Research ArticleMetabolic Disease

Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance

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Science Translational Medicine  26 Feb 2020:
Vol. 12, Issue 532, eaaw9709
DOI: 10.1126/scitranslmed.aaw9709

Muted macrophages

Obesity and impaired insulin sensitivity are known to predispose to nonalcoholic fatty liver disease. Azzimato et al. show that liver macrophages (LMs) contribute to a weakened antioxidant response to hepatic lipid accumulation in ob/ob mice fed a high-fat diet. LMs in the metabolically dysregulated animals showed increased transcription of miR-144, a microRNA that impaired the LM antioxidant response by targeting nuclear factor erythroid 2–related factor 2 (NRF2). Targeting this microRNA restored the LM response to oxidative damage in human 3D liver cell culture and improved insulin resistance in obese mice. miR-144 was also up-regulated in obese insulin-resistant humans, suggesting the potential clinical relevance of the mechanism.

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