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

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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.

Abstract

Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2–related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, miR-144, was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of miR-144 in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD.

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