JAZF1/TIP27 is a 27kD transcriptional co-regulator. GWAS studies have indicated that single nucleotide polymorphisms in the JAZF1 gene are associated with increased risk of typeII diabetes (T2D) and several autoimmune diseases. Diet induced obesity is a major risk factor for different metabolic disorders, including T2D and nonalcoholic fatty liver disease (NAFLD). To obtain greater insights into the physiological functions of JAZF1, we generated Jazf1 null mice (Jazf1-/-) and fed them a high fat diet (HFD) for 8 to 15 weeks. We demonstrated that Jazf1-/- mice fed-HFD exhibit lower body-weight and fat-mass compared to obese WT mice. HFD-fed Jazf1-/- mice maintained normal blood glucose levels and were more insulin sensitive and glucose tolerant than obese WT-littermates. Histological examination showed that Jazf1-/- mice were less susceptible to HFD-induced hepatic steatosis than WT littermates as indicated by the greatly reduced hepatic lipid droplets (LD) in Jazf1-/- liver. Furthermore, HFD-fed Jazf1-/-mice also showed reduced levels of serum aspartate aminotransferase, alkaline phosphatase, and sorbitol dehydrogenase, enzymes indicative of hepatocytoxicity. HFD-fed Jazf1-/-mice exhibited a dramatic decrease in the level of liver triglycerides. HFD-fed WT mice showed induction of Jazf1 expression in liver as compared to WT mice with normal diet. RNA-seq and qPCR analysis of liver demonstrated that LD-formation genes (e.g., Plin2/Plin3/Plin4/Cd36/Cidec/Cidea) were greatly suppressed in Jazf1-/- compared to WT mice. Go-term and IPA analysis revealed that inflammatory (e.g., Ccl7/Lcn2/Cd14) and hepatic fibrosis (Col1a1/Egr2/Timp1) were among top pathways down-regulated in HFD-fed Jazf1-/- liver. Our results indicate that JAZF1 functions as a critical regulator of LD formation and inflammation in NAFLD and loss of JAZF1 function protects against metabolic syndrome. Our study may provide new insights into the development of progression of metabolic syndrome and its complications.
C. Srivastava: None. K. Dorr: None. S. Grimm: None. L.M. DeGraff: None. A. Gruzdev: None. A.M. Jetten: None.
National Institutes of Health