Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells.

Abstract

Cytokines, important biochemical mediators of inflammation, cause a rapid fall in the plasma concentration of cholesterol in vivo. One mechanism by which cytokines may cause acquired hypocholesterolemia is by decreasing the hepatic synthesis and secretion of apolipoproteins. To test this hypothesis, we incubated Hep G2 cells with human recombinant tumor necrosis factor-a, interleukin-1/3, and interleukin-6. Each of the cytokines resulted in a dose-related reduction in the concentrations of apolipoprotein (apo) A-I, apoB, and lecithin:cholesterol acyltransferase (LCAT) activity in the medium after 24 hours of incubation. The effect of cytokines on apolipoprotein accumulation was not affected by preincubation of Hep G2 cells with fatty acids. Cytokines decreased the concentration of cellular apoA-I mRNA in a dose-related fashion but did not affect cellular concentrations of apoB mRNA. The concentrations of triglyceride and cholesterol were also reduced in the medium of cells incubated with cytokines. Total cell sterol synthesis rates were calculated by [ 14 C]acetate incorporation. Cells incubated with interleukin-6 had a 31% increase in sterol synthesis rate but a 41% decrease in sterol secretion. These data suggest that these cytokines can decrease the hepatic synthesis and/or secretion of apolipoproteins and that this may explain, in part, the acquired hypocholesterolemia seen during acute and chronic inflammation. A cute and chronic inflammation cause hypocholes-/ \ terolemia in humans and nonhuman pri--Z \ -mates. 17 Many of the effects of inflammation on lipoprotein metabolism appear to be mediated by cytokines.8 -17 Injection of interleukin-2, colony stimulating factor, or interferon results in hypocholesterolemia in humans, 11 ' 1314 whereas tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) cause a rapid fall in plasma cholesterol as well as the concentrations of apolipoprotein (apo) A-I and apoB in nonhuman primates.The effects of cytokines on lipoprotein metabolism are complex, and the mechanisms by which cytokines cause hypocholesterolemia have not been studied extensively. However, at least two changes in lipoprotein metabolism appear to be important in the development of acquired hypocholesterolemia from inflammation in primate species. First, the metabolism of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles is altered by inflammation; concentrations of both particles fall rapidly after injection of lipopolysaccharide and cytokines. Data from Schectman et al 11 suggest that inflammation causes a decrease in LDL production rates, as injection of interferon into normocholesterolemic humans reduced the LDL-apoB production rate but did not change the fractional catabolic rate. Second, injection of lipopolysaccharide and cytokines into nonhuman primates results in a significant reduction in the cholesterol ester content of HDL and LDL that is preceded by a rapid fall in the plasma concentration of lecithin:cholesterol acyltransferase (LCAT), suggesting that acute ...

Serum Cholesterol Levels in Neutropenic Patients with Fever

“…In accordance with previous studies, we found increased cytokine levels at the onset of fever during neutropenia (11,24,25). An increase in serum TNF and its soluble receptors at the onset of fever was accompanied by a reduction of cholesterol, possibly due to increased removal of circulating lipoproteins (18) or diminished synthesis rates (26).…”

Modulation of Autoimmunity and Atherosclerosis – Common Targets and Promising Translational Approaches Against Disease –

“…63, 64 These findings are consistent with previous work, in which IL-6 inhibited the production of apolipoproteins in hepatocytes in vitro. 65 In experimental atherosclerosis, the administration of recombinant IL-6 was found to accelerate atherogenesis in Apoe -/-mice. 66 However, not all animal studies show such activity of IL-6 in the development of atherosclerosis (reviewed by Kleemann et al 52 ).…”

Association of adipokines and inflammatory markers with lipid control in type 2 diabetes

“…Secondly, hypocholesterolemia (including low concentrations of HDL cholesterol) is commonly observed in inflammatory diseases and might be related to a dose-dependent reduction in secretion of both apolipoprotein (apo)B and apoA1 under TNF-α and IL-6 treatment, which was demonstrated in experimental studies. 38,39 Furthermore, both TNF-α and IL-6 were shown to adversely influence reverse cholesterol transport-the main mechanism responsible for antiatherogenic HDL properties-by decreasing lecithin-cholesterol acyltransferase activity. 39 Additionally, TNF-α was suggested to affect HDL cholesterol metabolism on other levels, including its formation and catabolism: in experimental studies, TNF-α attenuated intestinal cholesterol efflux to apoA1 as well as substantially enhanced macrophage degradation of HDL.…”