Metabolic dysfunction-associated steatotic liver disease can be alleviated by activating NO/cGMP signaling

Metabolic dysfunction-associated steatotic liver disease encompasses a spectrum of chronic liver diseases ranging from steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Hepatic stellate cells (HSCs), the pericytes of the liver, have been associated with the pathogenesis of MASH. In diseased livers, HSCs transdifferentiate into αSMA+ myofibroblasts. In this activated stage, they produce excess collagen as well as proinflammatory and profibrogenic cytokines. HSCs are known to express proteins of the NO/cGMP pathway. We hypothesized that modulation of this pathway may alter HSC transdifferentiation and thereby the progression of MASH. As a model for MASH, we used ApoE-deficient mice fed a Western diet. In comparison to wild-type mice receiving a normal diet, these animals showed characteristics of MASH, such as steatosis, fibrosis, and inflammation. Both quiescent HSCs and activated αSMA+ myofibroblasts expressed NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), indicating the existence of a functional NO/cGMP pathway in healthy as well as MASH livers. This was further supported by the real-time detection of NO-induced cGMP signals in HSCs isolated from mice expressing a FRET-based cGMP sensor. Moreover, we show that pharmacological treatment with a NO-GC activator elevates cGMP in HSCs and attenuates the pathological phenotype of MASH invivo. In drug-treated mice, we found a reduced amount of fat bubbles and fibrosis, decreased liver enzyme levels, and decreased expression of markers for activated myofibroblasts. In conclusion, we report the NO/cGMP/cGKI signaling pathway as a marker of HSCs and NO-GC activators as potential drugs for the treatment of MASH.