Characterization of Apoprotein Metabolism and Atherogenic Lipoproteins during Oral Isotretinoin Treatment

Abstract

Apoprotein, lipoprotein and lipid parameters of 36 normolipidemic subjects (23 males, mean age 22.7 ± 7.6 years; 13 females, mean age 26.2 ± 9.8 years) receiving oral isotretinoin (mean daily dose 0.73 ± 0.26 mg/kg body weight) for nodulocystic acne (n = 18), severe acne papulopustulosa (n = 15), gram-negative folliculitis (n = 2) and papulopustular rosacea (n = l) were monitored before and during isotretinoin therapy at biweekly intervals over a period of 14.6 ± 5.6 weeks. Pretreatment values of mean plasma triglycerides increased significantly (p < 0.001) from 81.8 ± 31.9 mg/dl to 112.4 ± 38.7 mg/dl (47.4%) during isotretinoin treatment. With respect to the mean percent increase of plasma triglycerides from pretreatment levels, patients were classified as nonresponders ( < 10% triglyceride increase), responders ( > 10% < 50% triglyceride increase) and hyperresponders ( > 50% triglyceride increase), revealing a distribution of 25.0, 36.1 and 38.9%, respectively. Isotretinoin treatment had no influence on the isoelectric focusing pattern of apoprotein E isoforms and C apoproteins. In particular, apoprotein C-II, the cofactor of lipoprotein lipase, was not affected. No correlation between apoprotein E phenotypes (2/3, 3/3, 3/4) and the mean plasma triglyceride increase could be demonstrated. Apoprotein B-48, a marker of chylomicrons and atherogenic chylomicron remnants, could not be detected by SDS-PAGE. On the other hand in 21.0% of patients with preexisting mean lipoprotein Lp(a) levels of 18.1 ± 12.9 mg/dl a moderate increase of atherogenic Lp(a) to mean levels of 37.0 ± 22.0 mg/dl was observed. Pretreatment values of very-low-density lipoprotein (VLDL) apoprotein (apo) B (7.5 ± 2.0 mg/dl), low-density lipoprotein apo B (67.3 ± 17.5 mg/dl) and total plasma apo B (76.6 ± 19.0 mg/dl) increased significantly to levels of 10.3 ± 2.4 mg/dl (p < 0.001), 75.7 ± 15.8 mg/dl (p < 0.10) and 85.9 ± 17.7 mg/dl (p < 0.05), respectively. As lipoprotein lipase and hepatic lipase activities have been shown to be unaffected by isotretinoin treatment, our data support the hypothesis that isotretinoin induces hepatic oversecretion of VLDL, a condition resembling type IV hyperlipidemia in diabetics, familial hypertriglyceridemia or familial combined hyperlipidemia.

Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.

“…Here, we demonstrate that the elevation of plasma triglycerides after isotretinoin treatment is associated with increased levels of apo C-III, an antagonist of plasma triglyceride metabolism. By contrast, plasma concentrations of apo E, which mediates the clearance of triglyceride-rich lipoprotein particles from plasma, did not change after retinoid treatment, data which are in line with a previous report (35). This increase of apo C-III may explain the delayed clearance of triglyceride-rich lipoproteins observed in humans treated with retinoids (36,37).…”

“…However, the physiological consequence of the effects of retinoids on the expression of these HDL apolipoproteins is unclear, since retinoid administration may decrease plasma HDL (5), without changing plasma apo A-I (48, 49) and apo A-II (50) concentrations in humans, whereas liver apo A-I gene expression decreases in rats in vivo (45,51). By contrast, both in humans and rats, retinoids induce a hypertriglyceridemia (5,52,53) with a mixed lipemia lipoprotein profile, such as in diabetes and familial combined hyperlipidemia (5,35), diseases in which apo C-III is an important factor (54,55). Since isotretinoin treatment influences neither postheparin plasma LPL activity nor plasma levels of apo C-II, the obligatory cofactor for LPL (5,35,56,57), and since increased plasma apo C-III levels result in impaired peripheral lipolysis by inhibiting triglyceride-rich lipoprotein binding to the endothelial surface (18,19), our results suggest a causal role for apo C-III in retinoid-induced dyslipidemia.…”

“…LG1069 (10 Ϫ 6 M) or vehicle (DMSO) for 24 h, washed in PBS, and incubated in methionine-free medium with 35 S-labeled methionine (0.02 mCi/ml) for 5 h. Cells were lysed in RIPA buffer (20 Construction of recombinant plasmids. The Ϫ 1415/ ϩ 24 genomic human apo C-III gene promoter, prepared by EcoRI/PvuII digestion, blunt-ended and cloned in the HincII site of pUC18, was excised by HindIII and BamHI digestion and subcloned in the corresponding restriction sites of the pBLCAT5 expression vector generating plasmid Ϫ 1415/ ϩ 24CIII-CAT.…”

Ácido retinóico: uma terapia promissora para carcinoma treoideano desdiferenciado?

“…Antes dos estudos da isotretinoína no câncer tireoideano, esta medicação já vem sendo utilizada no tratamento da acne e, portanto, os efeitos colaterais já são bem conhecidos (60). Os mais comuns são alteração de pele e mucosas, como ressecamento e prurido, e hipertrigliceridemia.…”

Effect of 13-cis-retinoic acid on the genetic expression profile of human umbilical vein endothelial cells (HUVECs) determined by microarray

“…Increases in lipid concentrations can result not only from an increase in the hepatic synthesis of lipoproteins (7), but also a decrease in the catabolism of circulating lipoproteins (8,9). The molecular mechanisms by which 13-cis RA influences these effects are not known, but could be via the transcriptional regulation of target genes implicated in lipid and glucose metabolism mediated by the RA receptors (RARa, b and g) and retinoid-X-receptors (RXRa, b and g) (10).…”