title: Apolipoprotein CIII reduces proinflammatory cytokine-induced apoptosis in rat pancreatic islets via the Akt prosurvival pathway.
abstract: Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic β-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse β-cells, exposure of rat islets to ApoCIII alone (50 μg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1β + interferon-γ, ApoCIII reduced cytokine-mediated islet cell death and impairment of β-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL-1β-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor κB-inhibitor inhibitor of κB and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt.
authors.affiliation: Hagedorn Research Institute, Niels Steensens Vej 1, 2820 Gentofte, Denmark. jstq@hagedorn.dk
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.forename: Gunilla
authors.initials: G
authors.lastname: Olivecrona
authors.forename: Michala C
authors.initials: MC
authors.lastname: Prause
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Thomas
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D053305:Apolipoprotein C-III; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D009569:Nitric Oxide; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium