Abstract
BackgroundMitochondrial ATP synthase is expressed as a plasma membrane receptor for apolipoprotein A-I (apoA-I), the major protein component in High Density Lipoproteins (HDL). On hepatocytes, apoA-I binds to cell surface ATP synthase (namely ecto-F1-ATPase) and stimulates its ATPase activity, generating extracellular ADP. This production of extracellular ADP activates a P2Y13-mediated HDL endocytosis pathway. Conversely, exogenous IF1, classically known as a natural mitochondrial specific inhibitor of F1-ATPase activity, inhibits ecto-F1-ATPase activity and decreases HDL endocytosis by both human hepatocytes and perfused rat liver.Methodology/Principal FindingsSince recent reports also described the presence of IF1 at the plasma membrane of different cell types, we investigated whether IF1 is present in the systemic circulation in humans. We first unambiguously detected IF1 in human serum by immunoprecipitation and mass spectrometry. We then set up a competitive ELISA assay in order to quantify its level in human serum. Analyses of IF1 levels in 100 normolipemic male subjects evidenced a normal distribution, with a median value of 0.49 µg/mL and a 95% confidence interval of 0.22–0.82 µg/mL. Correlations between IF1 levels and serum lipid levels demonstrated that serum IF1 levels are positively correlated with HDL-cholesterol and negatively with triglycerides (TG).Conclusions/SignificanceAltogether, these data support the view that, in humans, circulating IF1 might affect HDL levels by inhibiting hepatic HDL uptake and also impact TG metabolism.
Highlights
The role of High Density Lipoproteins (HDL) in protecting against atherosclerosis is well established but the mechanism supporting this is still debated
Two distinct mechanisms of HDL-cholesterol uptake have been described in hepatocytes: i) selective cholesterol uptake, a mechanism through which cholesterol is taken up while the protein components of the HDL particle are not; ii) HDL endocytosis resulting in the uptake and degradation of HDL holoparticle [2]
We unambiguously demonstrated the presence of Inhibitory Factor 1 (IF1) in human serum using a recently developed targeted proteomics approach allowing the identification of low-abundance proteins with high sensitivity and specificity [23]
Summary
The role of High Density Lipoproteins (HDL) in protecting against atherosclerosis is well established but the mechanism supporting this is still debated. In contrast to the well-established role of the Scavenger receptor class B member I (SR-BI) in selective cholesterol uptake by hepatocytes [3], a distinct pathway seems to be involved in HDL holoparticle endocytosis [4]. Apolipoprotein A-I (apoA-I) binding to ectoF1-ATPase stimulates extracellular ATP hydrolysis to ADP and the latter specially activates the nucleotide receptor P2Y13 resulting in HDL holoparticle endocytosis [6,7]. ApoA-I binds to cell surface ATP synthase (namely ecto-F1-ATPase) and stimulates its ATPase activity, generating extracellular ADP. This production of extracellular ADP activates a P2Y13-mediated HDL endocytosis pathway. Exogenous IF1, classically known as a natural mitochondrial specific inhibitor of F1-ATPase activity, inhibits ecto-F1-ATPase activity and decreases HDL endocytosis by both human hepatocytes and perfused rat liver
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