The pathogenic mutations of APOA5 in Chinese patients with hyperlipidemic acute pancreatitis.

BACKGROUND AND AIMS: To study the role of gene mutations in the development of severe hypertriglyceridemia (HTG) in patients with hyperlipidemic acute pancreatitis (HLAP), especially different apolipoprotein A5 (APOA5) mutations. METHODS: Whole-exome sequencing was performed on 163 patients with HLAP and 30 patients with biliary acute pancreatitis (BAP). The pathogenicity of mutations was then assessed by combining clinical information, predictions of bioinformatics programs, information from multiple gene databases, and residue location and conservation. The pathogenic mutations of APOA5 were visualized using the software. RESULTS: 1. Compared with BAP patients, pathogenic mutations of APOA5 were frequent in HLAP patients; among them, the heterozygous mutation of p.G185C was the most common. 2. All six pathogenic mutations of APOA5 identified in this study (p.S35N, p.D167V, p.G185C, p.K188I, p.R223C, and p.H182fs) were positively correlated with severe HTG; they were all in the important domains of apolipoprotein A-V (apoA-V). Residue 223 is strictly conserved in multiple mammals and is located in the lipoprotein lipase (LPL)-binding domain (Pro215-Phe261). When Arg 223 is mutated to Cys 223, the positive charge of this residue is reduced, which is potentially destructive to the binding function of apoA-V to LPL. 3. Four new APOA5 mutations were identified, namely c.563A > T, c.667C > T, c.788G > A, and c.544_545 insGGTGC. CONCLUSIONS: The pathogenic mutations of APOA5 were specific to the patients with HLAP and severe HTG in China, and identifying such mutations had clinical significance in elucidating the etiology and subsequent treatment.

Genetic and biochemical analysis of severe hypertriglyceridemia complicated with acute pancreatitis or with low post-heparin lipoprotein lipase mass.

Severe hypertriglyceridemia is a pathological condition caused by genetic factors alone or in combination with environmental factors, sometimes leading to acute pancreatitis (AP). In this study, exome sequencing and biochemical analyses were performed in 4 patients with hypertriglyceridemia complicated by obesity or diabetes with a history of AP or decreased post-heparin LPL mass. In a patient with a history of AP, SNP rs199953320 resulting in LMF1 nonsense mutation and APOE rs7412 causing apolipoprotein E2 were both found in heterozygous form. Three patients were homozygous for APOA5 rs2075291, and one was heterozygous. ELISA and Western blot analysis of the serum revealed the existence of apolipoprotein A-V in the lipoprotein-free fraction regardless of the presence or absence of rs2075291; furthermore, the molecular weight of apolipoprotein A-V was different depending on the class of lipoprotein or lipoprotein-free fraction. Lipidomics analysis showed increased serum levels of sphingomyelin and many classes of glycerophospholipid; however, when individual patients were compared, the degree of increase in each class of phospholipid among cases did not coincide with the increases seen in total cholesterol and triglycerides. Moreover, phosphatidylcholine, lysophosphatidylinositol, and sphingomyelin levels tended to be higher in patients who experienced AP than those who did not, suggesting that these phospholipids may contribute to the onset of AP. In summary, this study revealed a new disease-causing gene mutation in LMF1, confirmed an association between overlapping of multiple gene mutations and severe hypertriglyceridemia, and suggested that some classes of phospholipid may be involved in the pathogenesis of AP.

High density lipoprotein promotes nascent apolipoprotein A-V secretion from mRNA transfected cells.

Despite its exceptionally low circulating concentration, apolipoprotein (apo) A-V is a potent modulator of plasma triacylglycerol levels. The secretion efficiency of nascent apoA-V was investigated in cultured cells transfected with mRNA. Following transfection of HepG2 cells with wild type apoA-V mRNA, apoA-V protein was detectable in cell lysates by 6 h. At 24 h post transfection, evidence of apoA-V secretion into media was obtained, although most apoA-V was recovered in the cell lysate fraction. By contrast, apoA-I was efficiently secreted into the culture medium. A positive correlation between culture medium fetal bovine serum content and the percentage of apoA-V recovered in conditioned media was observed. When transfected cells were cultured in serum-free media supplemented with increasing amounts of high density lipoprotein, a positive correlation with apoA-V secretion was observed. The data indicate that, following signal sequence cleavage, the bulk of nascent apoA-V remains cell associated. Transit of nascent apoA-V out of cultured cells is enhanced by the availability of extracellular lipid particle acceptors.

Apolipoprotein A5 alleviates LPS/D-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-κB pathway.

BACKGROUND: Fulminant liver failure (FHF) is a serious clinical problem and liver transplantation is the major intervention. But the overall survival rate of FHF is low owing to the donated organ shortage. Apolipoprotein A-V (ApoA5) is a regulator of triglyceride metabolism and has been reported to act as a predictor for remnant liver growth after preoperative portal vein embolization and liver surgery. This study aimed to investigate the therapeutic effect of ApoA5 on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced fulminant liver failure in mice. METHODS: FHF mouse model was established using LPS/D-GalN and ApoA5 plasmid was injected by tail vein prior to LPS/D-GalN treatment. The expressions of ApoA5, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-κBp65) were assessed by real-time PCR and western blotting. Serum alanine aminotransferase (ALT) and tumor necrosis factor-α (TNF-α) levels were measured using automatic biochemical analyzer. Histological assessment and immunohistochemical (IHC) staining were conducted. Survival rate after LPS/D-GalN administration was also determined with Kaplan-Meier curve. Meanwhile, the expression of ApoA5 in injured huh7 cells was tested. Cell apoptosis analysis was performed after huh7 cells were transfected with ApoA5 plasmid and stimulated with LPS. RESULTS: The expressions of ApoA5 decreased both in injured huh7 cells and FHF mice. ApoA5 overexpression reduced cell death rate using flow cytometry. ApoA5 not only decreased the serum ALT and TNF-α levels but also attenuated hepatic damage in hematoxylin-eosin (HE)-stained liver section. The protein expressions of TLR4, MyD88 and NF-κBp65 were inhibited when ApoA5 overexpressed. But the inhibitory effect would weaken with the increasing concentration of LPS in spite of ApoA5 overexpression. Besides, ApoA5 improved liver injury in a dose-dependent manner and the survival rate in FHF mice increased with increasing concentration of ApoA5. CONCLUSION: ApoA5 had a protective effect against LPS/D-GalN-induced fulminant liver failure in mice within a certain range by inhibiting TLR4-mediated NF-κB pathway.

Effects and mechanisms of apolipoprotein A-V on the regulation of lipid accumulation in cardiomyocytes.

BACKGROUND: Apolipoprotein (apo) A-V is a key regulator of triglyceride (TG) metabolism. We investigated effects of apoA-V on lipid metabolism in cardiomyocytes in this study. METHODS: We first examined whether apoA-V can be taken up by cardiomyocytes and whether low density lipoprotein receptor family members participate in this process. Next, triglyceride (TG) content and lipid droplet changes were detected at different concentrations of apoA-V in normal and lipid-accumulation cells in normal and obese animals. Finally, we tested the levels of fatty acids (FAs) taken up into cardiomyocytes and lipid secretion through [14C]-oleic acid. RESULTS: Our results show that heart tissue has apoA-V protein, and apoA-V is taken up by cardiomyocytes. When HL-1 cells were transfected with low density lipoprotein receptor (LDLR)-related protein 1(LRP1) siRNA, apoA-V intake decreased by 53% (P<0.05), while a 37% lipid accumulation in HL-1 cells remain unchanged. ApoA-V localized to the cytoplasm and was associated with lipid droplets in HL-1 cells. A 1200 and 1800 ng/mL apoA-V intervention decreased TG content by 28% and 45% in HL-1 cells, respectively and decreased TG content by 39% in mouse heart tissue (P<0.05). However, apoA-V had no effects on TG content in either normal HL-1 cells or mice. The levels of FAs taken up into cardiomyocytes decreased by 43% (P < 0.05), and the levels of TG and cholesterol ester secretion increased by 1.2-fold and 1.6-fold, respectively (P < 0.05). CONCLUSION: ApoA-V is a novel regulator of lipid metabolism in cardiomyocytes.

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.

BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required.

The triglyceride-lowering effect of supplementation with dual probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032: Reduction of fasting plasma lysophosphatidylcholines in nondiabetic and hypertriglyceridemic subjects.

BACKGROUND AND AIMS: This study evaluated the triglyceride (TG)-lowering effects of consuming dual probiotic strains of Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on the fasting plasma metabolome. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study was conducted on 92 participants with hypertriglyceridemia but without diabetes. Over a 12-week testing period, the probiotic group consumed 2 g of powder containing 5 × 10(9) colony-forming units (cfu) of L. curvatus HY7601 and 5 × 10(9) cfu of L. plantarum KY1032 each day, whereas the placebo group consumed the same product without probiotics. Fasting plasma metabolomes were profiled using UPLC-LTQ-Orbitrap MS. After 12 weeks of treatment, the probiotic group displayed a 20% reduction (p = 0.001) in serum TGs and 25% increases (p=0.001) in apolipoprotein A-V (apoA-V). At the 12-week follow-up assessment, the following 11 plasma metabolites were significantly reduced in the probiotic group than the placebo group: palmitoleamide, palmitic amide, oleamide, and lysophosphatidyl choline (lysoPC) containing C14:0, C16:1, C16:0, C17:0, C18:3, C18:2, C18:1, and C20:3. In the probiotic group, changes (▵) in TG were negatively correlated with ▵ apoA-V, which was positively correlated with ▵ FFA. In addition, ▵ FFA was strongly and positively correlated with ▵ lysoPCs in the probiotic group but not the placebo group. CONCLUSIONS: The triglyceride-lowering effects of probiotic supplementation, partly through elevated apoA-V, in borderline to moderate hypertriglyceridemic subjects showed reductions in plasma metabolites, fatty acid primary amides and lysoPCs (NCT02215694; http://www.clinicaltrials.gov). Clinical trials: NCT02215694; http://www.clinicaltrials.gov.

Evaluation of apolipoprotein A5 variants: A cohort of patients with severe hypertriglyceridemia from Turkiye.

BACKGROUND: This study aims to show the clinical and biochemical features in patients with severe hypertriglyceridemia (HTG) associated with rare variants in the apolipoprotein A-V (APOA5) gene. MATERIALS AND METHODS: Demographics, blood lipid levels, body mass index (BMI) and APOA5 mutation subtypes were collected from the endocrinology clinic registry and analyzed for a retrospective cohort study of ten patients with severe HTG and APOA5 gene variants. RESULTS: Of the 10 cases, four were female, and six were male. The median age was 45.0 years (min-max: 21-60 years), the median triglyceride was 2429.5 mg/dL (27.5 mmol/L) (min-max: 1351-4087 mg/dL, 15.3-46.2 mmol/L), and the mean BMI was calculated as 30.4 ± 4.4 kg/m2 (min-max: 24.9-41.0 kg/m2). Four cases had diabetes mellitus (DM); two were on intensive insulin therapy, and two were on basal insulin therapy. The mean hemoglobin A1c was 9.2 ± 1.2 % (min-max: 8.3-11.0 %). Among the study group, eight different APOA5 gene mutations were detected. These variants were heterozygous in 2 patients and homozygous (bi-allelic) in 8 patients. One patient was homozygous for APOA5 p.Ser19Trp, a relatively common polymorphism that is a risk variant for HTG. CONCLUSION: We report a cohort of patients with biallelic and single copy APOA5 variants, who were diagnosed later in life. Most had secondary factors, such as DM or obesity with increased BMI. Most rare APOA5 variants found in our patients were of uncertain significance. Our results add to the growing evidence that rare variants in certain candidate genes may predispose to developing HTG, together with secondary factors such as obesity. The genetic basis of HTG in many other patients is still unknown and remains the subject of further investigation.

Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants.

BACKGROUND: Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. METHODS: Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. RESULTS: Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. CONCLUSIONS: Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity.

Low-density lipoprotein receptor and apolipoprotein A 5, myocardial infarction biomarkers in plasma-derived exosomes.

OBJECTIVES: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. Previously, rare mutations in low-density lipoprotein receptor (LDLR) genes and apolipoprotein A V (APOA5) have been shown to contribute to MI risk in individual families. Exosomes provide a potential source of biomarkers for MI. This study is to determine the role of LDLR and APOA5 as biomarkers for early diagnosis of MI. METHODS: In this study, we detected the levels of LDLR, APOA5, and cardiac troponin T in plasma-derived exosomes in MI patients and age-matched healthy people by enzyme linked immunosorbent assay and observed the morphology and number of exosomes using transmission electron microscope and nanoparticle tracking analysis. Oxygen-glucose deprivation (OGD) method was used to induce MI in H9C2 cardiomyocytes to explore the effect of exosomes. RESULTS: We found that the levels of LDLR and APOA5 in plasma-derived exosomes in MI patients were significantly decreased. Furthermore, exosomes of MI patients were significantly larger in size and the concentration of exosomes was higher than that of age-matched non-MI people. In vitro experiments showed that OGD treatment induced apoptosis of myocardial cells and decreased the expression of LDLR and APOA5, while addition of exosomes isolated from healthy people rescued these phenotypes. CONCLUSION: Exosomal APOA5 and LDLR are intimately associated with MI, and thereby have the potential to function as diagnostic markers of MI.

Proprotein convertase 7 (PCSK7) reduces apoA-V levels.

The locus of the human proprotein convertase subtilisin-kexin type-7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglyceride (TG), and exome sequencing of African Americans revealed the association of a low-frequency coding variant of PC7 (R504H; SNP rs142953140) with a ~ 30% TG reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter variant of the liver-derived apolipoprotein A-V (apoA-V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG levels. We thus hypothesized that PC7 regulates the levels/activity of apoA-V. Studies in the human hepatic cell line HuH7 revealed that wild-type (WT) PC7 and its endoplasmic reticulum (ER)-retained forms bind to and enhance the degradation of human apoA-V in acidic lysosomes in a nonenzymatic fashion. PC7-induced degradation of apoA-V is inhibited by bafilomycin A1 and the alkalinizing agents: chloroquine and NH4 Cl. Thus, the PC7-induced apoA-V degradation implicates an ER-lysosomal communication inhibited by bafilomycin A1. In vitro, the natural R504H mutant enhances PC7 Ser505 phosphorylation at the structurally exposed Ser-X-Glu507 motif recognized by the secretory kinase Fam20C. Co-expression of the phosphomimetic PC7-S505E with apoA-V resulted in lower degradation compared to WT, suggesting that Ser505 phosphorylation of PC7 lowers TG levels via reduced apoA-V degradation. In agreement, in Pcsk7-/- mice fed high-fat diet, plasma apoA-V levels and adipocyte LpL activity are increased, providing an in vivo mechanistic link for a role of liver PC7 in enhanced TG storage in adipocytes.

Apolipoprotein A-V variant (T-1131>C) affects plasma levels of non-high-density lipoprotein cholesterol in Caucasians.

BACKGROUND: The importance of apolipoprotein A-V (APOAV) gene variants in the determination of plasma triglyceride levels in humans has been proven in several population studies. OBJECTIVES: To investigate whether APOAV gene variants are associated with the different plasma cholesterol fractions. METHODS: The influence of APOAV polymorphisms (T-1131>C, Ser19>Trp and Val153>Met) on plasma cholesterol fractions was evaluated in 1191 men and 1368 women representatively selected from the Czech population. Low-density lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and HDL cholesterol levels were analyzed. RESULTS: The T-1131>C variation in the APOAV gene was found to affect plasma non-HDL cholesterol, showing significantly higher levels in C-1131 carriers than in T/T-1131 homozygotes. This association was observed in both men (4.61+/-1.09 mmol/L in C-1131 carriers versus 4.47+/-1.07 mmol/L in T/T-1131 homozygotes; P<0.01) and women (4.46+/-1.22 mmol/L in C-1131 carriers versus 4.24+/-1.17 mmol/L in T/T-1131 homozygotes; P<0.01). Interestingly, when low-density lipoprotein cholesterol (obtained by the Friedewald formula) or HDL cholesterol levels were analyzed, no significant association was detected. CONCLUSION: The APOAV gene variant T-1131>C may play a role not just in the genetic determination of triglyceride levels but may also influence plasma levels of non-HDL cholesterol.

Apolipoprotein A5 3'-UTR variants and cardiometabolic traits in Koreans: results from the Korean genome and epidemiology study and the Korea National Health and Nutrition Examination Survey.

BACKGROUND/OBJECTIVES: This study aimed to test the association between APOA5 3'-UTR variants (rs662799) and cardiometabolic traits in Koreans. SUBJECTS/METHODS: For this study, epidemiological data, Apolipoprotein A5 (APOA5) genotype information, and lymphoblastoid cell line (LCL) biospecimens from a subset of the Ansung-Ansan cohort within the Korean Genome and Epidemiology study (KoGES-ASAS; n = 7,704) as well as epidemiological data along with genomic DNA biospecimens of participants from a subset of the Korea National Health and Nutrition Examination Survey (KNHANES 2011-12; n = 2,235) were obtained. APOA5 mRNA expression was also measured. RESULTS: APOA5 rs662799 genotype distributions in both the KoGES-ASAS and KNHANES groups were 50.6% for TT, 41.3% for TC, and 8.1% for CC, which are similar to those in previous reports. In both groups, minor C allele carriers, particularly subjects with CC homozygosity, had lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels than TT homozygotes. Linear regression analysis showed that the minor C allele significantly contributed to reduction of circulating HDL cholesterol levels [ß = -2.048, P < 0.001; ß = -2.199, P < 0.001] as well as elevation of circulating triglyceride levels [ß = 0.053, P < 0.001; ß = 0.066, P < 0.001] in both the KoGES-ASAS and KNHANES groups. In addition, higher expression levels of APOA5 in LCLs of 64 healthy individuals were negatively associated with body mass index (r = -0.277, P = 0.027) and circulating triglyceride level (r = -0.340, P = 0.006) but not significantly correlated with circulating HDL cholesterol level. On the other hand, we observed no significant difference in the mRNA level of APOA5 according to APOA5 rs662799 polymorphisms. CONCLUSIONS: The C allele of APOA5 rs662799 was found to be significantly associated with cardiometabolic traits in a large Korean population from the KoGES-ASAS and KNHANES. The effect of this genotype may be associated with post-transcriptional regulation, which deserves further experimental confirmation.

Lack of Evidence of the Role of APOA5 3'UTR Polymorphisms in Iranian Children and Adolescents with Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) is a complex and multifactorial disorder characterized by insulin resistance, dyslipidaemia, hyperglycemia, abdominal obesity, and elevated blood pressure. The apolipoprotein A5 (APOA5) gene variants have been reported to correlate with two major components of MetS, including low levels of high density lipoprotein cholesterol (HDL-C) and high levels of triglyceride. In the present study, we explored the associations between five single nucleotide polymorphisms (SNPs) of APOA5 gene and the MetS risk. METHODS: In a case-control design, 120 Iranian children and adolescents with/without MetS were genotyped by polymerase chain reaction-sequencing for these SNPs. Then, we investigated the association of SNPs, individually or in haplotype constructs, with MetS risk. RESULTS: The rs34089864 variant and H1 haplotype (harboring the two major alleles of rs619054 and rs34089864) were associated with HDL-C levels. However, there was no significant association between different haplotypes/individual SNPs and MetS risk. CONCLUSION: These results presented no association of APOA5 3'UTR SNPs with MetS. Further studies, including other polymorphisms, are required to investigate the involvement of APOA5 gene in the genetic susceptibility to MetS in the pediatric age group.

Investigation of associations between apolipoprotein A5 and C3 gene polymorphisms with plasma triglyceride and lipid levels

SUMMARY OBJECTIVE: The aim of this study was to determine frequency and associations between APOA5 c.56C>G, −1131T>C, c.553G>T, and APOC3 −482C>T and SstI gene polymorphisms with hypertriglyceridemia. METHODS: Under a case-control study model, 135 hypertriglyceridemic and 178 normotriglyceridemic control participants were recruited. Polymerase chain reaction and restriction fragment length polymorphism methods were utilized for genotyping. Statistical calculations were performed by comparing allele and genotype frequencies between groups. Clinical characteristics were compared between groups and intra-group genotypes. RESULTS: APOC3 gene −482C>T and SstI polymorphic genotypes and allele frequencies were significantly higher in hypertriglyceridemic group (genotype frequencies, p=0.035, p=0.028, respectively). Regression analysis under unadjusted model confirmed that APOC3 −482C>T and SstI polymorphisms were significantly contributing to have hypertriglyceridemia (p=0.02, odds ratio [OR]=1.831 (95% confidence interval [CI] 1.095-3.060); p=0.04, OR=1.812 (1.031-3.183), respectively). APOA5 c.56C>G was in complete linkage disequilibrium with APOA5 c.553G>T polymorphism (D'=1). CONCLUSION: For the first time in a population sample from Turkey, among the five polymorphisms of APOA5 and APOC3 genes investigated, APOC3 −482C>T and SstI polymorphisms were associated with elevated serum TG levels, while APOA5 c.56C>G, −1131T>C, and c.553G>T polymorphisms were not.

Triglyceride-Lowering Effects of Two Probiotics, Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601, in a Rat Model of High-Fat Diet-Induced Hypertriglyceridemia.

The triglyceride-lowering effect of probiotics Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601 were investigated. Male SD Wistar rats were randomly divided into three groups and fed high-fat diet (HFD), HFD and probiotics (5 X 10(9) CFU/day of L. plantarum KY1032 and 5 X 10(9) CFU/day of L. curvatus HY7601), or normal diet for 6 weeks. Probiotic treatment significantly lowered the elevated plasma triglyceride and increased plasma free fatty acid, glycerol, and plasma apolipoprotein A-V (ApoA-V) levels. The probiotic-treated group showed elevated hepatic mRNA expression of PPARα, bile acid receptor (FXR), and ApoA-V. These results demonstrate that L. plantarum KY1032 and L. curvatus HY7601 lower triglycerides in hypertriglyceridemic rats by upregulating ApoA-V, PPARα, and FXR.

Rare and common variants in LPL and APOA5 in Thai subjects with severe hypertriglyceridemia: A resequencing approach.

BACKGROUND: Severe hypertriglyceridemia usually results from a combination of genetic and environmental factors. Few data exist on the genetics of severe hypertriglyceridemia in Asian populations. OBJECTIVE: To examine the genetic variants of 3 candidate genes known to influence triglyceride metabolism, LPL, APOC2, and APOA5, which encode lipoprotein lipase, apolipoprotein C-II, and apolipoprotein A-V, respectively, in a large group of Thai subjects with severe hypertriglyceridemia. METHODS: We identified sequence variants of LPL, APOC2, and APOA5 by sequencing exons and exon-intron junctions in 101 subjects with triglyceride levels ≥ 10 mmol/L (886 mg/dL) and compared with those of 111 normotriglyceridemic subjects. RESULTS: Six different rare variants in LPL were found in 13 patients, 2 of which were novel (1 heterozygous missense variant: p.Arg270Gly and 1 frameshift variant: p.Asp308Glyfs*3). Four previously identified heterozygous missense variants in LPL were p.Ala98Thr, p.Leu279Val, p.Leu279Arg, and p.Arg432Thr. Collectively, these rare variants were found only in the hypertriglyceridemic group but not in the control group (13% vs 0%, P < .0001). One common variant in APOA5 (p.Gly185Cys, rs2075291) was found at a higher frequency in the hypertriglyceridemic group compared with the control group (25% vs 6%, respectively, P < .0005). Altogether, rare variants in LPL or APOA5 and/or the common APOA5 p.Gly185Cys variant were found in 37% of the hypertriglyceridemic group vs 6% in the controls (P = 3.1 × 10(-8)). No rare variant in APOC2 was identified. CONCLUSIONS: Rare variants in LPL and a common variant in APOA5 were more commonly found in Thai subjects with severe hypertriglyceridemia. A common p.Gly185Cys APOA5 variant, in particular, was quite prevalent and potentially contributed to hypertriglyceridemia in this group of patients.

Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.

Apolipoprotein (apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol (TG) homeostasis. Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipoprotein lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of cardiovascular disease. Single nucleotide polymorphisms (SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction. Genetically engineered mouse models and human population studies suggest that, in certain instances, supplementation with wild type (WT) apoA-V may have therapeutic benefit. It is hypothesized that individuals that manifest elevated plasma TG owing to deleterious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance. On the other hand, subjects with hypertriglyceridemia of independent origin (unrelated to apoA-V function) may not respond to apoA-V augmentation in this manner. Improvement in the ability to identify individuals predicted to benefit, advances in gene transfer technology and the strong connection between HTG and heart disease, point to apoA-V supplementation as a viable disease prevention / therapeutic strategy. Candidates would include individuals that manifest chronic TG elevation, have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels.

Apolipoprotein A-V is not a major determinant of triglyceride levels during human sepsis.

PURPOSE: During critical illnesses, alterations in lipid metabolism occur. We examined levels of apolipoprotein A-V, a novel regulator of triglyceride metabolism, during sepsis in humans. METHODS: Seventy-five cases of sepsis and 75 cases of acute illnesses not associated with infection were recruited. Lipids and apolipoprotein A-V levels were measured by enzymatic methods and enzyme-linked immunosorbent assay, respectively, within 24 hours of diagnosis. Fifty healthy controls were also enrolled. RESULTS: During sepsis and acute illnesses, serum total cholesterol and high-density lipoprotein cholesterol levels were significantly lower than those in controls. Serum triglyceride levels, however, were not significantly different. Similarly, serum apolipoprotein A-V levels during sepsis were not significantly different from those during acute illnesses and those in controls (expressed as median [interquartile range]: 149.6 [97.5-257.1] vs 157.9 [98.4-238.2] and 155.9 [91.5-253.8] ng/mL, respectively; P = .98); and they were not correlated with serum triglyceride levels. Low apolipoprotein A-V levels were associated with higher mortality, but the association became nonsignificant after adjusting for high-density lipoprotein cholesterol levels. CONCLUSIONS: During sepsis or acute illnesses, serum apolipoprotein A-V levels were not significantly different from those in controls. Furthermore, apolipoprotein A-V levels were not linearly correlated with triglyceride levels, suggesting that it might not be a major determinant of triglyceride levels during sepsis.

Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduces fasting triglycerides and enhances apolipoprotein A-V levels in non-diabetic subjects with hypertriglyceridemia.

OBJECTIVE: Previous studies have indicated that supplementation with probiotics might improve lipid metabolism. The objective of the study was to evaluate the effect of supplementation with probiotic strains Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on triglyceride (TG) and apolipoprotein A-V (apo A-V) levels. METHODS: A randomized, double-blinded, placebo-controlled study was conducted with 128 non-diabetic subjects with hypertriglyceridemia. Over a 12-week test period, the probiotic group consumed 2 g/day of a powdered supplement containing L. curvatus HY7601 and L. plantarum KY1032, whereas the placebo group consumed a powder lacking probiotics. RESULTS: After the treatment, the probiotic group showed an 18.3% (P < 0.001) reduction in TGs and increases of 21.1% (P = 0.001) and 15.6% (P < 0.001) in the apo A-V and LDL particle size, respectively. The probiotic group had a significant reduction in TGs (P = 0.040) and increases in the plasma apo A-V (P = 0.003) and LDL particle size (P < 0.001) compared with the placebo group. In the probiotic group, the reduction in the TG levels was negatively correlated with changes in the apo A-V and baseline TGs, regardless of the APOA5 -1131T > C genotype. CONCLUSION: The consumption of two probiotic strains for 12 weeks reduced TGs and increased the apo A-V and LDL particle size in hypertriglyceridemic subjects. This effect was more pronounced in subjects with higher levels of fasting TGs regardless of their APOA5 -1131T > C genotype.