Atorvastatin enhances LDL receptor-mediated LDL-C uptake and modulates PCSK9 protein expression in pancreatic β-cells.

Abstract

Statins are widely used to treat hyperlipidemia and atherosclerotic cardiovascular diseases (ACVD) by significantly lowering low-density lipoprotein cholesterol (LDL-C) levels. However, their use has been associated with an increased risk of type 2 diabetes (T2D), a paradox given their lipid-lowering benefits. This study investigates the role of LDL receptors (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in the diabetogenic effects of atorvastatin on pancreatic β-cells. Using the MIN6 pancreatic β-cell line, we assessed the impact of atorvastatin on LDL-C uptake, PCSK9 expression, glucose-stimulated insulin release (GSIR), and cell proliferation. Cellular cholesterol assays, EdU labeling, Dil-LDL uptake, western blot analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and ELISA, were employed to measure relevant biomarkers and cellular responses. Male C57BL/6j mice were treated with atorvastatin to validate in vitro findings. Atorvastatin enhances LDL-C uptake by upregulating LDLR on the cell surface, without causing excess cholesterol accumulation. Additionally, atorvastatin suppresses PCSK9 expression, which is crucial for LDLR degradation. Interestingly, atorvastatin, combined with exogenous LDL-C, impairs glucose-stimulated insulin release (GSIR) but promotes cell proliferation, highlighting a potential mechanism for statin-associated diabetes. Oral administration of atorvastatin in mice reduced plasma PCSK9 and insulin levels, supporting the in vitro findings. These results indicate that while atorvastatin effectively lowers circulating cholesterol, it may adversely affect pancreatic β-cell function by modulating LDLR and LDL-C uptake, thereby increasing the risk of T2D. This study highlights the importance of further research to develop strategies mitigating the diabetogenic effects of statins while maintaining their cardiovascular benefits.