High‐fat diets impede the lowering effect of cyclosporine a on rat brain lipids and interact with the expression of apolipoproteins E and J

Abstract

Cyclosporine A (CsA), a common immunosuppressive agent, produces hyperlipidemia and apolipoprotein profile alterations in plasma as well as neurological and psychiatric complications. In rats, 10 mg CsA/kg/d treatments for 3 wk induce alterations of the electroencephalogram, and of the blood and brain lipids. Using this model, we evaluated whether triacylglycerol (TG)- and lecithin (PC)-enriched diets, reported to decrease epileptic episodes (TG) and to improve memory, could modify the effects of CsA treatment on brain lipids and possibly change apolipoprotein (apo) E and apoJ gene expression. To evaluate this hypothesis, three groups of rats were treated for 3 wk with CsA and received a low-fat, PC, or TG diet. Three other groups were fed the above-mentioned diets and were treated with the CsA solvent. As a control, one group was fed only the low-fat diet. The CsA-mediated decreases in brain cholesterol and PC contents, under a low-fat diet, were eliminated by the TG and PC diets. These high-fat diets induced a global increase in hippocampal transcriptional activity, as revealed by elevated polyadenylated RNA levels. The apoE and apoJ mRNA levels in the cortex and hippocampus of rats receiving the solvent were not statistically different between the TG- and PC-enriched diets but showed important variations compared with the low-fat diet solvent-treated group. A differential effect between the two high-fat diets was observed in the hippocampus, resulting in a significant increase of the apoE to apoJ ratio with the PC diet. The balance between apoE and apoJ is presumed to be important in encephalopathic mechanisms, by its involvement through low levels of brain cholesterol and PC, that might be associated with mental disorders. Our results therefore suggest that diet enrichment with polyunsaturated fat might be beneficial during CsA therapy. However, if the high levels in PC used here are more beneficial on CsA peripheral side effects than similar enrichment in TG, this does not seem to be the case in the brain. Thus, lower levels in PC should be tested.

Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis

“…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, it is necessary to eliminate the possibility that decreased hepatic TG accumulation was derived from secondary effects. We used the siRNA of CypD in vitro and gained consistent results, suggesting that CypD is a specific target for prevention and therapy of NAFLD.…”

Thyroid Stimulating Hormone Triggers Hepatic Mitochondrial Stress through Cyclophilin D Acetylation

“…These results suggest that CsA can be, to a certain degree, a potential therapeutic tool for hepatic mitochondrial stress. Considering the wide pharmacological effects of CsA as an immunosuppressant [65], it is necessary to eliminate the possibility that decreased hepatic mitochondrial stress was derived from secondary effects. The specific inhibition of CypD in vitro should be used to see whether there will be consistent results.…”