3-cis retinoic acid)-i nduced hyperlipidemia

A significant rise in plasma triacylglycerols from the control level of 0.89 mmovl to 1.88 mmom (P < 0.001) was observed in male Sprague-Dawley rats treated for 11 days with isomtinoin (oral dosing; 10 mg/day). This rise was due to an increased level of plasma very low density lipoproteins (VLDL). When VLDL from untreated rats were labeled with ‘251-labeled tyramine-cellobiose and injected intravenously into rats treated for 10 days with isotretinoin (n = 6) and in control rats (n = 6), it was found that the disappearance of radioactivity from the blood was dramatically retarded in the treated animals. The disappearance could be divided into two phases, a rapid (a) phase dominated the first 5 min and was followed by a slower (8) phase. The halflife of the @-phase increased significantly from 53 * 7 min in the controls, to 120 * 62 min after isotretinoin. VLDL prepared from isotretinoin-treated animals (n = 6) had about the same half-life in control animals (62 * 8 min) as had ordinary VLDL. The elimination of tracer from the blood was mainly due to uptake by the liver. The amount of radioactivity in the liver after 30 min of circulation was significantly reduced from 34 * 7% of injected dose in controls to 24 f 5% in the isotretinoin group (P = 0.013). The uptake in other organs was < 3% per organ and was essentially unaffected by the treatment. When the different liver cell populations were analyzed for radioactivity after separation by Percoll@ -centrifugation, it was found that the uptake by the parenchymal cells was significantly reduced from 32 * 7% of the injected dose to 21 * 4% (P = 0.007) by isotretinoin treatment, while the uptake in nonparenchymal cells was unaffected. Our results suggest that the hypertriglyceridemia seen after isotretinoin treatment is associated with reduced VLDL uptake by parenchymal cells of the liver. -Gustafson, S., C. Vahlquist, L. Sjoblom, A. Eklund, and A. Vihlquist. Metabolism of very low density lipoproteins in rats with isotretinoin (134s retinoic acid)-induced hyperlipidemia. J Lipid Res. 1990. 31: 183-190. Supplementary key words retinoids lipoproteins hyperlipidemia plasma triacylglycerols 1Z51-labeled tyramine-cellobiose kinetic studies liver uptake zation. Unfortunately, hyperlipidemia is a common sideeffect of retinoid therapy (for review see ref. 1). The associated lipoprotein changes are characterized by increased very low density lipoprotein (VLDL) triacylglycerol levels (2) and an increased low density lipoprotein (LDL) to high density lipoprotein (HDL) cholesterol ratio (3). Although these changes imply an increased risk for atherosclerosis (4-6), a detailed risk evaluation is not possible until the mechanisms underlying retinoid-induced hyperlipidemia are known. Hyperlipidemia may be the result of either an increased hepatic synthesis of lipoproteins or a decreased catabolism of circulating lipoprotein particles. Gerber and Erdman (7) have suggested that tretinoin (all-trans retinoic acid) enhances the synthesis of VLDL-triglycerides in rat liver. In the same study, however, they report decreased lipoprotein lipase activity in the gastrocnemius muscle during tretinoin treatment, suggesting a decreased catabolism of lipoproteins. Studies on retinoid-induced hyperlipidemia in humans have indicated that isotretinoin and etretinate (the ethyl ester of an aromatic analog of retinoic acid) elevate the apoB-lipoprotein levels in serum (2, 8). In addition, there are several reports showing that both these retinoids, as well as acitretin (the free acid of etretinate), impede the rate at which intravenously injected fat is removed from the blood (9-11). This implies that the efferent (catabolic) pathway of human lipoprotein metabolism is affected by retinoids. In congruence to this, decreased muscle lipoprotein lipase activities have been recorded in retinoidtreated subjects (9). Abbreviations: VLDL. very low densitv liwuroteins: IWLDL. VLDL , , , . . Isotretinoin (13-& retinoic acid; Accutane@) is a synfrom isotretinoin-treated rats; LDL, low density lipoproteins; HDL, hi& density lipoproteins; TC, tyramine-cellobiose; PC, liver parenchymd cells; IT. isotretinoin; 1251-=, 1251-laMed tyrathetic retinoid widely used for oral treatment of recalciliver nonDarendrvmal trant nodulocystic acne and severe disorders of keratinimine-cellobiose: Journal of Lipid Research Volume 31, 1990 183 by gest, on N ovem er 6, 2017 w w w .j.org D ow nladed fom A new approach to the study of lipid removal from the blood is to inject labeled lipoproteins and to monitor the transfer of label from serum to tissues. When '251-labeled tyramine-cellobiose ( 1251-TC) is used as labeling agent, the radioactivity will be trapped in the cells after the protein has been degraded. This permits quantitative analysis of the lipoprotein uptake in a particular tissue or organ, as well as more accurate measurement of its elimination from the blood (12). In this report we show that oral intake of isotretinoin, within a few days, markedly elevates the triacylglycerol and VLDL levels in rat plasma and impedes the clearance of injected '251-TC-VLDL particles. The reduced clearance is mainly due to a decreased fractional removal of lipoproteins by the liver parenchymal cells. MATERIALS AND METHODS