Skeletal Muscle Insulin Resistance Associated with Cholesterol-Induced Activation of Macrophages Is Prevented by High Density Lipoprotein

Andrew L Carey,Alaina K Natoli,Dmitri Sviridov,Andrew L Siebel,Brian G Drew,Peter J Meikle,Bronwyn A Kingwell,Medini Reddy-Luthmoodoo,Wilissa D’Souza,Makoto Kanzaki

doi:10.1371/journal.pone.0056601

Andrew L Carey, Alaina K Natoli + Show 8 more

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https://doi.org/10.1371/journal.pone.0056601

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Abstract

BackgroundEmerging evidence suggests that high density lipoprotein (HDL) may modulate glucose metabolism through multiple mechanisms including pancreatic insulin secretion as well as insulin-independent glucose uptake into muscle. We hypothesized that HDL may also increase skeletal muscle insulin sensitivity via cholesterol removal and anti-inflammatory actions in macrophages associated with excess adiposity and ectopic lipid deposition.MethodsHuman primary and THP-1 macrophages were treated with vehicle (PBS) or acetylated low density lipoprotein (acLDL) with or without HDL for 18 hours. Treatments were then removed, and macrophages were incubated with fresh media for 4 hours. This conditioned media was then applied to primary human skeletal myotubes derived from vastus lateralis biopsies taken from patients with type 2 diabetes to examine insulin-stimulated glucose uptake.ResultsConditioned media from acLDL-treated primary and THP-1 macrophages reduced insulin-stimulated glucose uptake in primary human skeletal myotubes compared with vehicle (primary macrophages, 168±21% of basal uptake to 104±19%; THP-1 macrophages, 142±8% of basal uptake to 108±6%; P<0.05). This was restored by co-treatment of macrophages with HDL. While acLDL increased total intracellular cholesterol content, phosphorylation of c-jun N-terminal kinase and secretion of pro- and anti-inflammatory cytokines from macrophages, none were altered by co-incubation with HDL. Insulin-stimulated Akt phosphorylation in human skeletal myotubes exposed to conditioned media was unaltered by either treatment condition.ConclusionInhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with acLDL was restored by co-treatment with HDL. However, these actions were not linked to modulation of common pro- or anti-inflammatory mediators or insulin signaling via Akt.

Highlights

While circulating high-density lipoprotein (HDL) is wellestablished to protect against atherosclerotic vascular disease, there is increasing evidence that it may have anti-diabetic properties [1–4]
Inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with acetylated low density lipoprotein (acLDL) was restored by co-treatment with high density lipoprotein (HDL)
These actions were not linked to modulation of common pro- or anti-inflammatory mediators or insulin signaling via Akt

Summary

Introduction

While circulating high-density lipoprotein (HDL) is wellestablished to protect against atherosclerotic vascular disease, there is increasing evidence that it may have anti-diabetic properties [1–4]. The mechanisms accounting for the actions of HDL on glucose metabolism are multiple and include actions both in the pancreas [2,4] and skeletal muscle [2]. HDL promotes glucose-stimulated insulin secretion via both direct effects [4] as well as secondary to cholesterol efflux [5–8]. Emerging evidence suggests that high density lipoprotein (HDL) may modulate glucose metabolism through multiple mechanisms including pancreatic insulin secretion as well as insulin-independent glucose uptake into muscle. We hypothesized that HDL may increase skeletal muscle insulin sensitivity via cholesterol removal and anti-inflammatory actions in macrophages associated with excess adiposity and ectopic lipid deposition

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