Intrahepatic paracrine signaling by cardiotrophin‐like cytokine factor 1 ameliorates diet‐induced NASH in mice

Background and Aims: The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease‐associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. Approach and Results: Here, we performed transcriptomic analyses and identified cardiotrophin‐like cytokine factor 1 (CLCF1), a member of the IL‐6 family cytokines, as a cholangiocyte‐derived paracrine factor that was elevated in the liver from diet‐induced NASH mice and patients with NASH. Adenovirus‐associated virus–mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet‐induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte‐specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. Conclusions: Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.