Post-transplantation Hypercholesterolaemia

Sammanfattning: The multidrug regimen, cyclosporine, corticosteroids, and azathioprine, is used in transplantation centres to prevent organ rejection. Several clinical studies have shown that cyclosporine and corticosteroids to cause increases in low density lipoprotein (LDL)-cholesterol, with subsequent development of atherosclerosis. The overall objective of the studies upon which this thesis is based was to investigate the aetiology and management of hypercholesterolaemia in transplanted patients. The highly differentiated HepG2 hepatocytic cells were used in tissue culture to study LDL catabolism. The results show cyclosporine and hydrocortisone (as an example of corticosteroids), either alone or combined, to decrease LDL catabolism due to a decrease in the synthesis of mRNA of the LDL receptor. 3-hydroxy-3-methylglutaryl CoA reductase inhibitors can compensate for the reducing effect of cyclosporine and hydrocortisone. Two of the major complications of corticosteroid therapy are impaired glucose tolerance and Cushing's syndrome, associated with a great risk of complication by insulin-resistant non-insulin dependent diabetes mellitus (NIDDM). Moreover, nephropathy is one of the long-term complications of diabetes mellitus, and associated with a risk of progression to renal failure necessitating transplantation. Troglitazone, a thiazolidinedione compound that is used in the treatment of insulin- resistant NIDDM, was examined to investigate its effect on LDL catabolism. The results showed troglitazone to increase LDL catabolism by increasing the synthesis of the LDL receptor mRNA. This effect may be due to an activation of peroxisome proliferator-activated receptor gamma (PPARg), as troglitazone is one of the PPAR gamma activators. Non steroidal anti-inflammatory drugs (NSAIDs) have recently been shown to activate PPARs but they also inhibit the release of different inflammatory mediators and cytokines. The results obtained in HepG2 cells , showed NSAIDs, particularly flufenamic acid and indomethacin, to enhance LDL catabolism by increasing the synthesis of LDL receptor mRNA. This effect may be due to an activation of PPARs. The conclusion to be drawn from the studies is that, after organ transplantation, cyclosporine and hydrocortisone decrease hepatic LDL receptor activity, which can be counteracted by HMG-CoA reductase inhibitors (statins). Also troglitazone, due to its increase in hepatic LDL receptor activity, should be well suited for use after organ transplantation of diabetic subjects. In addition to their anti-inflammatory effects, NSAIDs might be useful in controlling hypercholesterolaemia induced atherosclerosis. The hypocholesterolaemic effect of troglitazone and NSAIDs might provide a theoretical basis for the development of new strategies for the treatment of hypercholesterolaemia.