APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries.

Apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia in mice and humans. For years, the cause remained a mystery, but the mechanisms have now come into focus. Here, we review progress in defining APOA5's function in plasma triglyceride metabolism. Biochemical studies revealed that APOA5 binds to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppresses its ability to inhibit the activity of lipoprotein lipase (LPL). Thus, APOA5 deficiency is accompanied by increased ANGPTL3/8 activity and lower levels of LPL activity. APOA5 deficiency also reduces amounts of LPL in capillaries of oxidative tissues (e.g., heart, brown adipose tissue). Cell culture experiments revealed the likely explanation: ANGPTL3/8 detaches LPL from its binding sites on the surface of cells, and that effect is blocked by APOA5. Both the low intracapillary LPL levels and the high plasma triglyceride levels in Apoa5-/- mice are normalized by recombinant APOA5. Carboxyl-terminal sequences in APOA5 are crucial for its function; a mutant APOA5 lacking 40-carboxyl-terminal residues cannot bind to ANGPTL3/8 and lacks the ability to change intracapillary LPL levels or plasma triglyceride levels in Apoa5-/- mice. Also, an antibody against the last 26 amino acids of APOA5 reduces intracapillary LPL levels and increases plasma triglyceride levels in wild-type mice. An inhibitory ANGPTL3/8-specific antibody functions as an APOA5-mimetic reagent, increasing intracapillary LPL levels and lowering plasma triglyceride levels in both Apoa5-/- and wild-type mice. That antibody is a potentially attractive strategy for treating elevated plasma lipid levels in human patients.

APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

Overexpression of salusin­α upregulates AdipoR2 and activates the PPARα/ApoA5/SREBP­1c pathway to inhibit lipid synthesis in HepG2 cells.

Salusin­α and adiponectin, are vasoactive peptides with numerous similar biological effects related to lipid metabolism. Adiponectin has been shown to reduce fatty acid oxidation and to inhibit lipid synthesis of liver cells through its receptor, adiponectin receptor 2 (AdipoR2), but whether salusin­α is able to interact with AdipoR2, was not previously reported. To investigate this, in vitro experiments were carried out. The overexpression and interference recombinant plasmids were constructed with salusin­α. The lentiviral expression systems of salusin­α overexpression and interference were respectively synthesized in 293T cells, and 293T cells were infected with the lentivirus. Finally, the association between salusin­α and AdipoR2 was analyzed by semi­quantitative PCR. Subsequently, HepG2 cells were also infected with these viruses. The expression levels of AdipoR2, peroxisome proliferator­activated receptor­α (PPARα), apolipoprotein A5 (ApoA5) and sterol regulatory element­binding transcription factor 1 (SREBP­1c) were detected by western blotting, and AdipoR2 inhibitor (thapsigargin) and agonist [4­phenyl butyric acid (PBA)] were used to observe the resultant changes in the aforementioned molecules. The results obtained revealed that the overexpression of salusin­α increased the level of AdipoR2 in 293T and HepG2 cells, led to an upregulation of the levels of PPARα and ApoA5, and inhibited the expression of SREBP­1c, whereas the salusin­α interference lentivirus exerted the opposite effects. Notably, thapsigargin inhibited the expression of AdipoR2, PPARα and ApoA5 in HepG2 cells of pHAGE­Salusin­α group, and caused an increase in the level of SREBP­1c, whereas the opposite effects were observed in pLKO.1­shSalusin­α#1 group upon treatment with PBA. Taken together, these data demonstrated that overexpression of salusin­α upregulated AdipoR2, which in turn activated the PPARα/ApoA5/SREBP­1c signaling pathway to inhibit lipid synthesis in HepG2 cells, thereby providing theoretical data on which to base the clinical application of salusin­α as a novel peptide for molecular intervention in fatty liver disease.

Apolipoprotein A5 ameliorates MCT induced pulmonary hypertension by inhibiting ER stress in a GRP78 dependent mechanism.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic, progressive lung vascular disease accompanied by elevated pulmonary vascular pressure and resistance, and it is characterized by increased pulmonary artery smooth muscle cell (PASMC) proliferation. Apolipoprotein A5 (ApoA5) improves monocrotaline (MCT)-induced PAH and right heart failure; however, the underlying mechanism remains unknown. Here we speculate that ApoA5 has a protective effect in pulmonary vessels and aim to evaluate the mechanism. METHODS: ApoA5 is overexpressed in an MCT-induced PAH animal model and platelet-derived growth factor (PDGF)-BB-induced proliferating PASMCs. Lung vasculature remodeling was measured by immunostaining, and PASMC proliferation was determined by cell counting kit-8 and 5-ethynyl-2'-deoxyuridine5-ethynyl-2'-deoxyuridine incorporation assays. Coimmunoprecipitation-mass spectrometry was used to investigate the probable mechanism. Next, its role and mechanism were further verified by knockdown studies. RESULTS: ApoA5 level was decreased in MCT-induced PAH lung as well as PASMCs. Overexpression of ApoA5 could help to inhibit the remodeling of pulmonary artery smooth muscle. ApoA5 could inhibit PDGF-BB-induced PASMC proliferation and endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78 (GRP78). After knocking down GRP78, the protecting effects of ApoA5 have been blocked. CONCLUSION: ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism.

Apolipoprotein A5, a unique modulator of fasting and postprandial triglycerides.

The discovery of apolipoprotein A5 (APOA5) in 2001 has raised a number of intriguing questions about its role in lipid transport and triglyceride (TG) homeostasis. Genome-wide association studies have consistently identified APOA5 as a regulator of plasma TG levels, which is further supported by studies in transgenic and knockout mouse models. The present review describes recent concepts pertaining to the roles of APOA5 in TG metabolism as related to the vascular compartment, liver, adipose tissue and the gut. Recent evidence indicates that APOA5 may also affect postprandial TG metabolism through influencing chylomicron formation and transport by the intestine into the intestinal lymph. While substantial evidence supports the notion that APOA5 plays both extracellular and intracellular roles in TG homeostasis, mysteries remain on how this low-abundance, liver-derived protein may modulate TG homeostasis, including via the gut. Given the strong correlation between elevated plasma TG and cardiometabolic diseases, there is great scientific and public interest in understanding the intriguing mysteries presented by APOA5.

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses.

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

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.

Identifying functional non-coding variants in APOA5/A4/C3/A1 gene cluster associated with coronary heart disease.

Recent genome-wide association studies identified several polymorphisms in the APOA5/A4/C3/A1 gene cluster influencing lipids level and risk of coronary heart disease (CHD). However, few studies explored the molecular mechanism. The purposes of this study were to fine-map noncoding region between APOA1 and APOC3 and then explore the clinical relevance in CHD and potential underlying mechanisms. In this study, a 2.7-kb length of the non-coding region between APOA1 and APOC3 was screened and five polymorphisms were investigated in the case-control study. The molecular mechanism was explored. Our data confirmed the association between rs7123454, rs12721030, rs10750098, and rs12721028 with CHD in 828 patients and 828 controls and replicated it in an independent population of 405 patients and 405 controls. In addition, the rs10750098 and rs12721030 are significantly associated with decreased serum APOA1 levels (P = 4.2 × 10-4 and P = 3.2 × 10-5, combined analysis), while a significant association was observed between serum APOA1 level and CHD (OR: 0.43, 95% CI: 0.28-0.64, P < .01) with adjustment for clinical covariates and different population sets. In vitro evaluation of potential function of non-coding variants between APOA1 and APOC3 demonstrated that rs10750098 as being the most sufficient to confer the haplotype-specific effect on the regulation of APOs gene transcription. Our results strongly implicate the involvement of common noncoding DNA variants in APOA5/A4/C3/A1 gene cluster in the pathogenesis of dyslipidemia and the risk of CHD.

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.

Functional recombinant apolipoprotein A5 that is stable at high concentrations at physiological pH.

APOA5 is a low-abundance exchangeable apolipoprotein that plays critical roles in human triglyceride (TG) metabolism. Indeed, aberrations in the plasma concentration or structure of APOA5 are linked to hypertriglyceridemia, hyperchylomicronemia, myocardial infarction risk, obesity, and coronary artery disease. While it has been successfully produced at low yield in bacteria, the resulting protein had limitations for structure-function studies due to its low solubility under physiological buffer conditions. We hypothesized that the yield and solubility of recombinant APOA5 could be increased by: i) engineering a fusion protein construct in a codon optimized expression vector, ii) optimizing an efficient refolding protocol, and iii) screening buffer systems at physiological pH. The result was a high-yield (25 mg/l) bacterial expression system that produces lipid-free APOA5 soluble at concentrations of up to 10 mg/ml at a pH of 7.8 in bicarbonate buffers. Physical characterization of lipid-free APOA5 indicated that it exists as an array of multimers in solution, and far UV circular dichroism analyses show differences in total α-helicity between acidic and neutral pH buffering conditions. The protein was functional in that it bound and emulsified multilamellar dimyristoyl-phosphatidylcholine vesicles and could inhibit postprandial plasma TG accumulation when injected into C57BL/6J mice orally gavaged with Intralipid.

Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes.

OBJECTIVE: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. Approach and Results: Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical LPL, APOC2, APOA5, GP1HBP1, and LMF1. Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis. CONCLUSIONS: Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in LPL while APOA5 variants, in combination with high rare polygenic burden, were the most frequent genotype of MCS.

Phenotypic severity in a family with MEND syndrome is directly associated with the accumulation of potentially functional variants of cholesterol homeostasis genes.

BACKGROUND: Male EBP disorder with neurologic defects (MEND) syndrome is an X-linked disease caused by hypomorphic mutations in the EBP (emopamil-binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. METHODS: We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole-exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in-house scoring system. RESULTS: Twenty-seven from 105 missense variants found in 45 genes of the four exomes were considered significant (-5 to -9 scores). We found a direct genotype-phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. CONCLUSION: We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome.

Function of different proportions of apolipoprotein A-I cysteine mutants and apolipoprotein A-V on recombinant high-density lipoproteins in vitro.

To explore the anti-atherosclerotic effects of recombinant high-density lipoproteins (rHDL) of apolipoprotein AI wild-type (apoA-Iwt), apolipoprotein AI Milano (apoA-IM), apolipoprotein AI (N74C) (apoA-I (N74C) )and apolipoprotein AV (apoA-V). We constructed rHDL liposomes (rHDLs), which included apoA-Iwt, apoA-IM, and apoA-I (N74C), followed by the synthesis of rHDLs, with the indicated ratios of apoA-Iwt, apoA-IM, apoA-I (N74C) and apoA-V. We investigated the anti-atherosclerotic effects by experiments including the DMPC clearance assay and experiments that assessed the in vitro antioxidation against low-density lipoprotein, the cellular uptake of oxidized low-density lipoprotein (oxLDL) and the in vitro intracellular lipid accumulation. Electron microscopy results revealed that as more apoA-V was present in rHDLs, the particle size of rHDLs was larger. The DMPC clearance assay subsequently showed that rHDL protein mixtures could promote DMPC turbidity clearance when more apoA-V was included in the reaction mixtures, with apoAV-rHDL showing the strongest turbidity clearance ability (P<0.05 vs AI-rHDL). In vitro antioxidation against low-density lipoprotein assays indicated that rHDLs containing apoA-V had increasing oxidation resistance against low-density lipoprotein (LDL) with higher apoA-V contents. Finally, cellular uptake of oxLDL and intracellular lipids suggested an apparent oxidation resistance to LDL oxidation in vitro and a reduced intracellular lipid accumulation in THP-1-derived macrophages, with AIM-rHDL demonstrating the greatest ability to decrease intracellular lipid accumulation. Different proportions of apolipoprotein A-I cysteine mutants and apolipoprotein A-V of rHDL changed the lipid binding capacity, particle size, and antioxidant capacity. These changes may show a beneficial effect of rHDL on atherosclerosis.

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.

Lifestyle genomics and the metabolic syndrome: A review of genetic variants that influence response to diet and exercise interventions.

Metabolic syndrome (MetS) comprises a cluster of risk factors that includes central obesity, dyslipidemia, impaired glucose homeostasis and hypertension. Individuals with MetS have elevated risk of type 2 diabetes and cardiovascular disease; thus placing significant burdens on social and healthcare systems. Lifestyle interventions (comprised of diet, exercise or a combination of both) are routinely recommended as the first line of treatment for MetS. Only a proportion of people respond, and it has been assumed that psychological and social aspects primarily account for these differences. However, the etiology of MetS is multifactorial and stems, in part, on a person's genetic make-up. Numerous single nucleotide polymorphisms (SNPs) are associated with the various components of MetS, and several of these SNPs have been shown to modify a person's response to lifestyle interventions. Consequently, genetic variants can influence the extent to which a person responds to changes in diet and/or exercise. The goal of this review is to highlight SNPs reported to influence the magnitude of change in body weight, dyslipidemia, glucose homeostasis and blood pressure during lifestyle interventions aimed at improving MetS components. Knowledge regarding these genetic variants and their ability to modulate a person's response will provide additional context for improving the effectiveness of personalized lifestyle interventions that aim to reduce the risks associated with MetS.

Association of apolipoprotein A1 and A5 polymorphisms with stroke subtypes in Han Chinese people in Taiwan.

BACKGROUND AND PURPOSES: Stroke is a leading cause of death and serious disability worldwide. Now, evidences indicate that dyslipidemia may play an important role in stroke. APOA1 and APOA5 involve in lipid metabolism. In this study, we investigated the association of APOA1 rs670 and APOA5 rs662799 with different stroke subtypes in the Han Chinese population of Taiwan. METHODS: A total of 1751 participants, including 459 control subjects, 606 large artery atherosclerosis (LAA), 339 small vessel occlusion (SVO), and 347 hypertensive intracranial hemorrhage (HICH), were enrolled. The presence of rs670 and rs662799 was analyzed through polymerase chain react ion and matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry. RESULTS: Notably, the frequency of the rs662799 C allele was significantly lower in the SVO patients than in the controls (24.36% vs. 29.74%, P = 0.024). The frequencies of heterozygote TC [odd ratio (OR) = 0.732, 95% confidence interval (CI) = 0.544-0.984, P = 0.038] and TC + CC (OR = 0.719, 95% CI = 0.542-0.953, P = 0.022) genotypes were significantly lower in the SVO patients than in the controls. In addition, triglyceride levels in individuals carrying the rs662799 TC + CC genotype were significantly higher than in those carrying the TT genotype, especially in older age, female, and body mass index (BMI) ≥ 25 groups. On the contrary, the low-density lipoprotein-cholesterol (LDL-C) was significantly lower in rs662799 TC + CC genotype than TT genotype. The BMI was significantly lower in subjects with rs662799 TC + CC genotype than those with TT genotype, especially in older age and female. High-density lipoprotein-cholesterol (HDL-C) levels were higher in individuals carrying the rs670 GG genotype than in those carrying the AG + AA genotype, especially in BMI < 25 group. Logistic regression analysis showed that the rs662799 C allele (TC + CC) was an independent protective factor for SVO after adjustment for conventional risk factors (OR = 0.709, 95% CI = 0.526-0.956; P = 0.024). CONCLUSION: GG genotype of rs670 is correlated with high serum HDL-C levels, whereas TC + CC genotype of rs662799 is associated with high serum triglyceride and low LDL and BMI levels. In addition, the rs662799 C allele (TC + CC) is an independent protective factor for SVO in the Han Chinese population in Taiwan.

Association of APOA5 and APOC3 Genetic Polymorphisms With Severity of Hypertriglyceridemia in Patients With Cutaneous T-Cell Lymphoma Treated With Bexarotene.

Importance: Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives: To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants: This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures: Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results: Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance: These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

[The effect of lnc-RAP3 on 3T3-L1 preadipocyte differentiation in mouse].

The long non-coding RNAs (lncRNAs) are a type of RNAs with more than 200nt in length and without any long open reading frame, but often have mRNA structural features. They can regulate the expression of target genes in different manners at the transcriptional and post-transcriptional levels. In recent years, various studies demonstrated that lncRNAs play crucial roles in adipogenesis. The long non-coding RNA, lnc-RAP3, located on the mouse chromosome 17, possesses a significantly differential expression pattern during mouse adipocyte differentiation; but its specific biological function (s) remains unclear. To investigate the effect of lnc-RAP3 on adipogenesis in the mouse 3T3-L1 preadipocytes, we first constructed a eukaryotic expression vector pcDNA3.1-RAP3. pcDNA3.1-RAP3 and synthetic RAP3-siRNAs were transfected individually into 3T3-L1 preadipocytes by Lipofectamine TM 2000, thereby over-expressing and knocking-down lnc-RAP3 expression, respectively. The transfected preadipocytes were induced to undergo adipogenic differentiation. Oil Red O staining and qRT-PCR were used to detect the effects of lnc-RAP3 overexpression/knockdown on 3T3-L1 preadipocyte differentiation. The results showed that overexpression of lnc-RAP3 led to a notable decrease in lipid accumulation (P<0.05) and remarkably reduced the mRNA expression levels of C/EBPα, Glut4, PPARγ, LPL and FAS on day 0, day 2, and day 4 post differentiation (P<0.05, P<0.01). In contrast, quantitative analysis of Oil Red O on day 4 of differentiation revealed that inhibition of lnc-RAP3 increased the formation of neutral lipid droplets (P<0.05). In addition, silencing lnc-RAP3 also significantly increased the mRNA expression of PPARγ, LPL, C/EBPα, FAS and Glut4 on day 0 and day 2 post differentiation (P<0.05, P<0.01). Our study suggests that lnc-RAP3 might suppress 3T3-L1 preadipocyte differentiation by affecting the expression of the genes involved in adipogenic differentiation.

New insights into apolipoprotein A5 in controlling lipoprotein metabolism in obesity and the metabolic syndrome patients.

Apolipoprotein A5 (apoA5) has been identified to play an important role in lipid metabolism, specifically in triglyceride (TG) and TG-rich lipoproteins (TRLs) metabolism. Numerous evidence has demonstrated for an association between apoA5 and the increased risk of obesity and metabolic syndrome, but the mechanism remains to be fully elucidated. Recently, several studies verified that apoA5 could significantly reduce plasma TG level by stimulating lipoprotein lipase (LPL) activity, and the intracellular role of apoA5 has also been proved since apoA5 is associated with cytoplasmic lipid droplets (LDs) and affects intrahepatic TG accumulation. Furthermore, since adipocytes provide the largest storage depot for TG and play a crucial role in the development of obesity, we could infer that apoA5 also acts as a novel regulator to modulate TG storage in adipocytes. In this review, we focus on the association of gene and protein of apoA5 with obesity and metabolic syndrome, and provide new insights into the physiological role of apoA5 in humans, giving a potential therapeutic target for obesity and associated disorders.

HDL in CKD-The Devil Is in the Detail.

The picture of HDL cholesterol (HDL-C) as the "good" cholesterol has eroded. This is even more surprising because there exists strong evidence that HDL-C is associated with cardiovascular disease (CVD) in the general population as well as in patients with impairment of kidney function and/or progression of CKD. However, drugs that dramatically increase HDL-C have mostly failed to decrease CVD events. Furthermore, genetic studies took the same line, as genetic variants that have a pronounced influence on HDL-C concentrations did not show an association with cardiovascular risk. For many, this was not surprising, given that an HDL particle is highly complex and carries >80 proteins and several hundred lipid species. Simply measuring cholesterol might not reflect the variety of biologic effects of heterogeneous HDL particles. Therefore, functional studies and the involvement of HDL components in the reverse cholesterol transport, including the cholesterol efflux capacity, have become a further focus of study during recent years. As also observed for other aspects, CKD populations behave differently compared with non-CKD populations. Although clear disturbances have been observed for the "functionality" of HDL particles in patients with CKD, this did not necessarily translate into clear-cut associations with outcomes.