Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance
Authors: Cecilia Morgantini
André Sulen
Myriam Aouadi
Laura Levi
Valerio Azzimato
Carolina Oses
Mikael Rydén
Connie Xu
Xidan Li
Robin P Choudhury
Anders Thorell
Emelie Barreby
Kerstin Wålhen
Erik Näslund
Siobhan M Craige
Volker M Lauschke
Jennifer Jager
Ping Chen
Naveed Akbar
Joanne X Shen
Joost Willerbrords
Lars Haag
Ewa Ellis
Journal: Science Translational Medicine (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Obesity; Insulin resistance; Nonalcoholic fatty liver disease (NAFLD); Lipid accumulation; Oxidative stress
Affiliations: Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden., Université Côte d’Azur, Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity, 06000 Nice, France., Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Solna, Sweden., Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DU Oxford, UK., Department of Laboratory Medicine, Laboratory Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden., Division of Transplantation Surgery, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 141 57 Huddinge, Sweden., Unit of Endocrinology Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden., Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 182 88 Stockholm, Sweden., Department of Surgery, Ersta Hospital, Karolinska Institutet, 116 28 Stockholm, Sweden., Human Nutrition, Food, and Exercise Department, Virginia Tech, Blacksburg, VA 24060, USA.

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. 

Retracted: No

PubPeer comments:
 Theu00a0Y-axis in all GTT graphs inu00a0 figures 5Q, S1b, S4Du00a0 should be inu00a0mmol L, not inu00a0 mg dl. With the current Y-axisu00a0unit, the basal glucose levels are extremely low. The mice will experienceu00a0lossu00a0ofu00a0consciousness, or evenu00a0death before reaching these values of extremeu00a0hypoglycemiau00a0(10 mg dl).u00a0I assume there should be an editing error.u00a0 , 
 ![file] In figure 4G, the GATA4 panel seems to have been vertically and horizontallyu00a0flipped. This would changeu00a0the order of theu00a0scramble and GeRP-amiR-144u00a0groups and, therefore, the plotted differenceu00a0ofu00a0p-GATA4u00a0in the barplot would no longer be valid. The correct alignmentu00a0may only show au00a0differenceu00a0in GATA 4 amounts between the two groups if the samples loading were equal. Can you check u00a0and share the uncropped membrane s raw images for GATA4 andu00a0p-GATA4, which visualize the membrane s edges?u00a0 Did you check Erbb3 expression? ,