH by suppressing disease-associated hepatocyte induction and hepatocyte senescence in mice

Abstract

Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction–associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus–mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.

Authors

Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza A.P. Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, Jiandie D. Lin

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Figure 6

Themis regulates senescence in a cellular autonomous manner via Erk signaling.

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Themis regulates senescence in a cellular autonomous manner via Erk sign...
(A) Immunoblotting of total lysates from WT and Themis-KO livers. (B) Immunoblotting of total lysates from Themis Flox and HKO livers. (C) Immunoblotting of total lysates from mouse and human primary hepatocytes transduced with Ad-GFP or Ad-Themis. (D) Immunoblotting of Themis Flox and HKO mice primary hepatocytes stimulated with 100 ng/mL EGF at indicated time points. (E) RAS activity assessment of EGF-treated primary hepatocytes isolated from Flox and HKO mice fed MASH diet for 5 months. (F and G) Hepa1 cells overexpressing either GFP or Themis were treated with 50 nM doxorubicin (Dox) for 3 days. (F) SA-β-GAL staining of Hepa1 cells. (G) Immunoblotting of total lysates from Hepa1 cells. (H) Immunoblotting of total lysates. Hepa1 cells overexpressing either GFP or Themis were treated with 1 μM Dox for 2 hours, followed by 10 nM MEK inhibitor trametinib treatment for 3 days. Scale bars: 50 μm (F).