Prednisone and Its Active Metabolite Prednisolone Attenuate Lipid Accumulation in Macrophages

Abstract

Background: Synthetic forms of glucocorticoids (GCs; eg, prednisone, prednisolone) are anti-inflammatory drugs that are widely used in clinical practice. The role of GCs in cardiovascular diseases, including atherosclerosis, is highly controversial, and their impact on macrophage foam cell formation is still unknown. We investigated the effects of prednisone and prednisolone on macrophage oxidative stress and lipid metabolism. Methods and Results: C57BL/6 mice were intraperitoneally injected with prednisone or prednisolone (5 mg/kg) for 4 weeks, followed by lipid metabolism analyses in the aorta and peritoneal macrophages. We also analyzed the effect of serum samples obtained from 9 healthy human volunteers before and after oral administration of prednisone (20 mg for 5 days) on J774A.1 macrophage atherogenicity. Finally, J774A.1 macrophages, human monocyte-derived macrophages, and fibroblasts were incubated with increasing concentrations (0-200 ng/mL) of prednisone or prednisolone, followed by determination of cellular oxidative status, and triglyceride and cholesterol metabolism. Prednisone and prednisolone treatment resulted in a significant reduction in triglyceride and cholesterol accumulation in macrophages, as observed in vivo, ex vivo, and in vitro. These effects were associated with GCs’ inhibitory effect on triglyceride- and cholesterol-biosynthesis rates, through downregulation of diacylglycerol acyltransferase 1 and HMG-CoA reductase expression. Glucocorticoid-induced reduction of cellular lipid accumulation was mediated by the GC receptors on the macrophages, because the GC-receptor antagonist (RU486) abolished these effects. In fibroblasts, unlike macrophages, GCs showed no effects. Conclusion: Prednisone and prednisolone exhibit antiatherogenic activity by protecting macrophages from lipid accumulation and foam cell formation.

Dirty Jobs: Macrophages at the Heart of Cardiovascular Disease

“…In order to elicit the anti-inflammatory properties, the synthetic glucocorticoids prednisone and prednisolone were administered to mice. The glucocorticoid-treated mice showed reduced triglyceride and cholesterol accumulation [ 97 ]. This finding supports the protective role of glucocorticoids in the inflammatory process of foam cell formation, and ultimately in the development of atherosclerosis [ 97 , 98 ].…”

“…The glucocorticoid-treated mice showed reduced triglyceride and cholesterol accumulation [ 97 ]. This finding supports the protective role of glucocorticoids in the inflammatory process of foam cell formation, and ultimately in the development of atherosclerosis [ 97 , 98 ]. Another known regulator of inflammation is ApoA-I, which counteracts the inflammatory response through binding to ABCA1 to export cholesterol out of macrophages.…”

Systemic sclerosis with cerebral infarction and severe stenosis of internal carotid artery and coronary artery: A case report

“…18,19 In contrast, Jeries et al discovered that glucocorticoids presented antiatherogenic effect by protecting macrophages from lipid accumulation and foam cell formation. 20 After comprehensive consideration, the patient in this case receiving longterm low-dose prednisone and immunosuppressant and had no recurrence of vascular events during the 2-year follow-up. Therefore, we tend to think the macrovascular stenosis may be more related to SSc instead of prednisone.…”

“…Recent studies demonstrated glucocorticoid was associated with a dose‐dependent increase in risk of cardiovascular events, even low‐dose glucocorticoid increases the risk of cardiovascular disease 18,19 . In contrast, Jeries et al discovered that glucocorticoids presented antiatherogenic effect by protecting macrophages from lipid accumulation and foam cell formation 20 . After comprehensive consideration, the patient in this case receiving long‐term low‐dose prednisone and immunosuppressant and had no recurrence of vascular events during the 2‐year follow‐up.…”

Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?

“…This suggests long-term glucocorticoid exposure over the course of atheroma development can be athero-protective by reducing monocyte/macrophage recruitment and foam cell formation. Indeed, this is supported by a recent study demonstrating the direct ability of prednisone/prednisolone to reduce cholesterol accumulation in macrophages [65].…”