Research Articles
High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation[S]

https://doi.org/10.1194/jlr.M043281Get rights and content
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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.

insulin resistance
apolipoprotein AI
cellular signalling

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This work was supported by the University of Technology-Sydney Chancellor's Postdoctoral Research Fellowship Scheme and the Diabetes of Australia Research Trust. The authors have no conflicts of interest to disclose.

    Abbreviations:

    ChREBP

    carbohydrate responsive element binding protein

    G6Pase

    glucose-6-phosphatase

    HFD

    high-fat diet

    HOMA-IR

    homeostatic model assessment of insulin resistance

    HuH-7

    human hepatoma cell line

    IκB

    inhibitor κB

    IKK

    IκB kinase

    IKK-β

    inhibitor of nuclear factor κB kinase subunit β IL, interleukin

    IPGTT

    intraperitoneal glucose tolerance test

    IPITT

    intraperitoneal insulin tolerance test

    NF-κB

    nuclear factor κB

    PEPCK

    phosphoenolpyruvate carboxykinase

    PLPC

    1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine

    rHDL

    reconstituted HDL containing apolipoprotein AI

    SAA1

    serum amyloid A1

    StD

    standard chow diet

    SREBP-1

    sterol regulatory element binding protein 1

[S]

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of five figures and one table.