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 2

Induction of Themis expression in mouse and human MASH livers.

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Induction of Themis expression in mouse and human MASH livers. (A) Class...
(A) Classification of top differentially expressed genes according to their zonal expression patterns. (B) Feature plots showing Themis expression in chow and MASH hepatocytes. (C) qPCR analysis of Themis expression in control and diet-induced MASH livers (n = 7 per group). (D) Immunoblotting analysis of total liver lysates. (E) Correlation analysis of hepatic Themis expression with plasma ALT levels in a cohort of MASH diet–fed mice (n = 15). (F) Correlation analysis of hepatic Themis expression with liver TAG content in a cohort of diet-induced obese mice (n = 55). (G) qPCR analysis of hepatic THEMIS expression in 2 cohorts of individuals without MASH (cohort 1: n = 8, cohort 2: n = 6) and individuals with MASH (cohort 1: n = 7, cohort 2: n = 6). (H) RNA scope analysis of THEMIS expression in non-MASH and MASH human liver biopsies. (I) qPCR analysis of Themis expression in primary hepatocytes treated with vehicle, 300 μM palmitic acid (PA), 300 μM oleic acid (OA), 5 ng/mL TGF-β, 20 ng/mL LPS, and 20 ng/mL IFN-γ for 24 hours. (J) Immunoblotting analysis of total lysates from treated hepatocytes. (K) qPCR analysis of hepatic Themis expression in MASH diet–fed mice receiving either PBS or lipid droplet treatment via tail vein injection (n = 6). Data in C, G, I, and K represent mean ± SEM; statistical comparisons were conducted using 2-tailed unpaired Student’s t test for C, G, and K) and with 1-way ANOVA with post hoc Tukey’s HSD test in I. *P < 0.05, ***P < 0.001. Scale bars: 50 μm (H).