title: Induction of heme oxygenase-1 with dietary quercetin reduces obesity-induced hepatic inflammation through macrophage phenotype switching.
abstract: OBJECTIVE
  Obesity-induced steatohepatitis accompanied by activated hepatic macrophages/Kupffer cells facilitates the progression of hepatic fibrinogenesis and exacerbates metabolic derangements such as insulin resistance. Heme oxyganase-1 (HO-1) modulates tissue macrophage phenotypes and thus is implicated in protection against inflammatory diseases. Here, we show that the flavonoid quercetin reduces obesity-induced hepatic inflammation by inducing HO-1, which promotes hepatic macrophage polarization in favor of the M2 phenotype.
  
  
  METHODS
  Male C57BL/6 mice were fed a regular diet (RD), high-fat diet (HFD), or HFD supplemented with quercetin (HF+Que, 0.5g/kg diet) for nine weeks. Inflammatory cytokines and macrophage markers were measured by ELISA and RT-PCR, respectively. HO-1 protein was measured by Western blotting.
  
  
  RESULTS
  Quercetin supplementation decreased levels of inflammatory cytokines (TNFα, IL-6) and increased that of the anti-inflammatory cytokine (IL-10) in the livers of HFD-fed mice. This was accompanied by upregulation of M2 macrophage marker genes (Arg-1, Mrc1) and downregulation of M1 macrophage marker genes (TNFα, NOS2). In co-cultures of lipid-laden hepatocytes and macrophages, treatment with quercetin induced HO-1 in the macrophages, markedly suppressed expression of M1 macrophage marker genes, and reduced release of MCP-1. Moreover, these effects of quercetin were blunted by an HO-1 inhibitor and deficiency of nuclear factor E2-related factor 2 (Nrf2) in macrophages.
  
  
  CONCLUSIONS
  Quercetin reduces obesity-induced hepatic inflammation by promoting macrophage phenotype switching. The beneficial effect of quercetin is associated with Nrf2-mediated HO-1 induction. Quercetin may be a useful dietary factor for protecting against obesity-induced steatohepatitis.
authors.affiliation: Department of Food Science and Nutrition, University of Ulsan, 93 Daehak-ro, Nam-ku, Ulsan 44610, Korea.
authors.forename: Chu-Sook
authors.initials: CS
authors.lastname: Kim
authors.affiliation: Department of Biological Science, University of Ulsan, Ulsan 44610, Korea.
authors.forename: Hye-Seon
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Biological Science, University of Ulsan, Ulsan 44610, Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Science, University of Ulsan, Ulsan 44610, Korea.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Food Science and Nutrition, University of Ulsan, 93 Daehak-ro, Nam-ku, Ulsan 44610, Korea.
authors.forename: Rina
authors.initials: R
authors.lastname: Yu
keywords: Obesity; inflammation; macrophage; quercetin