2451-P: Hepatocyte-Intrinsic Inflammatory Signaling Is Reduced in Type 2 Diabetes

Introduction and Objective: Chronic inflammation is a hallmark of obesity and metabolic syndrome and contributes to the development of insulin resistance and type 2 diabetes (T2D). Although hepatic inflammation is well characterized in these conditions, whether this is due to hepatocyte-intrinsic versus extrinsic mechanisms is poorly understood. In this study, we assessed cell-intrinsic hepatic inflammation in people with T2D using iPS cells in vitro. Methods: Induced pluripotent stem cellsfrom people with and without T2D were differentiated into hepatocytes (iHeps) in vitro, and inflammatory pathway gene expression in the basal and insulin-stimulated states assessed by RNA sequencing. Results: iHeps derived from individuals with T2D retained key features of hepatic insulin resistance in vitro including reduced phosphorylation of proteins in the insulin signaling pathway and impaired insulin-mediated suppression of gluconeogenic gene expression. Transcriptomic analyses showed that in the basal state in T2D iHeps, the most upregulated genes were those involved in FGF receptor signaling, while surprisingly, the most downregulated in T2D iHeps were genes regulating TNF-α signaling. Insulin regulated a subset of inflammatory and immune-related genes, and insulin-dependent regulation of several of these genes was attenuated in T2D iHeps. Overall, gene set enrichment analysis demonstrated a global reduction in inflammatory signaling pathways in T2D iHeps, including pathways associated with IFN-γ, TNF-α, and IL-6 signaling, both at baseline and following insulin stimulation. Conclusion: Using iPS-derived hepatocytes we demonstrate that cell-intrinsic inflammatory gene expression is lower and shows reduced responsiveness to insulin in hepatocytes from individuals with T2D, indicating that the hepatic inflammation observed in T2D is driven by extrinsic, rather than hepatocyte-intrinsic, mechanisms. This underscores the importance of circulating signals and other cell types in driving hepatic inflammation in metabolic disease. Disclosure B. Kunkemoeller: None. A. Gattu: None. J. Dreyfuss: None. C. Kahn: Consultant; Current; TIXiMED, Alnylam Pharmaceuticals, Inc. Board Member; Current; 1825 Therapeutics. Consultant; Ended; Cellarity.