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

Marko Groeger, Koji Matsuo, Emad Heidary Arash, Ashley Pereira, Dounia Guillou, Cindy Pino, Kayque A. Telles-Silva, Jacquelyn J. Maher, Edward C. Hsiao and Holger Willenbring ()
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Marko Groeger: University of California San Francisco
Koji Matsuo: University of California San Francisco
Emad Heidary Arash: University of California San Francisco
Ashley Pereira: University of California San Francisco
Dounia Guillou: University of California San Francisco
Cindy Pino: University of California San Francisco
Kayque A. Telles-Silva: University of California San Francisco
Jacquelyn J. Maher: University of California San Francisco
Edward C. Hsiao: University of California San Francisco
Holger Willenbring: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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 TNFα and IL1β 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-κB 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39311-w

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DOI: 10.1038/s41467-023-39311-w

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