Lipoprotein profile assessed by 1H NMR, BMI and blood pressure are associated with vascular alterations in children with familial hypercholesterolaemia.

BACKGROUND AND AIMS: Children with familial hypercholesterolaemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C) concentrations since birth, which increases the risk of cardiovascular disease in adulthood. Arterial injury and stiffness parameters, including carotid intima media thickness (cIMT), pulse wave velocity (PWV) and distensibility (DIST), can be detected early in childhood. We studied the associations between cIMT, PWV and DIST with the lipoprotein profile assessed by proton nuclear magnetic resonance (1H NMR) and with influential variables such as blood pressure (BP) or body mass index (BMI) in children with FH. METHODS AND RESULTS: In this cross-sectional study, we included 201 children (96 with FH and 105 non-FH controls). Clinical history, physical examination and standard biochemical studies were performed. FH genetic testing was performed when clinically indicated. Carotid ultrasonography and an advanced lipoprotein profile by 1H NMR were performed. Multivariate and classification methods were used. There were no differences between cIMT, PWV and DIST between FH and non-FH children. FH children presented more total LDL and large, medium and small particles. Small LDL particles, BMI and systolic BP determined the presence of pathological IMT in the FH group. LDL size, high-density lipoproteins and very low-density lipoprotein particles together with blood pressure determined the presence of pathological arterial wall elasticity. CONCLUSIONS: Alterations in lipoprotein parameters assessed by are associated with early structural and functional arterial characteristics in children with FH. BMI and BP act as boosting factors. Cardiovascular prevention should start early in children with FH, encompassing all components of a healthy lifestyle.

Factors hindering hypertension control: perspectives of front-line health professionals in rural Ghana.

OBJECTIVE: Hypertension (HTN) control remains a major public health challenge in sub-Saharan Africa (SSA). Health professionals influence patient adherence and self-management practices for HTN particularly in rural and lower socio-economic communities in SSA. Contextual evidence on the reasons for the suboptimal control of HTN in clinical settings is crucial to improving health delivery practices for HTN and preventing HTN related-complications. STUDY DESIGN: A cross-sectional qualitative study. METHODS: Semistructured interviews were conducted among 40 purposively sampled front-line health professionals in seven health facilities in northern Ghana. Data were analysed using a thematic approach through pre-identified and evolving themes. RESULTS: We identified three key themes underlying the poor HTN control. First, health professionals' barriers included communication difficulties, poor collaboration and referrals among health professionals and limited training on HTN and other non-communicable diseases (NCDs). Secondly, health system-related barriers included limited health personnel, drug shortages, inadequate facilities and equipment and challenges with National Health Insurance (NHIS). The third theme was patient-related barriers including non-adherence, use of traditional treatments, sociocultural factors and lack of appreciation. CONCLUSION: A holistic public health approach, which builds upon health professionals' capacities, harnesses and integrates into existing health policy and systems structures and empowers and collaborates with communities could contribute to improving HTN control in rural settings. Health policymakers need to consider the sociocultural, economic and geographical characteristics in such settings, which influence health service delivery practices in designing and implementing HTN interventions. There is also a need for health policy to integrate NCD training and management of multiple and comorbid conditions into the training curriculum of health training institutions to build health professionals capacity to facilitate the uptake of evidence-based NCD interventions and manage the double burden of diseases.

Extracellular FABP4 uptake by endothelial cells is dependent on cytokeratin 1 expression.

AIMS: The aim of this study is to determine the physical and functional interplay between fatty acid-binding protein 4 (FABP4) and its membrane receptor-like candidate protein, cytokeratin 1 (CK1), and to determine the effect of hindering CK1-mediated FABP4 cellular uptake on non-disturbed or metabolically stressed endothelial cells. METHODS: We monitored the direct interaction between FABP4 and CK1 using surface plasmon resonance, and the effects of blocking exogenous FABP4 (eFABP4) cellular uptake were determined by using specific siRNA to knock down the expression of CK1 in human umbilical vein endothelial cells (HUVECs). The expression and nuclear translocation of transcription factors involved in oxidative stress (NRF2) and inflammation (p65 subunit of NF-ĸB transcription factor) were determined by Western blotting analysis. RESULTS: Our data showed that FABP4 and CK1 bind to each other and that the putative FABP4 binding domain would be within the 151GIQEVTINQSLLQPLNVEID170 CK1 sequence. We determined that in non-disturbed or metabolically stressed endothelial cells, eFABP4 regulates the cellular response to oxidative stress. In addition, we also found that in the presence of palmitate, eFABP4 increases the pro-inflammatory effects induced by palmitate per se, probably due to an increase in the transport of palmitate inside cells, suggesting that these FABP4-mediated pro-oxidative and pro-inflammatory effects are dependent on CK1 expression. CONCLUSIONS: We demonstrated that CK1 facilitates eFABP4 cellular uptake in endothelial cells. Therefore, the CK1-targeted inhibition of exogenous FABP4 cellular uptake might be a potential therapeutic strategy to protect endothelial cells against FABP4-induced activation of inflammation and oxidative stress.

The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5.

The adipose tissue microenvironment plays a key role in tumour initiation and progression because it provides fatty acids and adipokines to tumour cells. The fatty acid-binding protein (FABP) family is a group of small proteins that act as intracellular fatty acid transporters. Adipose-derived FABPs include FABP4 and FABP5. Both have an important role in lipid-related metabolic processes and overexpressed in many cancers, such as breast, prostate, colorectal and ovarian. Moreover, their expression in peritumoural adipose tissue is deregulated, and their circulating levels are upregulated in some tumours. In this review, we discuss the role of the peritumoural adipose tissue and the related adipokines FABP4 and FABP5 in cancer initiation and progression and the possible pathways implicated in these processes.

HDL-c levels predict the presence of pleural effusion and the clinical outcome of community-acquired pneumonia.

OBJECTIVES: To investigate if HDL cholesterol (HDL-c) could be a biomarker of the degree of severity according to prognostic prediction scores in community-acquired pneumonia (CAP) or the development of clinical complications such as pleural effusion. METHODS: We included in a retrospective study 107 patients admitted to the hospital that fulfilled diagnostic criteria for CAP between the 30th October 2011 and 1st September 2012. HDL-c levels at admission, CAP prognosis scores (PSI and CURB65) and clinical outcomes were recorded for the study. RESULTS: Basal HDL-c levels were not statistically different according to prognostics scores neither PSI nor CURB-65. Significantly lower levels of HDL-c were also associated to the development of septic shock and admission to the intensive care unit. HDL-c were inversely correlated with acute phase reactants CRP (r = -0.585, P < 0.001), ESR (r = -0.477, P < 0.001), and leukocytes cell count (r = -0.254, P < 0.009). Patients with pleural effusion showed significant lower levels of HDL-c [28.9 (15.5) mg/dl vs. 44.6 (21.1) mg/dl]; P = 0.007. HDL-c is a good predictor of the presence of pleural effusion in multivariate analyses and using ROC analyses [AUC = 0.712 (0.591-0.834), P = 0.006]. HDL-c levels of 10 mg/dl showed a sensitivity of 97.6 % and a specificity of 82.4 % for the presence of pleural effusion. CONCLUSION: Monitoring HDL-c in CAP is an useful serum marker of acute phase response, clinical outcome and the presence of pleural effusion.

Serum palmitoleate acts as a lipokine in subjects at high cardiometabolic risk.

BACKGROUND AND AIM: Clinical data on the role as a lipokine of de novo lipogenesis-derived palmitoleic acid (C16:1n-7cis) in serum non-esterified fatty acids (palmitoleate) are scarce. We aimed to assess whether palmitoleate relates to cardiometabolic risk. METHODS AND RESULTS: In this cross-sectional study we included 358 individuals aged 30-65-years at high cardiovascular risk. We tested the association of palmitoleate (determined by gas chromatography) with metabolic syndrome (MS) and its components (defined by ATPIII criteria), fatty liver index (a surrogate of non-alcoholic fatty liver disease [NAFLD]), and subclinical atherosclerosis (determined as ultrasound-measured carotid intima-media thickness and arterial stiffness). Palmitoleate concentration was higher in women compared with men (median ± range interquartile, 1.36 ± 0.96 vs. 0.97 ± 0.77 µmol/L respectively, P < 0.001). In both genders palmitoleate concentration was associated with a higher prevalence of MS: men, odds ratio [OR: 1.12 (95%CI: 1.03; 1.23, P = 0.010)]; women [OR: 1.07 (95%CI: 1.03; 1.13, P = 0.005)], and all of its components except low HDL-cholesterol and hypertriglyceridemia. Palmitoleate was also associated with increased risk of NAFLD in both men [OR: 1.12 (95%CI: 1.03; 1.29, P = 0.031)] and women [OR: 1.11 (95%CI: 1.05; 1.19, P = 0.001)]. No associations with subclinical atherosclerosis were detected. CONCLUSIONS: Our observational data supports a relationship between de novo lipogenesis-derived circulating palmitoleic acid (palmitoleate) and increased cardiometabolic risk.

FABP4 plasma concentrations are determined by acquired metabolic derangements rather than genetic determinants.

BACKGROUND AND AIMS: Circulating FABP4 is strongly associated with metabolic and cardiovascular risk (CVR) and has been proposed as a new risk biomarker. Several FABP4 gene polymorphisms have been associated with protein expression in vitro and metabolic and vascular alterations in vivo. The aim of this study is to evaluate the impact of FABP4 polymorphisms on FABP4 plasma levels and subclinical arteriosclerosis in patients with obesity, metabolic syndrome (MS) or type 2 diabetes (T2DM). METHODS AND RESULTS: We studied 440 individuals with obesity, MS, T2DM or other cardiovascular risk conditions who attended the vascular medicine and metabolism unit of our hospital. Anamnesis, physical examination and anthropometry data were recorded. Standard biochemical parameters were determined. Plasma FABP4 concentrations were measured. Carotid intima-media thickness (cIMT) was assessed using ultrasonography. The following FABP4 gene single-nucleotide polymorphisms (SNPs) were analyzed: rs3834363, rs16909233, rs1054135, rs77878271, rs10808846 and rs8192688. None of the studied gene allele variants were hyper-represented in patients grouped according the presence of metabolic alterations nor were they associated with the FABP4 concentration. The FABP4 gene variants did not determine cIMT differences between the groups. In a multivariate analysis, gender and BMI, but not gene variants, significantly determined plasma FABP4 concentrations. CONCLUSIONS: In clinical settings, the circulating FABP4 levels are determined by the acquired metabolic derangements and not genetic variation.

LDL cholesterol and apolipoprotein B are associated with ascending aorta dilatation in bicuspid aortic valve patients.

BACKGROUND: The factors related to ascending aorta dilation (AAD) in patients with bicuspid aortic valve (BAV) are not completely understood. In addition, the role of cholesterol metabolism in AAD has not been studied. METHODS: We analyzed the relationship between different lipid parameters and the ascending aorta diameter/presence of aortic dilatation in 91 consecutive patients with BAV. RESULTS: We observed a positive linear correlation between the total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels and the ascending aorta diameter. The patients with AAD had higher LDL cholesterol and ApoB levels. Whereas LDL cholesterol and ApoB were identified as independent factors predictors of the aortic root diameter, only ApoB predicted the diameter of the ascending aorta. On the other hand, the levels of ApoB were an independent factor related to the dilatation of the aortic root. CONCLUSIONS: We have observed that cholesterol is associated with ascending aorta diameter and dilation in BAV patients. Further experimental and clinical studies are needed to explain the pathobiology of this association.

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function.

BACKGROUND: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. OBJECTIVE: We aimed to study the impact of a lower level of PA on cardiovascular health. DESIGN: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P<0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r=0.341, P=0.022), GPx (r=0.303, P=0.047) and decreases in RHR (r=-0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21-4.01), decrease in RHR (1.91, 95%CI: 1.01-4.98), and an increase in GPx (2.61, 95%CI: 1.16-5.01). CONCLUSION: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity.

Functional foods and cardiometabolic diseases* International Task Force for Prevention of Cardiometabolic Diseases.

Mounting evidence supports the hypothesis that functional foods containing physiologically-active components may be healthful. Longitudinal cohort studies have shown that some food classes and dietary patterns are beneficial in primary prevention, and this has led to the identification of putative functional foods. This field, however, is at its very beginning, and additional research is necessary to substantiate the potential health benefit of foods for which the diet-health relationships are not yet scientifically validated. It appears essential, however, that before health claims are made for particular foods, in vivo randomized, double-blind, placebo controlled trials of clinical end-points are necessary to establish clinical efficacy. Since there is need for research work aimed at devising personalized diet based on genetic make-up, it seems more than reasonable the latter be modeled, at present, on the Mediterranean diet, given the large body of evidence of its healthful effects. The Mediterranean diet is a nutritional model whose origins go back to the traditional dietadopted in European countries bordering the Mediterranean sea, namely central and southern Italy, Greece and Spain; these populations have a lower incidence of cardiovascular diseases than the North American ones, whose diet is characterized by high intake of animal fat. The meeting in Naples and this document both aim to focus on the changes in time in these two different models of dietary habits and their fall out on public health.

Subclinical atherosclerosis determinants in morbid obesity.

BACKGROUND AND AIMS: Obesity is associated with increased cardiovascular risk. However, the impact of morbid obesity on vascular structure and function is not well understood. This study was designed to appraise subclinical atherosclerosis markers, including carotid intima media thickness (cIMT), endothelial function, and arterial wall stiffness, and their determinants, in morbidly obese patients. METHODS AND RESULTS: In this cross-sectional study 194 overweight and obese patients were distributed in morbid-obese patients (MOP, n = 110), obese (OP, n = 84) and overweight patients (OwP, n = 33) groups. Demography, anthropometry, clinical and standard biochemical data were recorded. cIMT, endothelial function, defined as the small artery reactivity index (saRHI), and artery wall rigidity, studied by the augmentation index, were determined. More than 50% of the MOP, OP and OwP had a cIMT above the 75th percentile per age and gender. No differences in cIMT or saRHI were observed, although overweight and obese patients (OOP) had higher arterial rigidity compared with the morbid-obese patients. In a multivariate regression test, while cholesterol was the main determinant of cIMT in overweight and obese patients, glucose metabolism was the determinant in MOP. CONCLUSION: More than half of the population have a cIMT above general population ranges. OwP, OP and MOP have similar cIMT and saRHI. However, OOP have greater arterial wall rigidity. Dysglycemia is the main factor associated with subclinical atherosclerosis in MOP.

Dietary supplementation contributes to lifestyle improvement in hypercholesterolemic patients in real-life contexts.

AIMS: Assess the evolution of cardiovascular lifestyle behaviors in hypercholesterolemic patients concomitantly with changes in their daily intake of phytosterol-supplemented yoghurt (Phyto-SY). METHODS: Nationwide prospective observational study conducted in general practices across France and Spain. Each practitioner suggested lifestyle changes to five consecutive patients with hypercholesterolemia (whether or not they were taking hypocholesterolemic drugs) and recommended daily consumption of Phyto-SY. The study design involved an inclusion visit, a patient's self-monitoring assessment after 1 month, and a final visit after 4 months. Primary evaluation criterion: changes in dietary habits assessed by a standardized Nutritional Lifestyle score. Secondary criteria: changes in lipid profile, anthropometry (waist circumference) and lifestyle behavior. RESULTS: A total of 2376 hypercholesterolemic patients (of whom 54.8% were women) were included. The average age was 56.2 years old. The Nutritional Lifestyle score improved from 15.4 ± 5.4 to 8.7 ± 4.0 (p < 0.0001). Total cholesterol decreased by 10.6% (<0.0001), HDL-C increased by 8.0% (<0.0001), and LDL-C fell by 12.7% (<0.0001). Similar results were observed in patients treated with statins and those who were not. Frequency of walking (>30 min) increased from 59.3% to 78.3% (p < 0.0001). The overweight rate decreased from 22.8% to 17.5% (p < 0.0001) and waist circumference from 94.6 ± 13.3 cm to 93.0 ± 12.8 cm (p < 0.0001). Nutritional Lifestyles and other lifestyle markers' improvement were parallel to adherence to Phyto-SY adherence. CONCLUSION: Improvements in Nutritional Lifestyle scores, which included regular consumption of Phyto-SY over 4 months, was significantly linked to healthier lifestyles and to beneficial modifications in atherogenic lipid profiles, which reflected patient empowerment in a 'real life' context.

Circulating FABP4 is a marker of metabolic and cardiovascular risk in SLE patients.

The aim of this study is to determine if circulating fatty acid-binding protein 4 (FABP4) plasma levels are a possible marker of metabolic risk in SLE patients. Circulating levels of adipose FABP4 are associated with adiposity, insulin resistance (IR), metabolic syndrome, diabetes and cardiovascular diseases. Patients affected by systemic lupus erythematosus (SLE) show an accelerated atherosclerosis that cannot be entirely explained by traditional cardiovascular risk factors. Sixty consecutive patients with SLE and 34 non-SLE age-matched controls were recruited for the study. Total plasma lipids and circulating FABP4 were determined. Subclinical atherosclerosis was evaluated by measuring carotid intimae-media thickness (c-IMT) by sonography, and the distribution of lipoprotein subclasses was analysed by nuclear magnetic resonance (NMR) spectroscopy. In the SLE group, FABP4 was associated with IR, atherogenic dyslipidaemia, as measured by NMR, and the presence of subclinical atherosclerosis. In multivariate analyses FABP4 was associated with increased c-IMT independent of the inflammatory state of the patient. In sum, circulating FABP4 is involved in the metabolic disturbances of SLE affecting lipid metabolism and IR, and it could be a biomarker of atherosclerosis in this population.

Pilot study to validate a computer-based clinical decision support system for dyslipidemia treatment (HTE-DLP).

UNLABELLED: Pilot study to validate a Computerized Decision Support Systems (CDS) (HTE-DLP) for improving treatment of hyperlipidemia. METHODS: HTE-DLP was programmed to offer automatic specific reminders for lipid treatment. Seventy-seven patients with high cardiovascular risk were randomized. 10 expert physicians in cardiovascular-risk management were recruited. We assessed number of patients at LDL <70 mg/dl after 12 weeks of treatment. RESULTS: A greater proportion of intervention group reached the LDL-C <70 mg/ml [55.0% vs 12.5%, p = 0.003; OR: 3.26 IC (1.16-9.15)]. "High potency statins" and combined therapy were used more frequently in the intervention group than the control group (p = 0.001). Seven adverse effects were documented in the intervention group and two in the control group. An acceptable relationship was observed with regard to costeffectiveness in the intervention group. Physicians expressed good agreement with HTE-DLP (86.1%) and comfortable ease-of-use (85%). CONCLUSIONS: Use of a CDSS in high-risk cardiovascular patients resulted in a significant reduction in LDL-C levels.

Body weight loss by very-low-calorie diet program improves small artery reactive hyperemia in severely obese patients.

BACKGROUND: Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). METHODS: Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. RESULTS: SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 ± 0.236 vs. 1.737 ± 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (ß -0.049, IC 95 % -0.091-0.008, p = 0.021). CONCLUSIONS: Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP.

Carotid atherosclerosis and lipoprotein particle subclasses in familial hypercholesterolaemia and familial combined hyperlipidaemia.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) and familial combined hyperlipidaemia (FCH) are common atherogenic disorders with great variability in cardiovascular disease (CVD). No direct atherosclerosis burden comparisons have been performed between FH and FCH in relation to lipoprotein particle distribution. METHODS AND RESULTS: Risk factors and three measures of carotid intima-media thickness (IMT) in both sides were determined in 572 FH, 250 FCH and 200 controls. Lipoproteins were assessed by nuclear magnetic resonance (NMR) spectroscopy. Compared with controls, IMT measures were increased in FH and FCH. FCH had the highest adjusted mean-maximum IMT. FH had twice low-density lipoprotein (LDL) particles than controls, but similar LDL subclass size and distribution. FCH subjects also had increased LDL particles and the highest number of small LDL (1519 ± 731 nmol l(-1) vs. 887 ± 784 nmol l(-1) in FH and 545 ± 409 nmol l(-1) in controls). Age, gender, cholesterol/high-density lipoprotein (HDL) ratio, smoking and systolic blood pressure were independently associated with IMT in FH (r(2) = 0.38). The same variables, except cholesterol/HDL ratio, were associated with IMT in FCH (r(2) = 0.40). Among NMR lipoproteins, only VLDL and chylomicrons increased IMT prediction in FCH by 0.8%. CONCLUSION: FH and FCH subjects show increased carotid atherosclerosis in relation to classical risk factors. Lipoprotein subclasses do not substantially contribute to IMT variability.

Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity.

BACKGROUND AND AIMS: Abdominal obesity (AO) is associated with endothelial function (EF) alteration and increased global cardiovascular (CV) risk. Therapeutic lifestyle changes (TLSC) reduce CV risk, but the impact on EF assessed by peripheral artery tonometry (PAT) is unknown. In this study, we aimed to prospectively assess the effects of TLSC on EF measured by PAT in increased CV risk patients with AO. METHODS AND RESULTS: 150 patients with AO and moderate CV risk were randomized to groups receiving a one-year intervention of either conventional medical care (control group, CG) or an intensive TLSC program (intervention group, IG). Vascular studies (EF by PAT, intima-media thickness (IMT)) and lifestyle (LS) assessment were performed before and after intervention. The PAT ratio improved in the IG and worsened in the CG. The global CV risk was reduced (P = 0.017) in the IG due to a significant decrease in systolic blood pressure (P < 0.001), increase in HDL cholesterol and ApolipoproteinA1 (P = 0.013). More individuals in the IG than in the CG quit smoking (P = 0.001) and increased their physical activity (P = 0.014). The improvement in at least two LS components was associated with a PAT ratio increase (2.44 IC: 95% 0.99-6.00, P = 0.051). The PAT ratio increase determined less IMT progression (-1.1 IC: 95% 0.91-1.00, P = 0.053). CONCLUSIONS: Good adherence to a TLSC program reduces global CV risk and determines PAT ratio improvement. The PAT ratio increase is the main determinant of lower IMT progression.

APOA5 gene expression in the human intestinal tissue and its response to in vitro exposure to fatty acid and fibrate.

BACKGROUND AND AIMS: APOA5, a key gene regulating triglyceride (TG) levels, is reported to be expressed exclusively in the liver where it may regulate TG-rich particle synthesis and secretion. Since the same lipoprotein processing occurs in the intestine, we have postulated that this organ would also express APOA5. METHODS AND RESULTS: We have detected the APOA5 gene expression in C57BL/6J mouse and in human small intestine samples. In humans, it is expressed mainly in the duodenum and colon, with messenger RNA (mRNA) levels four orders of magnitude lower than in the liver, and the protein product being one-sixth of the liver equivalent. Subsequently, we carried out in vitro experiments in TC-7/CaCo(2) human intestinal cells to analyse the expression of APOA5, APOC3, APOB and MTP genes after the incubation with long- and short-chain fatty acids, and a peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wy 14643, a fibrate therapeutic agent). In the TC-7 cell line, APOA5 expression was significantly upregulated by saturated fatty acids. The short-chain fatty acid butyrate increased APOA5 expression almost fourfold while APOB was downregulated by increasing butyrate concentrations. When TC-7 cells were incubated with PPARα agonist, the APOA5 expression was increased by 60%, while the expression of APOB, MTP and APOC3 was decreased by 50%, 30% and 45%, respectively. CONCLUSION: Our results demonstrate that APOA5 is expressed in the intestine, albeit at a much lower concentration than in the liver. While it remains to be determined whether intestinal apo A-V is functional, our in vitro experiments show that its expression is modifiable by dietary and pharmacological stimuli.