Objective-Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a central player in the regulation of cholesterol homeostasis, increasing the low-density lipoprotein (LDL) receptor degradation. Our study aimed at exploring the pathogenic consequences in vivo and in vitro of a PCSK9 prodomain mutation found in a family with hypobetalipoproteinemia (FHBL). Methods and Results-A white 49-year-old diabetic man had profound FBHL (LDLC: 16 mg/dL) whereas his daughter and sister displayed a milder phenotype (LDLC 44 mg/dL and 57 mg/dL, respectively), all otherwise healthy with a normal liver function. A monoallelic PCSK9 double-mutant R104C/V114A cosegregated with FBHL, with no mutation found at other FHBL-causing loci. A dose-effect was also found in FBHL relatives for plasma APOB and PCSK9 (very-low to undetectable in proband, Ϸ50% decreased in sister and daughter) and LDL catabolic rate (256% and 88% increased in proband and daughter). Transient transfection in hepatocytes showed severely impaired processing and secretion of the double mutant which acted as a dominant negative over secretion of wild-type PCSK9. Conclusion-These results show that heterozygous PCSK9 missense mutations may associate with profound hypobetalipoproteinemia and constitute the first direct evidence in human that decrease of plasma LDLC concentrations associated to PCSK9 LOF mutations are attributable to an increased clearance rate of LDL. Key Words: PCSK9 Ⅲ LDL Ⅲ mutation Ⅲ hypobetalipoproteinemia H ypobetalipoproteinemia (HBL) refers to a heterogeneous group of monogenic disorders characterized by very low plasma concentrations of low-density lipoprotein cholesterol (LDLC) and apolipoprotein B (apoB) (ie, Ͻ5 percentile of the distribution in the population; for review see 1 ). HBL includes 3 inherited disorders: (1) familial hypobetalipoproteinemia (FHBL; OMIM 107730), (2) abetalipoproteinemia (ABL; OMIM 200100), and (3) chylomicron retention disease (CRD; OMIM 246700). The frequency of subjects with heterozygous FHBL has been estimated to be 1:500/1:1000. 2 FHBL heterozygotes are often asymptomatic or express mild clinical manifestations such as fatty liver disease and intestinal fat malabsorption. 3 FHBL are often caused by APOB gene mutations. 1,4 However, a substantial number of FHBL (varying to 36% 1 to 56% 5 in the literature) do not harbor apoB mutations.In the last 5 years, proprotein convertase subtilisin/kexin 9 (PCSK9) has emerged as a crucial modulator of cholesterol metabolism. 6 PCSK9 is primarily expressed in the liver and the intestine. PCSK9 inhibits the LDL receptor (LDLR) pathway in a posttranscriptional manner. 6 In human, PCSK9 was initially reported as the third gene causing autosomal dominant hypercholesterolemia, in addition to LDLR and APOB mutations. 7 Indeed, PCSK9 gain-of-function (GOF) mutations lead to increased plasma LDLC levels and premature atherosclerosis. 7,8 In contrast, PCSK9 loss-of-function (LOF) mutations are associated with low LDLC levels and protection against coronary diseases. 9,10 To dat...

Objectives-Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low-density lipoprotein receptor, and its deficiency in humans results in low plasma LDL-cholesterol and protection against cardiovascular disease. We explored whether PCSK9 expression impacts postprandial triglyceridemia, another important cardiovascular risk factor. Methods and Results-Real-time PCR and confocal microscopy were used to show that PCSK9 is expressed throughout the entire small intestine and in human enterocytes. On olive oil gavage, PCSK9-deficient mice showed a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Lymph analysis revealed that intestinal TG output is not quantitatively modified by PCSK9 deletion. However, PCSK9 Ϫ/Ϫ mice present with a significant reduction of lymphatic apoB secretion compared to PCSK9 ϩ/ϩ mice. Modulating PCSK9 expression in polarized CaCo-2 cells confirmed the relationship between PCSK9 and apoB secretion; PCSK9 Ϫ/Ϫ mice consistently secrete larger TG-rich lipoprotein than wild-type littermates. Finally, kinetic studies showed that PCSK9-deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates. G ain-of-function mutations affecting proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with autosomal dominant hypercholesterolemia and premature atherosclerosis. 1 It is now established that PCSK9 is a natural inhibitor of the low-density lipoprotein receptor (LDLr), acting posttranscriptionally. 2 Circulating PCSK9 binds to the EGF-A extracellular domain of the hepatic LDLr and prevents its recycling to the cell surface. 3 A breakthrough study reported that blacks harboring PCSK9 loss-of-function mutations had an 88% risk reduction for coronary heart disease. 4 Although the lower concentrations of LDL cholesterol over one's lifetime is suggested to be the main reason for this very high level of protection, we hypothesized that PCSK9 deficiency might also affect other risk factors. Low levels of HDL cholesterol (HDL-c) and elevated nonfasted triglycerides (TG) levels are associated with increased risk for cardiovascular disease. No association between PCSK9 loss-of-function mutations and plasma HDL-c levels has been noticed. 4,5 However, to our knowledge, nonfasting plasma TG were not measured in PCSK9-deficient individuals. They are an important contributor to the risk for cardiovascular disease. 6,7 Rashid et al reported the phenotype of PCSK9-deficient mice (PCSK9 Ϫ/Ϫ ) mice and observed that they exhibit lower plasma cholesterol levels (Ϫ50%) and are hypersensitive to statins. 8 The potential role of PCSK9 in the intestine in mice and humans remains unexplored. Conclusion-TheseDuring the postprandial period, dietary lipids are actively absorbed into the enterocyte. After intracellular reesterification, long chain fatty acids and cholesterol esters are associated with phospholipids and apolipoproteins, particularly apoB48, to produce TG-rich lipoproteins, mainly chy...