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

Sci Transl Med. 2020 Feb 26;12(532):eaaw9709. doi: 10.1126/scitranslmed.aaw9709.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants*
  • Humans
  • Insulin Resistance*
  • Kupffer Cells*
  • Liver
  • Mice
  • MicroRNAs
  • NF-E2-Related Factor 2
  • Non-alcoholic Fatty Liver Disease*
  • Obesity


  • Antioxidants
  • MIRN144 microRNA, human
  • MIRN144 microRNA, mouse
  • MicroRNAs
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nfe2l2 protein, mouse