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Alpo Vuorio,1,2 Matti J Tikkanen,3 Petri T Kovanen4 1Health Center Mehiläinen, Vantaa, Finland; 2Finnish Institute of Occupational Health, Lappeenranta, Finland; 3Heart and Lung Center, Helsinki University Central Hospital, Folkhälsan Research Center, Biomedicum, Helsinki, Finland; 4Wihuri Research Institute, Biomedicum, Helsinki, Finland Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density lipoprotein (LDL)-receptor gene (LDLR). Patients with homozygous FH (hoFH) have inherited a mutated LDLR gene from both parents, and therefore all their LDL-receptors are incapable of functioning normally. In hoFH, serum LDL levels often exceed 13 mmol/L and tendon and cutaneous xanthomata appear early (under 10 years of age). If untreated, this extremely severe form of hypercholesterolemia may cause death in childhood or in early adulthood. Based on recent data, it can be estimated that the prevalence of hoFH is about 1:500,000 or even 1:400,000. Until now, the treatment of hoFH has been based on high-dose statin treatment combined with LDL apheresis. Since the LDL cholesterol-lowering effect of statins is weak in this disease, and apheresis is a cumbersome treatment and not available at all centers, alternative novel pharmaceutical therapies are needed. Lomitapide is a newly introduced drug, capable of effectively decreasing serum LDL cholesterol concentration in hoFH. It inhibits the microsomal triglyceride transfer protein (MTTP). By inhibiting in hepatocytes the transfer of triglycerides into very low density lipoprotein particles, the drug blocks their assembly and secretion into the circulating blood. Since the very low density lipoprotein particles are precursors of LDL particles in the circulation, the reduced secretion of the former results in lower plasma concentration of the latter. The greatest concern in lomitapide treatment has been the increase in liver fat, which can be, however, counteracted by strictly adhering to a low-fat diet. Lomitapide is a welcome addition to the meager selection of drugs currently available for the treatment of refractory hypercholesterolemia in hoFH patients. Keywords: microsomal triglyceride transfer protein inhibitor, familial hypercholesterolemia, LDL-cholesterol, metabolism, lomitapide

Whereas LDL-derived cholesterol accumulates in atherosclerotic lesions, HDL particles are thought to facilitate removal of cholesterol from the lesions back to the liver thereby promoting its fecal excretion from the body. Because generation of cholesterol-loaded macrophages is inherent to atherogenesis, studies on the mechanisms stimulating the release of cholesterol from these cells and its ultimate excretion into feces are crucial to learn how to prevent lesion development or even induce lesion regression. Modulation of this key anti-atherogenic pathway, known as the macrophage-specific reverse cholesterol transport, has been extensively studied in several mouse models with the ultimate aim of applying the emerging knowledge to humans. The present review provides a detailed comparison and critical analysis of the various steps of reverse cholesterol transport in mouse and man. We attempt to translate this in vivo complex scenario into practical concepts, which could serve as valuable tools when developing novel HDL-targeted therapies. (C) 2016 Elsevier B.V. All rights reserved.

Background: Electronegative LDL (LDL(-)), a modified LDL fraction found in blood, induces the release of inflammatory mediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(-) have not been fully defined. We aim to study whether LDL(-) induced release of the first-wave proinflammatory IL-1 beta in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved. Methods: LDL(-) was isolated from total LDL by anion exchange chromatography. Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(-) (100 mg apoB/L). Results: In monocytes, LDL(-) promoted IL-1 beta release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1 beta release induced by LDL(-) than by native LDL LDL(-)-induced IL-1 beta release involved activation of the CD14-TLR4 receptor complex. LDL(-) induced priming, the first step of IL-1 beta release, since it increased the transcription of pro-IL-1 beta (8-fold) and NLRP3 (3-fold) compared to native LDL Several findings show that LDL(-) induced inflammasome activation, the second step necessary for IL-1 beta release. Preincubation of monocytes with K+ channel inhibitors decreased LDL(-)-induced IL-1 beta release. LDL(-) induced formation of the NLRP3-ASC complex. LDL(-) triggered 2-fold caspase-1 activation compared to native LDL and IL-1 beta release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(-) promoted IL-1 beta release, which was also associated with caspase-1 activation. Conclusions: LDL(-) promotes release of biologically active IL-1 beta in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. Significance: By IL-1 beta release, LDL(-) could regulate inflammation in atherosclerosis. (C) 2015 Elsevier B.V. All rights reserved.

In the arterial intima, macrophages become cholesterol-enriched foam cells and atherosclerotic lesions are generated. This atherogenic process can be attenuated, prevented, or even reversed by HDL particles capable of initiating a multistep pathway known as the macrophage-specific reverse cholesterol transport. The macrophage-derived cholesterol released to HDL is taken up by the liver, secreted into the bile, and ultimately excreted in the feces. Importantly, the absorptive epithelial cells lining the lumen of the small intestine, the enterocytes, express several membrane-associated proteins which mediate the influx of luminal cholesterol and its subsequent efflux at their apical and basolateral sides. Moreover, generation of intestinal HDL and systemic effects of the gut microbiota recently revealed a direct link between the gut and the cholesterol cargo of peripheral macrophages. This review summarizes experimental evidence establishing that the reverse cholesterol transport pathway which initiates in macrophages is susceptible to modulation in the small intestine. We also describe four paths which govern cholesterol passage across the enterocyte and define a role for the gut in the regulation of reverse cholesterol transport. Understanding the concerted function of these paths may be useful when designing therapeutic strategies aimed at removing cholesterol from the foam cells which occupy atherosclerotic lesions. (C) 2013 Elsevier Ltd. All rights reserved.

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (

Mast cells are tissue-resident cells, which have been proposed to participate in various inflammatory diseases, among them the cardiovascular diseases (CVDs). For mast cells to be able to contribute to an inflammatory process, they need to be activated to exocytose their cytoplasmic secretory granules. The granules contain a vast array of highly bioactive effector molecules, the neutral protease tryptase being the most abundant protein among them. The released tryptase may act locally in the inflamed cardiac or vascular tissue, so contributing directly to the pathogenesis of CVDs. Moreover, a fraction of the released tryptase reaches the systemic circulation, thereby serving as a biomarker of mast cell activation. Actually, increased levels of circulating tryptase have been found to associate with CVDs. Here we review the biological relevance of the circulating tryptase as a biomarker of mast cell activity in CVDs, with special emphasis on the relationship between activation of mast cells in their tissue microenvironments and the pathophysiological pathways of CVDs. Based on the available in vitro and in vivo studies, we highlight the potential molecular mechanisms by which tryptase may contribute to the pathogenesis of CVDs. Finally, the synthetic and natural inhibitors of tryptase are reviewed for their potential utility as therapeutic agents in CVDs.

Obesity and high blood pressure (BP) are strongly related and weight loss is mightily associated with a significant BP decrease. The aim of the present meta-analysis was to evaluate and quantify the BP decrease associated with orlistat use in randomized controlled trials. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to June 05, 2017, to identify randomized controlled trials investigating the impact of orlistat on blood pressure. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Our meta-analysis included 27 randomized controlled clinical trials which comprehended overall 8150 subjects (4419 in the orlistat group and 3731 in the control one). We observed a statistically significant decreasing effect of orlistat on both systolic BP (-1.15 mmHg [-2.11, -0.19]) and diastolic BP (-1.07 mmHg [-1.69, -0.45]), regardless of its dosage. Significant associations were found between changes in systolic BP and diastolic BP with treatment duration but not with corresponding baseline BP values. In conclusion, Orlistat use contributes weight loss associated decrease in BP in overweight and obese subjects.

Item does not contain fulltext Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.