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

Tae Hyo Kim, Bubu A. Banini, Faizal Z. Asumda, Nellie A. Campbell, Chunling Hu, Catherine D. Moser, Abdirashid M. Shire, Shaoshan Han, Chenchao Ma, Anuradha Krishnan, Taofic Mounajjed, Thomas A. White, Gregory J. Gores, Nathan K. LeBrasseur, Michael R. Charlton, Lewis Rowland Roberts

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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 downregulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wild-type 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 mo. WT mice on FFD showed a threefold increase in hepatic Sulf2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression compared with WT mice on SC. Knockout of Sulf2 led to a significant decrease in diet-mediated weight gain and dyslipidemia compared with WT mice on FFD. Knockout of Sulf2 also abrogated diet-induced steatohepatitis and hepatic fibrosis compared with WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFβR2 and PDGFRβ were significantly decreased in Sulf2-KO mice compared with 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.

Original languageEnglish (US)
Pages (from-to)G333-G344
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume319
Issue number3
DOIs
StatePublished - Sep 2020

Keywords

  • Fast-food diet
  • Liver fibrosis
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Obesity
  • SULF2
  • Sulfatase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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