title: High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation.
abstract: Obesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor κB (NF-κB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFα-induced NF-κB activation, correlating with decreased NF-κB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-κB activation.
authors.affiliation: Faculty of Science, School of Medical and Molecular Biosciences, University of Technology-Sydney, Sydney, NSW, Australia.
authors.forename: Kristine C
authors.initials: KC
authors.lastname: McGrath
authors.forename: Xiao Hong
authors.initials: XH
authors.lastname: Li
authors.forename: Phillippa T
authors.initials: PT
authors.lastname: Whitworth
authors.forename: Robert
authors.initials: R
authors.lastname: Kasz
authors.forename: Joanne T
authors.initials: JT
authors.lastname: Tan
authors.forename: Susan V
authors.initials: SV
authors.lastname: McLennan
authors.forename: David S
authors.initials: DS
authors.lastname: Celermajer
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Alison K
authors.initials: AK
authors.lastname: Heather
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006520:Hepatitis, Animal / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008075:Lipoproteins, HDL / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; D007328:Insulin; D015850:Interleukin-6; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose
keywords: apolipoprotein AI; cellular signalling; insulin resistance