Objective-Neural apoptosis-regulated convertase (NARC)-1 is the newest member of the proprotein convertase family implicated in the cleavage of a variety of protein precursors. The NARC-1 gene, PCSK9, has been identified recently as the third locus implicated in autosomal dominant hypercholesterolemia (ADH). The 2 other known genes implicated in ADH encode the low-density lipoprotein receptor and apolipoprotein B. As an approach toward the elucidation of the physiological role(s) of NARC-1, we studied its transcriptional regulation. Methods and Results-Using quantitative RT-PCR, we assessed NARC-1 regulation under conditions known to regulate genes involved in cholesterol metabolism in HepG2 cells and in human primary hepatocytes. We found that NARC-1 expression was strongly induced by statins in a dose-dependent manner and that this induction was efficiently reversed by mevalonate. NARC-1 mRNA level was increased by cholesterol depletion but insensitive to liver X receptor activation. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element (SRE) and an Sp1 site. Conclusions-PCSK9 regulation is typical of that of the genes implicated in lipoprotein metabolism. In vivo, PCSK9 is probably a target of SRE-binding protein (SREBP)-2.

Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in vivo. Plasma analyses of AnxA2−/− mice revealed: i) a ∼1.4-fold increase in LDL-cholesterol without significant changes in VLDLs or HDLs, and ii) a ∼2-fold increase in circulating PCSK9 levels. Western blotting and immunohistochemistry of AnxA2−/− tissues revealed that the LDLR was decreased by ∼50% in extrahepatic tissues, such as adrenals and colon. We also show that AnxA2-derived synthetic peptides block the PCSK9≡LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo. These results suggest that AnxA2 acts as an endogenous regulator of LDLR degradation, mostly in extrahepatic tissues. Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans.

This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).Healthy WAT is able to respond promptly to postprandial signals, such as insulin increasing the hydrolysis of dietary TRL and the uptake and storage of generated NEFA, thus reestablishing the homeostasis in plasma lipids. The storage versus the release of TRL-generated NEFA in human subcutaneous WAT was reported to be almost absent in the fasting state, to increase to 100% 1 h after the ingestion of a meal, and to decrease to 10-30% 6 h after the meal ( 5 ). Accordingly, delayed plasma clearance of postprandial TRL by WAT is believed to increase the infl ux of dietary TRL remnants and NEFA into nonadipose peripheral tissues, including muscle, pancreas, and liver, inducing lipotoxicity and insulin resistance ( 6-8 ). In the liver, this also leads to increased synthesis and secretion of VLDL, which further reduces chylomicron clearance due to competitive binding to LPL ( 9-14 ). Altogether, this increases the plasma concentrations of apoB-lipoproteins, which is measured as plasma apoB and represents mostly LDL particles (>90%) ( 14-16 ). Dysfunctional WAT is thus Postprandial hypertriglyceridemia is an independent risk factor for cardiometabolic disease ( 1 ). Many factors have been implicated in the etiology of hyperlipidemia;