Knockout of Sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease.

Sulfatase 2 (SULF2) is a heparan sulfate editing enzyme that regulates the milieu of growth factors and cytokines involved in a variety of cellular processes. We used a murine model of diet-induced steatohepatitis to assess the effect of SULF2 down-regulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wildtype B6;129 mice (WT) and Sulf2-knockout B6;129P2-SULF2Gt(PST111)Byg mice (Sulf2-KO) were fed a fast food diet (FFD) rich in saturated fats, cholesterol and fructose or a standard chow diet (SC) ad libitum for 9 months. WT mice on FFD showed a 3-fold increase in hepatic SULF2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression, compared to WT mice on SC. Knockout of Sulf2-led to a significant decrease in diet-mediated weight gain and dyslipidemia compared to WT mice on FFD. Knockout of Sulf2-KO also abrogated diet-induced steatohepatitis and hepatic fibrosis compared to WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFβR2 and PDGFRβ were significantly decreased in Sulf2-KO mice compared to WT mice on FFD. Together, our data suggest that knockout of Sulf2 significantly downregulates dyslipidemia, steatohepatitis and hepatic fibrosis in a diet-induced mouse model of NAFLD, suggesting that targeting of SULF2 signaling may be a potential therapeutic mechanism in NASH.