The Effects of Apolipoprotein F Deficiency on High Density Lipoprotein Cholesterol Metabolism in Mice

Abstract

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls.

Genetic manipulation of the ApoF/Stat2 locus supports an important role for type I interferon signaling in atherosclerosis

“…We previously generated mice with a targeted deletion of the ApoF gene 5 in which the ApoF coding sequence was replaced with a Beta galactosidase reporter cassette. Surprisingly, deletion of the ApoF gene had no discernible effect on circulating lipids or lipoproteins 5 .…”

“…We previously showed that Apo F overexpression reduces HDL cholesterol levels in mice, and results in HDL particles that are more efficient acceptors of macrophage cholesterol 4 . Surprisingly, ApoF deficiency does not substantially alter plasma lipid or lipoprotein levels in mice 5 . In the current study, we considered the possibility that Apo F may reside on lipoproteins for a function other than simple lipid transport and may play an important role in atherosclerosis.…”

“…ApoF KO mice generated on a C57BL6 background 5 were crossed with Ldlr KO mice to generate ApoF/Ldlr DKO mice. Mice were housed in an AAALAC accredited animal facility in polycarbonate cages with filter tops and maintained on a 6 am to 6 pm light cycle, with free access to food and water.…”

Liver-Specific Cholesteryl Ester Hydrolase Deficiency Attenuates Sterol Elimination in the Feces and Increases Atherosclerosis in Ldlr −/− Mice

“…While treatment with estrogen (30) or estrogen-agonists (31) reduces atherosclerosis without affecting plasma lipids, the underlying mechanism(s) is not completely understood. Gender specific differences in hepatic cholesterol content have recently been reported (32). Several studies have demonstrated an increase in CE hydrolase activity by estradiol (33-35).…”

Effect of an Isoenergetic Traditional Mediterranean Diet on the High-Density Lipoprotein Proteome in Men with the Metabolic Syndrome

“…ApoF is a lipid transfer inhibitor protein known to inhibit cholesteryl ester transfer protein [31]. Although an overexpression of apoF has been shown to reduce HDL-C concentrations in mice [32], knocking out the apoF gene in mice had no effect on HDL-C concentrations, size and protein content [33]. In humans, apoF has also been positively associated with HDL-C concentrations in normolipidemic men [34].…”