title: Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response.
abstract: 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.
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Noam
authors.initials: N
authors.lastname: Bourquard
authors.forename: Carey J
authors.initials: CJ
authors.lastname: Ng
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D007328:Insulin; D043303:Aryldialkylphosphatase