The effect of interferon on the metabolism of LDLs.

Abstract

Interferons have been shown to lower low density lipoprotein (LDL) cholesterol concentrations by 20-50%. To evaluate the effect of interferons on LDL metabolic behavior in individuals with normal and mildly elevated LDL cholesterol levels, autologous LDL labeled with '"I was administered to subjects at baseline and during interferon treatment Interferon beta^^,, (IFN-ft^.,,) was administered intravenously at 4.5 x 10' units daily for at least 3 weeks before the start of kinetic study and continued for an additional 2 weeks. Results were analyzed by using a multicompartmental model that allows for two intravascular LDL compartments. In normal subjects, TFN-fi mttIM reduced LDL cholesterol and apolipoprotein (apo) B levels by 25% and 27%, respectively (p<0.05); LDL apo B synthesis was decreased by 59% (p<0.05). In hypercholesterolemic subjects, IFN-^KH,, reduced LDL cholesterol levels by 38% (p<0.05); however, apo B concentrations and production rates were not significantly decreased. Clearance of LDL from the first intravascular apo B pool was markedly reduced in these subjects, resulting in a shift in the distribution of LDL apo B from the second to the first intravascular LDL apo B pool. We conclude that interferon's actions on LDL metabolism differ in normocholesterolemic and hypercholesterolemic subjects. In normal subjects, interferon decreased LDL cholesterol and apo B levels through a reduction in the LDL apo B production rate. However, in hypercholesterolemic subjects, interferon reduced LDL cholesterol by altering the distribution of apo B mass between LDL subspecies. ( lesterol of 20% and 50% at the two doses studied, 4.5xlO 6 and 9.0 xlO 7 units, respectively. 5 Both doses were well tolerated.The mechanism behind the effects of interferons in reducing LDL cholesterol and apo B concentrations is unknown. Administration of both interferon gamma and alfa inhibits hepatic and lipoprotein lipase activity, enzymes necessary for the synthesis of LDL from very low density lipoprotein (VLDL).46 Inhibition of this pathway may result in decreased synthesis of LDL. On the other hand, interferons may act as important modulators of cellular protein synthesis by upregulating LDL receptors and enhancing LDL clearance. Because LDL synthetic and catabolic rates are abnormal in hypercholesterolemic subjects, the extent to which interferon affects LDL kinetic behavior may also depend on the presence or absence of normal lipoprotein metabolism. The effect of interferon on individuals with hypercholesterolemia has not been studied. The purpose of this study was to evaluate the effect of recombinant human IFN-fte,,,* on LDL composition and metabolism when administered to normal and mildly hypercholesterolemic subjects. Methods SubjectsKinetic studies were performed before and after intravenous administration of IFM-fte^ injections to 10 subjects. Six had mild hypercholesterolemia with LDL

1179 Interferon Lambda Genotype and Low Serum LDL Cholesterol Levels in Patients With Chronic Hepatitis C Infection

“…Our data on rs12979860 genotype association with lipids support this theory as well. Administration of exogenous interferons alpha, beta, and gamma in the setting of treatment for chronic HCV infection and other conditions has been shown to lower LDL cholesterol, and raise triglyceride in VLDL, concomitant with suppression of lipoprotein lipase (28,(36)(37)(38). The effect of interferon lambdas on serum lipids has not been previously explored, although it is believed that interferon lambdas stimulate an interferon signaling gene response via a common pathway with type 1 interferons(39).…”

Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host

“…IL-1 inhibits cholesterol synthesis and decreases cholesterol and apoB secretion, whereas IL-6 increases cholesterol synthesis but decreases cholesterol secretion (98). IFN-␤ also decreases apoB synthesis (99).…”

Interleukin-6 Stimulates LDL Receptor Gene Expression via Activation of Sterol-Responsive and Sp1 Binding Elements

“…6,7 Cytokines may affect plasma levels of cholesterol and lipoproteins by modulating the synthesis and secretion of apolipoproteins, lipolytic enzyme activities, or the expression of lipoprotein receptors. 8,9 One of the major determinants of plasma cholesterol levels is the activity of the LDL receptor (LDL-R). The LDL-R mediates the cellular uptake and degradation of plasma LDL.…”