Inflammatory Stress Induces Statin Resistance by Disrupting 3-Hydroxy-3-Methylglutaryl-CoA Reductase Feedback Regulation

Abstract

Objective-The risk of cardiovascular disease is increased by up to 33 to 50× in chronic inflammatory states and convention doses of statins may not provide the same cardiovascular protection as in noninflamed patients. This study investigated whether the increase in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-R)-mediated cholesterol synthesis observed under inflammatory stress was resistant to the action of statins and if so, whether this was because of interference with the sterol regulatory element binding protein cleavage-activating protein pathway. Approach and Results-Inflammatory stress was induced by adding cytokines (interleukin-1β, tumor necrosis factor-α, and interleukin-6) and lipopolysaccharides to vascular smooth muscle cells in vitro and by subcutaneous casein injection in apolipoprotein E/scavenger receptors class A/CD36 triple knockout mice in vivo. Inflammatory stress exacerbated cholesterol ester accumulation and was accompanied in vitro and in vivo by increased HMGCoA-R mRNA and protein expression mediated via activation of the sterol regulatory element binding protein cleavageactivating protein/sterol regulatory element binding protein-2 pathway. Atorvastatin reduced HMGCoA-R enzymatic activity and intracellular cholesterol synthesis in vitro. However, inflammatory stress weakened these suppressive effects. Atorvastatin at concentrations of 16 μmol/L inhibited HMGCoA-R activity by 50% in vascular smooth muscle cells, but the same concentration resulted in only 30% of HMGCoA-R activity in vascular smooth muscle cells in the presence of interleukin-1β. Knocking down sterol regulatory element binding protein cleavage-activating protein prevented statin resistance induced by interleukin-1β, and overexpression of sterol regulatory element binding protein cleavage-activating protein induced statin resistance even without inflammatory stress. In vivo, the amount of atorvastatin required to lower serum cholesterol and decrease aortic lipid accumulation rose from 2 to 10 mg/kg per day in the presence of inflammatory stress. Conclusions-Increased

Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease

“…Another plausible hypothesis is that the associations with the cholesterol metabolism network genes that we have observed in monocyte samples may also reflect changes in other tissues or cells that are not accessible in the population setting (e.g., hepatic cells, β-cells). Supporting this notion, inflammatory stimuli produced gene expression changes in several cell types, including hepatocytes and vascular smooth muscle cells (27,30), which are consistent with the correlations we observed between IL-6 and the network genes in human monocytes samples. We and others have also highlighted the importance of β-cell cholesterol homeostasis in T2D (41,43,).…”

“…However, this negative feedback regulation of cholesterol metabolism can be overridden by inflammatory stress. In vitro and in vivo studies confirm that inflammatory stress results in altered expression of the network genes and can increase intracellular cholesterol content in several cell types, including hepatocytes, vascular smooth muscle cells, and macrophages (26–30). In addition, human experimental data from us (monocytes) and others (adipose tissue) (31–34) show that weight loss rebalanced the expression of members of the cholesterol metabolism gene network.…”

Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis

“…Furthermore, approximately 20% of patients fail to respond to statins and appear to be ‘statin-resistant’. In this context, we previously demonstrated that inflammatory stress may cause statin resistance12. Patients with chronic kidney disease (CKD), diabetes, and other inflammatory diseases are at particular risk of statin resistance.…”

Men and Women – Similar But Not Identical: Insights Into LDL-lowering Therapy in Women From the Cholesterol Treatment Trialists Collaboration

“…The extent to which the degree of LDL-C reduction by statins is dictated by the biology of the patient rather than the dose of the drug used is relatively understudied. The individual response to statins may relate to variations in drivers of cholesterol metabolism (absorption, synthesis, clearance and sensitivity to HMG CoA reductase inhibition), and inflammation (which causes statin resistance [19], as well as predicting increased event rates and less regression in patients receiving statins [20]). The safety and tolerability of high-dose statins in older women of lower body mass and with comorbidities such as renal failure, receiving many other drugs for unrelated comborbidities may also be important [21] for safety and long-term drug tolerability.…”