| First Author | Bourquard N | Year | 2011 |
| Journal | Biochem J | Volume | 436 |
| Issue | 1 | Pages | 91-100 |
| PubMed ID | 21361875 | Mgi Jnum | J:172089 |
| Mgi Id | MGI:5003410 | Doi | 10.1042/BJ20101891 |
| Citation | Bourquard N, et al. (2011) Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response. Biochem J 436(1):91-100 |
| abstractText | Hepatic glucose metabolism is strongly influenced by oxidative stress and pro-inflammatory stimuli. PON2 (paraoxonase 2), an enzyme with undefined antioxidant properties, protects against atherosclerosis. PON2-deficient (PON2-def) mice have elevated hepatic oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages. In the present paper, we demonstrate that PON2 deficiency is associated with inhibitory insulin-mediated phosphorylation of hepatic IRS-1 (insulin receptor substrate-1). Unexpectedly, we observed a marked improvement in the hepatic IRS-1 phosphorylation state in PON2-def/apoE (apolipoprotein E)-/- mice, relative to apoE-/- mice. Factors secreted from activated macrophage cultures derived from PON2-def and PON2-def/apoE-/- mice are sufficient to modulate insulin signalling in cultured hepatocytes in a manner similar to that observed in vivo. We show that the protective effect on insulin signalling in PON2-def/apoE-/- mice is directly associated with altered production of macrophage pro-inflammatory mediators, but not elevated intracellular oxidative stress levels. We further present evidence that modulation of the macrophage inflammatory response in PON2-def/apoE-/- mice is mediated by a shift in the balance of NO and ONOO- (peroxynitrite) formation. Our results demonstrate that PON2 plays an important role in hepatic insulin signalling and underscores the influence of macrophage-mediated inflammatory response on hepatic insulin sensitivity. |
