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Abnormally high blood cholesterol levels in low density lipoprotein (LDL) increases the risk of heart disease. Cell surface receptors such as LDL-receptors (LDLr) regulate the clearance of LDL from blood circulation. As cholesterol levels decrease, cells promote cholesterol synthesis and cholesterol uptake by increasing LDLr expression. Another regulatory protein of plasma cholesterol clearance is proprotein convertase subtilisin/kexin type 9 (PCSK9). It is secreted from the liver into circulation where it can bind to and target LDLr to the lysosome for subsequent degradation. The current model of cholesterol regulation describes how increased cholesterol content down-regulates the number of LDLr promoted by PCSK9 mediated degradation, however minimal knowledge is not known about LDLr and PCSK9 kinetics using heavy water labeling, and how cholesterol enriched diet affects LDLr and PCSK9 kinetics in vivo. Therefore, our objective(s) were to establish a method 1) to measure the kinetics of LDLr and PCSK9 via stable isotopic metabolic labeling with heavy water (2H2O) in vivo 2) to further test established models of cholesterol metabolic regulation on LDLr and PCSK9 turnover after feeding mice a cholesterol enriched diet. We hypothesize that a cholesterol enriched diet will decrease both LDLr and PCSK9 synthesis rates. In order to test this, mice were fed a cholesterol enrich diet for 1 week and metabolically labeled with heavy water (2H2O) up to 36 hours. LDLr and PCSK9 were immunoprecipitated from liver and deuterium incorporation into LDLr and PCSK9 were measured via mass spectrometry. Our results revealed high cholesterol feeding down-regulated cholesterol synthesis and LDLr fractional synthesis rate decreased from 10.0% to 6% per hour. PCSK9 concentration also decreased from 1 to 0.2 (ng/ml / total mg protein), but the synthesis rate increased from 9.0%/day in control mice to 19.5%/day in high cholesterol diet. These results suggest high cholesterol feeding increases PCSK9 synthesis that potentially depletes the intracellular pool to target LDLr to the lysosome thus decreasing LDLr turnover. This research provides a flux-based approach to measure the kinetics of LDLr and PCSK9 for a molecular based kinetic insight of their functions in physiology, disease and therapy.

journal of the endocrine society

SAT-LB95 Low Density Lipoprotein Receptor and Proprotein Convertase Subtilisin/Kexin Type 9 Kinetics Using Heavy Water (2H2O) Labeling and Mass Spectrometry