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.
Highlights
Obesity-induced liver inflammation can drive insulin resistance
NF-B activation involves a complex series of signaling events that begins with activation of the 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; IB, inhibitor B; IKK, IB kinase; IKK-, inhibitor of nuclear factor B kinase subunit ; IL, interleukin; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; NF-B, nuclear factor B; PEPCK, phosphoenolpyruvate carboxykinase; PLPC, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine; rHDL, reconstituted High density lipoproteins (HDLs) containing apolipoprotein AI; SAA1, serum amyloid A1; StD, standard chow diet; SREBP-1, sterol regulatory element binding protein 1
The increase in body weight was associated with increased serum triglyceride, hepatic neutral lipid levels, and key transcriptional regulators of lipogenic gene expression in the liver sterol regulatory element binding protein 1 (SREBP-1) and carbohydrate responsive element binding protein (ChREBP) (P < 0.001; Fig. 1B, C)
Summary
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. Genetic manipulation to inhibit hepatic NF-B activity directly protects against insulin resistance in response to a HFD in mice [4] Such findings provide strong evidence that the liver is a primary site of inflammatory action that causes insulin resistance, and that NF-B is a central pathogenic factor underlying inflammation-induced insulin resistance. NF-B activation involves a complex series of signaling events that begins with activation of the 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; IB, inhibitor B; IKK, IB kinase; IKK-, inhibitor of nuclear factor B kinase subunit ; IL, interleukin; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; NF-B, nuclear factor B; 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. Once phosphorylated, IB is targeted for ubiquitination and subsequent degradation, leaving NF-B free to translocate to the nucleus and initiate transcription of target genes [9]
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