Interleukin-1β enhances the intracellular accumulation of cholesterol by up-regulating the expression of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase in podocytes

Abstract

The aim of this article is to investigate whether interleukin-1β (IL-1β) could regulate the intracellular accumulation of cholesterol and the expression of lipid-metabolism-related regulators in podocytes in vitro and the potential mechanisms. Podocytes were treated with 200 μg/ml of low-density protein (LDL), 20 ng/ml of IL-1β, or 200 μg/ml of LDL plus 5-20 ng/ml of IL-1β for 24 h in vitro. The contents of intracellular cholesterol were determined by enzymatic assays and Oil Red O staining. The levels of LDL receptor (LDLr), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, sterol regulatory element binding protein 2 (SREBP-2), SREBP cleavage activating protein (SCAP), and insulin-induced gene-1 (Insig-1) expression were characterized by real-time polymerase chain reaction (RT-PCR) and Western blot assays. Treatment with IL-1β or LDL alone increased the contents of intracellular cholesterol (P < 0.05 for both) and lipid droplets, and treatment with both IL-1β and LDL further increased the accumulation of intracellular cholesterol in podocytes (P < 0.05 vs. LDL alone). While loading with LDL significantly inhibited the expression of LDLr, HMG-CoA reductase, nuclear SREBP-2 (nSREBP-2), SCAP, and Insig-1 by 40-62% treatment with IL-1β enhanced the expression of LDLr, HMG-CoA reductase and nSREBP-2, but not Insig-1, in podocytes (P < 0.05 vs. control). Treatment with both LDL and IL-1β significantly increased the levels of LDLr and HMG-CoA reductase expression and the ratio of SCAP to Insig-1, as compared with that in the LDL-treated podocytes (P < 0.05 vs. LDL alone). Our data indicated that IL-1β mitigated the LDL-triggered SCAP-SREBP-2-mediated feedback inhibition on the expression of LDLr and HMG-CoA reductase, leading to the intracellular accumulation of LDL-cholesterol in podocytes in vitro.

Interleukin-1β Causes Anxiety by Interacting with the Endocannabinoid System

“…In this respect, GABA-mediated inhibition of striatal neuron activity possibly disrupts a circuitry normally limiting fearful or anxiety-related behaviors (Rogan et al, 2005), and enhancement of cAMP signaling in the striatum has been associated with increased anxious-depressive behavior in mice (Favilla et al, 2008;Zhang et al, 2008). This information confirms the relevance of our findings for the pathophysiology of emotional disorders.…”

“…In addition, cholesterol can modulate the activity of GPCRs by promoting receptor dimerization and hence reducing agonist binding . We have demonstrated that IL-1␤ controls striatal CB1R (GABA) activity by regulating cholesterol metabolism, extending for the first time to neuronal elements the described effects of IL-1␤ on cholesterol synthesis in other cell types (Zhang et al, 2011).…”

“…IL-1␤ has been already demonstrated to increase cholesterol intracellular accumulation (Zhang et al, 2011), raising the possibility that altered lipid composition in rafts might mediate the effects of IL-1␤ on CB1Rs (GABA) . Thus, we first investigated whether MCD, which causes a significant depletion of cholesterol in striatal slices , was able to reverse the effects of IL-1␤ on CB1R (GABA) sensitivity.…”

“…We focused on CB1Rs controlling GABA synapses (CB1Rs (GABA) ) in the striatum because this brain area is emerging as a key structure in mood regulation in humans (Reiman et al, 1989;Yoo et al, 2005;Mathew and Ho, 2006) and in rodents (Nestler and Carlezon, 2006;Favilla et al, 2008;Zhang et al, 2008;Steiner et al, 2010). In addition, anxious-depressive behavior is associated with reduced sensitivity of striatal CB1Rs (GABA) , whose activity is rescued by mood-enhancing and antianxiety pharmacological and environmental manipulations Hill and Gorzalka, 2009;De Chiara et al, 2010a,b).…”

Uremic Toxins Enhance Statin-Induced Cytotoxicity in Differentiated Human Rhabdomyosarcoma Cells

“…For example, Zhang et al reported that interleukin-1β increased HMG-CoA reductase mRNA, which caused the intracellular accumulation of LDL-cholesterol in glomerular endothelial cells [26]. In addition, Biswas et al reported that oxidative stress altered many proteins function and the affinity for protein substrates by oxidizing cysteine residues [27].…”