1598-P: MIF-upregulated CD74 in Liver Contributes to the Development of NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysfunctions, such as obesity. Macrophage migration inhibitory factor (MIF), a pro-cytokine, was also identified to regulate NAFLD, but the molecular mechanisms remain unclear. We presently indicated that MIF has a non-inflammatory effect on triggering NAFLD through upregulating its cell membrane receptor, CD74. MIF increased CD74 protein rather than gene expression in liver cells in a time-dependent manner. That was not associated with any changes in the expression of pro-inflammatory factors, such as TNF-α, IL-6 and IL-1β. In a MIF overexpressed animal model (Mif lung Tg), high circulating MIF levels increased hepatic CD74 proteins but not genes in the absence of inflammation in the liver. High fat diet also increased circulating MIF levels leading to an upregulation of hepatic CD74. All these animal models with high circulating MIF and hepatic CD74 were accompanied with steatosis and fibrosis in the liver. These alterations could be reversed by either MIF neutralization or MIF knockout. Caspase 4 facilitates the degradation of CD74. MIF endocytosis inhibited caspase 4 cleavage and activation. Thus, inhibition of MIF upregulated cleaved caspase 4 leading to a degradation in CD74. Overall, our findings indicate that MIF stabilizes CD74 through suppressing caspase 4 and this may be an important mechanism in regulating NAFLD in the absence of inflammation. Disclosure L. Chen: None. L. Li: None. Y. Huang: None. X. Chen: None. Y. Qi: None. H. Tong: None. H. Wu: None. D. Qi: None. Funding Canadian Institutes of Health Research (PJT156116); Research and Development Corporation; National Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); National Institutes of Health (AR-078334); China Scholarship Council (to L.C., Y.H., L.L.)