We previously demonstrated that Haptoglobin (Hpt) binds the Apolipoprotein A-I (ApoA-I), and impairs its stimulation on Lecithin:cholesterol acyl-transferase (LCAT), an enzyme playing a major role in the reverse cholesterol transport (RCT). ApoE, like ApoA-I, promotes different steps of RCT and plays a fundamental role against the development of atherosclerosis. In particular it stimulates the release of excess cholesterol from peripheral cells, activates LCAT for cholesterol esterification, and mediates lipoproteins binding to specific liver receptors for endocytosis and cholesterol elimination. ApoE contains aminoacid sequences which are homologous to the ApoA-I region bound by Hpt, therefore in our study we aimed at investigating whether Hpt might also bind ApoE. We found that the Hpt subunit  actually binds ApoE, or ApoE containing lipoproteins (LDL, VLDL, and HDL). In competition assays we demonstrated that the Hpt affinity for ApoE was higher than that for ApoA-I. Moreover, high levels of Hpt inhibit ApoE in stimulating LCAT (down to 46% of the control value, i.e. without Hpt), and it significantly impair the ApoE-mediated delivery of cholesterol from reconstituted lipoproteins to hepatocytes in culture (down to 50% of the control value). The increase in Hpt concentration, as occurring during the acute phase of inflammation, might impair RCT efficiency by inhibiting LCAT enzyme activity and by producing harmful imbalances in the concentration of circulating lipoproteins.

Hpt impairs the anti-atherosclerotic function of Apolipoprotein E.

CIGLIANO, LUISA;ABRESCIA, PAOLO
2009

Abstract

We previously demonstrated that Haptoglobin (Hpt) binds the Apolipoprotein A-I (ApoA-I), and impairs its stimulation on Lecithin:cholesterol acyl-transferase (LCAT), an enzyme playing a major role in the reverse cholesterol transport (RCT). ApoE, like ApoA-I, promotes different steps of RCT and plays a fundamental role against the development of atherosclerosis. In particular it stimulates the release of excess cholesterol from peripheral cells, activates LCAT for cholesterol esterification, and mediates lipoproteins binding to specific liver receptors for endocytosis and cholesterol elimination. ApoE contains aminoacid sequences which are homologous to the ApoA-I region bound by Hpt, therefore in our study we aimed at investigating whether Hpt might also bind ApoE. We found that the Hpt subunit  actually binds ApoE, or ApoE containing lipoproteins (LDL, VLDL, and HDL). In competition assays we demonstrated that the Hpt affinity for ApoE was higher than that for ApoA-I. Moreover, high levels of Hpt inhibit ApoE in stimulating LCAT (down to 46% of the control value, i.e. without Hpt), and it significantly impair the ApoE-mediated delivery of cholesterol from reconstituted lipoproteins to hepatocytes in culture (down to 50% of the control value). The increase in Hpt concentration, as occurring during the acute phase of inflammation, might impair RCT efficiency by inhibiting LCAT enzyme activity and by producing harmful imbalances in the concentration of circulating lipoproteins.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/368176
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