title: Genetic manipulation of the ApoF/Stat2 locus supports an important role for type I interferon signaling in atherosclerosis.
abstract: Apolipoprotein F (ApoF) is a sialoglycoprotein that is a component of the HDL and LDL fractions of human serum. We sought to test the hypothesis that ApoF plays an important role in atherosclerosis in mice by modulating lipoprotein function. Atherosclerosis was assessed in male low density lipoprotein receptor knockout (Ldlr KO) and ApoF/Ldlr double knockout (DKO) mice fed a Western diet for 16 weeks. ApoF/Ldlr DKO mice showed a 39% reduction in lesional area by en face analysis of aortas (p < 0.05), despite no significant differences in plasma lipid parameters. ApoF KO mice had reduced expression of Interferon alpha (IFNα) responsive genes in liver and spleen, as well as impaired macrophage activation. Interferon alpha induced gene 27 like 2a (Ifi27l2a), Oligoadenylate synthetases 2 and 3 (Oas2 and Oas3) were significantly reduced in the ApoF KO mice relative to wild type controls. These effects were attributable to hypomorphic expression of Stat2 in the ApoF KO mice, a critical gene in the Type I IFN pathway that is situated just 425 base pairs downstream of ApoF. These studies implicate STAT2 as a potentially important player in atherosclerosis, and support the growing evidence that the Type I IFN pathway may contribute to this complex disease.
authors: Division of Translational Medicine and Human Genetics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: lagor@bcm.edu.
authors: William R
authors: WR
authors: Lagor
authors: Division of Translational Medicine and Human Genetics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: David W
authors: DW
authors: Fields
authors: Division of Translational Medicine and Human Genetics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Robert C
authors: RC
authors: Bauer
authors: Department of Microbiology and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Alison
authors: A
authors: Crawford
authors: Department of Microbiology and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Michael C
authors: MC
authors: Abt
authors: Department of Microbiology and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
authors: David
authors: D
authors: Artis
authors: Department of Microbiology and Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA.
authors: E John
authors: EJ
authors: Wherry
authors: Division of Translational Medicine and Human Genetics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Daniel J
authors: DJ
authors: Rader
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D001053:Apolipoproteins / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007370:Interferon Type I / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*; D050795:STAT2 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001053:Apolipoproteins; D007370:Interferon Type I; D011973:Receptors, LDL; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; C036321:apolipoprotein F
keywords: ApoF; Atherosclerosis; STAT2; Type I IFN