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Familial Hypobetalipoproteinemia in a Hospital Survey

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Familial Hypobetalipoproteinemia in a Hospital Survey 155 Familial hypobetalipoproteinemia in a hospital survey. ORIGINAL, 2011; 10 (2): 155-164 ARTICLE April-June, Vol. 10 No.2, 2011: 155-164 Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease Carlos Gutiérrez-Cirlos,* María Luisa Ordóñez-Sánchez,** María Teresa Tusié-Luna,*** Bruce W. Patterson,**** Gustav Schonfeld,**** Carlos A. Aguilar-Salinas** * Departamento de Medicina Interna, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México. ** Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México. *** Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, México. **** Department of Medicine, Washington University School of Medicine, St. Louis MO, USA. ABSTRACT Introduction. Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disease characterized by abnormally low levels of apolipoprotein-B (apoB) containing lipoproteins. FHBL is caused by APOB, PCSK9 or ANGPTL3 mutations or is associated with loci located in chromosomes 10 and 3p21. However, other genes should be involved. This study describes the kinetic parameters of the apoB containing lipoproteins and sequence abnormalities of the APOB and PCSK9 genes of FHBL patients identified in a large hospital based survey. Material and methods. Cases with primary or secondary causes of hypobetalipoproteinemia were identified. ApoB kinetics were measured in cases with primary forms in whom truncated forms of apoB were not present in VLDL (n = 4). A primed constant infusion of [13C] leucine was administered, VLDL and LDL apoB production and catabolic rates measured by a multicompartmental model and compared to nor- molipemic controls. In addition, these subjects had an abdominal ultrasound and direct sequencing was carried out for the PCSK9 and apoB genes. Results. Three individuals had normal apoB production with in- creased catabolic rate; the remaining had reduced synthetic and catabolic rates. Various polymorphisms, some of them previously unreported (*), in the PCSK9 gene (R46L, A53V, I474V, D480N*, E498K*) and in the apoB gene (N441D*, Y1395C, P2712L, D2285E*, I2286V, T3540S*, T3799M*) were found in the FHBL patients. We found hepatic ultrasound changes of hepatic steatosis in only one of the four probands. Conclusion. FHBL without truncated apoB is a heterogeneous disease from a metabolic and a genetic perspective. Hypobetalipoproteinemia is a risk factor but not an obligate cause of steatosis. Key words. Hypocholesterolemia. Proprotein convertase subtilisin/kexin type 9. ApoB-100 kinetics and metabolism. Hepatic steatosis. INTRODUCTION Framingham population, revealed that individuals with FHBL are less susceptible to develop cardiovas- Familial heterozygous hypobetalipoproteinemia cular disease3 and run a greater risk of nonalcoholic (FHBL) is an autosomal dominant disease, charac- fatty liver disease caused by the imbalance in the he- terized by low serum levels of total cholesterol, LDL patic synthesis and export of lipids.4 There are seve- cholesterol and apoB.1 Its presence is suspected ral causes of FHBL. ApoB mutations resulting in when plasma cholesterol is below 3.88 mmol/L (150 truncations are best characterized, with more than mg/dL) in an otherwise healthy individual.2 Long- 30 truncated forms reported.5,6 Hypobetalipoprotei- term follow-up of a number of cohorts, such as the nemia may result from a decreased apoB secretion (of both normal and truncated apoB) or from an in- creased plasma depuration of the apoB variant.6-9 However, this represents less than 2% of the Correspondence and reprint request: Carlos Gutiérrez-Cirlos, MD. 10 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, FHBL. Latour described the kinetic abnormalities Dirección Médica, Departamento de Medicina Interna, of the apoB-containing lipoproteins (using endoge- Vasco de Quiroga 15 Col. Sección XVI, Tlalpan, Ciudad de México, D.F. nous labeling with [13C] leucine) in four FHBL sub- C.P. 14000, Tel.: 015255-56559068. jects without truncated apoB.11 They found a normal E-mail: [email protected] Manuscript received: December 17, 2010. VLDL- and LDL-apoB production rate and a two to Manuscript accepted: January 16, 2011. three fold increase in its catabolic rate.12 Yuan des- 156 Gutiérrez-Cirlos C, et al. , 2011; 10 (2): 155-164 cribed one FHBL kindred with a chromosome 3p21 without secondary causes for hypocholesterolemia. loci linkage;13 in this case there was a reduced apoB The cholesterol threshold used for the definition of production and an increased LDL-apoB catabolic FHBL is beneath the 5th percentile for the adult rate.14 Some apoB mutations that affect its kinetic Mexican population.27 Cases were recruited at a uni- behavior without truncated variants have been des- versity hospital. All plasma lipid analyses performed cribed in FHBL. The mutations L343V and R463W15 during a one year period at the laboratory of our enhance the affinity of the apoB domain ba1 with Institute were recorded. The sample was composed the microsomal triglyceride transfer protein (MTP), of 22270 cases, 80% of them were attending the out- increasing the retention of nascent VLDL particles patient clinics. For cases with hypocholesterolemia, in the endoplasmic reticulum, and lowering their se- first degree relatives were invited to have a plasma cretion. The R3480P mutation increases the affinity lipid profile and were considered affected if their cho- of apoB for the LDL receptor leading to a lower con- lesterol levels were 3.36 mmol/L (130 mg/dL) or version (up to 70%) of VLDL to LDL.16 Finally, less. SNPs like P2712L alters the structure and function of apoB by modifying the alpha helixes.17-19 The Analytical methods functional characteristics of P2712L have not been described, even though it has been identified among Blood was collected in tubes with EDTA and plas- subjects with hypocholesterolemia. Loss-of-function ma was separated from blood cells by low-speed cen- mutations and SNPs of the PCSK9 gene are linked trifugation. Subsequently, VLDL (δ < 1.006 g/mL), with hypocholesterolemia20-24 and are a possible cau- IDL (δ = 1.006 to 1.035 g/mL) and LDL (δ = 1.036 se of FHBL and include: L82X, G106R, Y142X, to1.064 g/mL) were isolated from 4 mL of plasma by W428X and C679X.21 As well as in the apoB-100 sequential ultracentrifugation. We looked for trun- gene, numerous SNPs can be related with low cho- cated forms of apoB using 3 to 6% gradient sodium lesterol levels.25 Recently, Musunuru and coworkers dodecyl sulfate (SDS)–polyacrylamide gels stained found two ANGPTL3 mutations in FHLB pa- with Coomassie blue. tients.26 Thus, various pathogenic mechanisms and genes participate in FHBL. The heterogeneity of Metabolic study this condition was identified primarily by studying the kinetics of the apoB containing lipoproteins in Patients were admitted at the Metabolic Unit of probands identified in lipid clinics. As a consequen- our Institute to assess the kinetics of the apoB con- ce, the association with various phenotypes linked taining lipoproteins. Patients were asked to keep with FHLB (i.e. hepatic steatosis and type 2 diabe- their diet unaltered during the two previous weeks. tes) has been difficult to be assessed due to the refe- They attend the clinic after a 12 hour-fasting period. rral bias. Special interest exists in cases without A bolus of [13C] leucine (0.85 mg/kg) was administe- apoB truncations, since information about the co- red through an intravenous catheter in one arm fo- existing conditions of these cases is scant. llowed by a constant infusion of 0.85 mg · kg-1 · h-1 This study describes the kinetic parameters of the for 8 hours. After the infusion of [13C] leucine stop- apoB containing lipoproteins, the sequence abnorma- ped, patients remained fasting for 8 hours more and lities of the apoB and PCSK9 genes and the hepatic then resumed their usual diets. A total of 37 sam- ultrasonography from FHBL patients without apoB ples were drawn through a second intravenous ca- truncations identified in a hospital based survey. theter in the other arm. Blood samples were taken at the following time periods (min): -30 (prior to the MATERIALS AND METHODS infusion), 0 (beginning of the infusion), 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150, 180, 210, Selection of subjects 240, 300, 360, 420, 480 (end of the infusion), 495, 510, 525, 540, 570, 600, 630, 660, 720, 780, 840, 960, The protocol was approved by the Ethics Commit- 1440 and in days 3 and 5. All samples were used for tee of the Instituto Nacional de Ciencias Médicas y determination of plasma leucine enrichment, and 31 Nutrición and all patients gave informed consent. for VLDL and LDL apoB leucine enrichment. ApoB FHBL was defined by total serum cholesterol levels and lipid concentrations were measured in five sam- below 3.36 mmol/L (130 mg/dL) on two separate oc- ples during each kinetic study to evaluate the pre- casions, affecting at least one first degree family sence of a steady state, at 1, 4, 8, 12, and 16 member (ascendant, descendent or sibling), and hours.28-30 157 Familial hypobetalipoproteinemia in a hospital survey. , 2011; 10 (2): 155-164 Isolation of Model showing the metabolism plasma amino acids of apoB and calculation of kinetic parameters Plasma amino acids were separated from 0.3 mL A multicompartmental model was used (Figure 1) of plasma by cation exchange chromatography.31 to describe the tracer-tracee ratios of leucine in VLDL, and LDL apoB using the SAAM II program Isolation and hydrolysis of apoB (University of Washington, St. Louis MO). Each compartment or pool represents a group of kinetically ApoB was separated by precipitation with buta- homogenous particles. The model represents the mi- nol-isopropyl ether. Precipitated apoB was dried un- nimum structural complexity in order to explain the der nitrogen and hydrolyzed in 6N HCl for 16 hours data for [13C] leucine enrichment and the relative at 110°C; HCl was subsequently evaporated.32 mass of apoB throughout each fraction of lipopro- teins.
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