Letter From Le May and Cariou Regarding Article, "Proprotein Convertase Subtilisin Kexin Type 9 Promotes Intestinal Overproduction of Triglyceride-Rich Apolipoprotein B Lipoproteins Through Both Low-Density Lipoprotein Receptor-Dependent and -Independent Mechanisms"

International audienceWe read with interest the article by Rashid and colleagues 1 in Circulation in which they studied the physiological role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in intestinal triglyceride-rich lipoprotein production. In that article, Rashid et al stated that few investigators have characterized the functional importance of PCSK9 in the small intestine and its regulatory role on triglyceride-rich lipo-protein metabolism. 1 However, they omitted 2 seminal articles that previously addressed the question. We demonstrated and published in 2009 in Arteriosclerosis, Thrombosis, and Vascular Biology that PCSK9-deficient mice display reduced postprandial hypertriglyceridemia after an olive oil gavage. 2 Using the lymph duct cannulation method, we also showed that PCSK9-deficient mice have reduced intestinal apolipoprotein B production compared with wild-type mice. 2 Finally, we confirmed this relationship between intestinal PCSK9 and apolipoprotein B secretion in vitro in differentiated human Caco-2 cells by showing that adenoviral PCSK9 overexpression or silencing of PCSK9 with targeted SiRNA led to a significant increase or reduction of apolipo-protein B secretion, respectively. 2 In 2013, Levy and collaborators 3 further confirmed the role of PCSK9 in lipid metabolism in Caco-2 cells. In their study, they revealed a role for PCSK9 in cholesterol absorption. 3 Most important, they demonstrated for the first time that the addition of exogenous PCSK9 in the cultured media of Caco-2 cells significantly alters intestinal apo-lipoprotein B secretion. 3 They were also the first to demonstrate that PCSK9 could affect NPC1L1 expression, 3 as reported by Rashid et al. A second concern is the mode of administration and the dose of exogenous PCSK9 used in the study by Rashid et al. It is unclear in the article whether exogenous PCSK9 was added at the apical or basolateral side of Caco-2 cells, and it must be precised. Levy et al 3 have shown that PCSK9 could be secreted at the basolateral side of Caco-2 cells. In contrast, the presence or secretion of PCSK9 at the luminal side of enterocytes is not yet demonstrated. Second, although the authors stated that they added a physiological dose of PCSK9 on Caco-2 cells, plasma circulating PCSK9 mean concentration values were estimated to range from 80 to 4000 ng/mL, depending on the population screened and the type of anti-PCSK9 used in ELISA assays. 4 This suggests that the dose chosen is at least 2-to 3-fold higher than the highest physiological human PCSK9 concentration. In comparison, Levy's group 3 used 4 times less exogenous PCSK9 in similar experimental conditions. References 1. Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S. Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and-independent mechanisms