<p class="first" dir="auto" id="d5999204e100">In the liver, NO-sensitive guanylyl cyclase (NO-GC) is expressed in hepatic stellate cells (HSC) and smooth muscle cells (SMC). Here, we explored the role of hepatic NO-GC by examining the liver of mice lacking NO-GC globally (NO-GC knock out, GCKO). <p dir="auto" id="d5999204e102"> 8-10-week-old male GCKO mice and their wildtype (WT) siblings were fed control diet or Western diet (21 % fat, 0.2 % cholesterol) with 42 g/l fructose in drinking water for 16 weeks. Thereafter, mouse livers were analyzed using HE, Sirius red staining, immunofluorescence, and confocal microscopy. <p dir="auto" id="d5999204e107">GCKO mice on control diet had mild portal hepatitis with periportal inflammation, altered ductular architecture of the biliary system and increased ductular proliferation. Cholangiocyte proliferation and myofibroblast formation were evident by the upregulation of cytokeratin 19 and α-SMA expression, respectively. T cells (CD3, CD4 and CD8) were increased significantly in GCKO mice vs WT. Western diet worsened all these parameters as well as the fibrosis stage in GCKO mice. To our surprise, steatosis, steatohepatitis, and chicken wire fibrosis were obvious in WT but absent in GCKO mice after feeding Western diet. <p dir="auto" id="d5999204e109"> Taken together, absence of the NO receptor in mice leads to spontaneous primary sclerosing cholangitis (PSC) and biliary fibrosis. The PSC phenotype worsens upon feeding Western diet. Thus, we identify a so far unknown role of NO-GC in bile duct homeostasis thereby preventing the development of primary sclerosing cholangitis.

Spontaneous biliary fibrosis in NO-GC-deficient mice