Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages

Author(s)

Groeger, Marko ; Matsuo, Koji ; Arash, Emad Heidary ; Pereira, Ashley ; Le Guillou, Dounia ; Pino, Cindy ; Telles-Silva, Kayque A. ; Maher, Jacquelyn J. ; Hsiao, Edward C. ; Willenbring, Holger

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 14, n. 1, p. 14-pg., 2023-07-03.

Abstract

Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNF & alpha; and IL1 & beta; as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-& kappa;B or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver. Hepatic insulin resistance is an established driver of type 2 diabetes but is difficult to model in vitro. Here researchers use co-culture of hepatocytes and macrophages derived from the same human iPSC line to show how inflammation disrupts insulin-mediated regulation of hepatic glucose metabolism and identify targets for therapy of hepatic insulin resistance. (AU)

• FAPESP's process: 22/08157-5 - Investigation of possible etoposide-induced hepatocyte maturation mechanisms in vitro
• Grantee: Kayque Alves Telles Silva
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)