Yoko Hashimoto and Harumi Okuyama
While statins are being used worldwide for the prevention of cardiovascular diseases, statin users have an increased probability of developing diabetes, arteriosclerosis, and other lifestyle-related diseases. Here, we review the molecular mechanisms underlying the onset of osteoporosis, chronic kidney disease, type 2 diabetes, and arteriosclerosis, and lowered testosterone levels induced by statin use. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is a rate-limiting enzyme of the mevalonate pathway that generates geranylgeranyl diphosphate (GGPP), 7-dehydrocholesterol (7-DHC), and cholesterol. GGPP is essential for vitamin K2 (VK2) synthesis from ingested vitamin K1. 7-DHC is a precursor of vitamin D3 (VD3). VD3 and VK2 upregulate the mRNA expression of osteocalcin (OC) and matrix Gla protein (MGP), respectively, via activation of their respective nuclear receptors. VK is essential for γ-carboxylation-mediated activation of several proteins. γ-Carboxylated MGP inhibits arterial and kidney calcifications. Insulin synthesis is stimulated by OC and γ-carboxylated protein S. GGPP is essential for secretion of insulin and luteinizing hormone (LH), and insulin action. VK2, OC, and LH stimulate testosterone synthesis via activation of protein kinase A. Both VK2 and VD3 are essential for these processes, and their deficiency leads to the onset of diabetes, vascular calcifications/ arteriosclerosis, and disruption of testosterone synthesis. VD and VK2 supplementations ameliorate the symptoms of chronic kidney disease and osteoporosis; therefore, statin is contraindicated in those patients. Thus, caution must be exercised when prescribing statins for long-term use. Collectively, deficiencies of VD3 and VK2 induced by long-term statin use promote the onset of lifestylerelated diseases.
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