270-OR: Loss of Myeloid IFNgamma Signaling Prevents Hepatic Inflammation and NASH in Obesity

Nonalcoholic steatohepatitis (NASH) is a major complication of obesity, and interferon-γ (IFNγ) is a key regulator of innate and adaptive immunity by priming macrophages and inducing an inflammatory response. We have recently generated mice with conditional deletion of IFNγ receptor in myeloid cells (Lyz-IFNγR2 KO) . After weeks of high-fat diet (HFD) , male KO and wild-type (WT) mice (n=6) developed fatty liver with a 70% increase in hepatic triglyceride levels compared to chow-fed mice (Figure 1; *P<0.vs. Chow) . Despite fatty liver, Luminex analysis found 20% to 80% decreases in intrahepatic levels of IL-1β, IL-7, IL-15, IFNγ, IL-9, KC, and MIG in KO mice (Figure 2; *P<0.vs. WT) . Next, male mice were fed with a methionine-choline deficient (MCD) diet (n=3) for NASH induction, and liver steatosis and fibrosis were noninvasively measured using Sonovol Ultrasound Imaging System. After 4 weeks of MCD diet, WT mice developed liver fibrosis, but KO mice showed significant attenuation of fibrosis, as indicated by a 20% decrease in liver stiffness (Figure 3) . Taken together, these results indicate that mice with conditional loss of IFNγ signaling in myeloid cells are protected from obesity-mediated hepatic inflammation and diet-induced NASH.

In conclusion, our findings identify myeloid IFNγ signaling as a potential therapeutic target in treating metabolic liver disease.

View largeDownload slide

View largeDownload slide

Close modal