Low-Density Lipoprotein Receptor–Dependent and Low-Density Lipoprotein Receptor–Independent Mechanisms of Cyclosporin A–Induced Dyslipidemia

Abstract

H yperlipidemia is observed in 40% to 60% of organ transplant recipients and has been linked to the use of immunosuppressant agents such as corticosteroids, sirolimus, and cyclosporine A (CsA).1-3 Transplant hyperlipidemia is characterized by high plasma cholesterol and triglyceride levels. Specifically, CsA increases very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) concentrations and shows variable effects on plasma high-density lipoprotein. Although multiple factors potentially contribute to hyperlipidemia in patients, such as post-transplantation obesity, multiple drug therapy, and diabetes mellitus, CsA monotherapy can independently lead to elevated plasma triglyceride and cholesterol levels in humans which are reversible on cessation of immunosuppression therapy. 4 The immunosuppressive effect of CsA is mediated by inhibition of protein phosphatase 2B (calcineurin) and subsequent activation of the transcription factor nuclear factor of transcription. The mechanism(s) by which CsA leads to hyperlipidemia © 2016 American Heart Association, Inc.

Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis

“…That is to say, the former presented a preventive effect and the latter presented a therapeutic effect. Kockx et al have confirmed that CsA‐induced hyperlipidemia is associated with abnormal serum cholesterol clearance . So CsA may mediate lipid metabolism by down‐regulating the contents of TG in liver, inhibiting the clearance of cholesterol in blood, or both.…”

“…Kockx et al have confirmed that CsA-induced hyperlipidemia is associated with abnormal serum cholesterol clearance. (49) So CsA may mediate lipid metabolism by down-regulating the contents of TG in liver, inhibiting the clearance of cholesterol in blood, or both. Considering the wide pharmacological effects of CsA, (50) it is necessary to eliminate the possibility that decreased hepatic TG accumulation was derived from secondary effects.…”

Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta-cell failure

“…Several studies investigating the potential mechanisms underlying the pathogenesis of new-onset diabetes following tacrolimus-based treatments had focused on insulin-resistance [ 8 , 10 , 33 – 37 ]. Alterations in peripheral insulin-signaling have been also reported in response to other immunomodulators, including rapamycin, cyclosporine A, and steroids [ 38 – 42 ]. In fact, ultrastructural analysis has revealed that cyclosporine A causes mitochondrial dysmorphology in renal allograft biopsies [ 43 ].…”

A Comprehensive Update on the Chylomicronemia Syndrome

“…Both sirolimus and everolimus have been associated with the development of severe HTG (106,107). These agents increase APOC3 levels and inhibit LPL (108,109).…”