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

Abstract

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.

CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis

“…Notably, other members of the IL-6 family, such as IL-6, CT1, CNTF, and LIF, have been confirmed to be involved in metabolic homeostasis, which exert antiobesity effects but mainly by acting on the central nervous system ( 11 – 16 ). Interestingly, a recent study showed that CLCF1 was a cholangiocyte-derived paracrine factor and played adaptive and protective roles during NASH pathogenesis ( 38 ). However, the role of CLCF1 in regulating metabolic homeostasis and whether CLCF1 could also target the central nervous system remain uncertain.…”

CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes

“…Here, we identified CLCF1 as an adipocyte-derived cytokine and revealed that CLCF1 autocrine signaling was a pivotal suppressor of thermogenic capacity, thereby leading to metabolic disorders. In addition, a recent study revealed that CLCF1 was an intrahepatic cholangiocyte-derived secreted factor that was elevated in the liver in nonalcoholic steatohepatitis (NASH) patients, and it performed a protective role during NASH pathogenesis ( 45 ). According to our findings and those of others, CLCF1 expression is increased in both adipose tissues and the liver under metabolic stress conditions, but CLCF1 has an adverse effect on adipocyte thermogenesis and a favorable effect in hepatic metabolism, illustrating the complex role of CLCF1 in maintaining tissue homeostasis.…”

Emerging novel targets for nonalcoholic fatty liver disease treatment: Evidence from recent basic studies

“…Cardiotrophin-like cytokine factor 1 is another cholangiocyte-derived paracrine factor that exerts beneficial effects in NASH. Downregulation of a subunit of its receptor complex leukemia inhibitory factor receptor contributes to the progression of NASH[ 103 ]. Compared with other nonparenchymal cells, there are fewer studies addressing the effects of cholangiocytes on NASH, and a related therapeutic approach is still lacking.…”