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1.
Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans.
Pavanello, C, Ossoli, A, Strazzella, A, Risè, P, Veglia, F, Lhomme, M, Parini, P, Calabresi, L
Journal of lipid research. 2022;(7):100232
Abstract
Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0-37.8] mg/dl) and slightly reduced in heterozygotes (218 [153-234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.
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2.
Effects of PCSK9 inhibitors on HDL cholesterol efflux and serum cholesterol loading capacity in familial hypercholesterolemia subjects: a multi-lipid-center real-world evaluation.
Palumbo, M, Giammanco, A, Purrello, F, Pavanello, C, Mombelli, G, Di Pino, A, Piro, S, Cefalù, AB, Calabresi, L, Averna, M, et al
Frontiers in molecular biosciences. 2022;:925587
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond regulating LDL cholesterol (LDL-c) plasma levels, exerts several pleiotropic effects by modulating lipid metabolism in extrahepatic cells such as macrophages. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, including the HDL capacity to promote cell cholesterol efflux (CEC) and the serum capacity to promote cell cholesterol loading (CLC). The aim of this observational study was to investigate the effect of PCSK9 inhibitors (PCSK9-i) treatment on HDL-CEC and serum CLC in patients with familial hypercholesterolemia (FH). 31 genetically confirmed FH patients were recruited. Blood was collected and serum isolated at baseline and after 6 months of PCSK9-i treatment. HDL-CEC was evaluated through the main pathways with a radioisotopic cell-based assay. Serum CLC was assessed fluorimetrically in human THP-1 monocyte-derived macrophages. After treatment with PCSK9-i, total cholesterol and LDL-c significantly decreased (-41.6%, p < 0.0001 and -56.7%, p < 0.0001, respectively). Total HDL-CEC was not different between patients before and after treatment. Conversely, despite no changes in HDL-c levels between the groups, ABCG1 HDL-CEC significantly increased after treatment (+22.2%, p < 0.0001) as well as HDL-CEC by aqueous diffusion (+7.8%, p = 0.0008). Only a trend towards reduction of ABCA1 HDL-CEC was observed after treatment. PCSK9-i significantly decreased serum CLC (-6.6%, p = 0.0272). This effect was only partly related to the reduction of LDL-c levels. In conclusion, PCSK9-i treatment significantly increased HDL-CEC through ABCG1 and aqueous diffusion pathways and reduced the serum CLC in FH patients. The favorable effect of PCSK9-i on functional lipid profile could contribute to the cardiovascular benefit of these drugs in FH patients.
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3.
Interactions of Oxysterols with Atherosclerosis Biomarkers in Subjects with Moderate Hypercholesterolemia and Effects of a Nutraceutical Combination (Bifidobacterium longum BB536, Red Yeast Rice Extract) (Randomized, Double-Blind, Placebo-Controlled Study).
Cicolari, S, Pavanello, C, Olmastroni, E, Puppo, MD, Bertolotti, M, Mombelli, G, Catapano, AL, Calabresi, L, Magni, P
Nutrients. 2021;(2)
Abstract
BACKGROUND Oxysterol relationship with cardiovascular (CV) risk factors is poorly explored, especially in moderately hypercholesterolaemic subjects. Moreover, the impact of nutraceuticals controlling hypercholesterolaemia on plasma levels of 24-, 25- and 27-hydroxycholesterol (24-OHC, 25-OHC, 27-OHC) is unknown. METHODS Subjects (n = 33; 18-70 years) with moderate hypercholesterolaemia (low-density lipoprotein cholesterol (LDL-C:): 130-200 mg/dL), in primary CV prevention as well as low CV risk were studied cross-sectionally. Moreover, they were evaluated after treatment with a nutraceutical combination (Bifidobacterium longum BB536, red yeast rice extract (10 mg/dose monacolin K)), following a double-blind, randomized, placebo-controlled design. We evaluated 24-OHC, 25-OHC and 27-OHC levels by gas chromatography/mass spectrometry analysis. RESULTS 24-OHC and 25-OHC were significantly correlated, 24-OHC was correlated with apoB. 27-OHC and 27-OHC/total cholesterol (TC) were higher in men (median 209 ng/mL and 77 ng/mg, respectively) vs. women (median 168 ng/mL and 56 ng/mg, respectively); 27-OHC/TC was significantly correlated with abdominal circumference, visceral fat and, negatively, with high-density lipoprotein cholesterol (HDL-C). Triglycerides were significantly correlated with 24-OHC, 25-OHC and 27-OHC and with 24-OHC/TC and 25-OHC/TC. After intervention, 27-OHC levels were significantly reduced by 10.4% in the nutraceutical group Levels of 24-OHC, 24-OHC/TC, 25-OHC, 25-OHC/TC and 27-OHC/TC were unchanged. CONCLUSIONS In this study, conducted in moderate hypercholesterolemic subjects, we observed novel relationships between 24-OHC, 25-OHC and 27-OHC and CV risk biomarkers. In addition, no adverse changes of OHC levels upon nutraceutical treatment were found.
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4.
HDL-Mediated Cholesterol Efflux and Plasma Loading Capacities Are Altered in Subjects with Metabolically- but Not Genetically Driven Non-Alcoholic Fatty Liver Disease (NAFLD).
Di Costanzo, A, Ronca, A, D'Erasmo, L, Manfredini, M, Baratta, F, Pastori, D, Di Martino, M, Ceci, F, Angelico, F, Del Ben, M, et al
Biomedicines. 2020;(12)
Abstract
Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (-18.6%; p < 0.001) as well as that mediated by cholesterol transporters (-25.3% ABCA1; -16.3% ABCG1; -14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.
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5.
Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020.
Pavanello, C, Calabresi, L
Current opinion in lipidology. 2020;(4):232-237
Abstract
PURPOSE OF REVIEW Genetic LCAT deficiency is a rare metabolic disorder characterized by low-plasma HDL cholesterol levels. Clinical manifestations of the disease include corneal opacification, anemia, and renal disease, which represents the major cause of morbidity and mortality in carriers. RECENT FINDINGS Biochemical and clinical manifestations of the disease are very heterogeneous among carriers. The collection of large series of affected individuals is needed to answer various open questions on this rare disorder of lipid metabolism, such as the cause of renal damage in patients with complete LCAT deficiency and the cardiovascular risk in carriers of different LCAT gene mutations. SUMMARY Familial LCAT deficiency is a rare disease, with serious clinical manifestations, which can occur in the first decades of life, and presently with no cure. The timely diagnosis in carriers, together with the identification of disease biomarkers able to predict the evolution of clinical manifestations, would be of great help in the identification of carriers to address to future available therapies.
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6.
Dysfunctional HDL as a Therapeutic Target for Atherosclerosis Prevention.
Ossoli, A, Pavanello, C, Giorgio, E, Calabresi, L, Gomaraschi, M
Current medicinal chemistry. 2019;(9):1610-1630
Abstract
Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction.
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7.
Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Ruscica, M, Pavanello, C, Gandini, S, Macchi, C, Botta, M, Dall'Orto, D, Del Puppo, M, Bertolotti, M, Bosisio, R, Mombelli, G, et al
Nutrition journal. 2019;18(1):13
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Plain language summary
Probiotics have been shown to reduce total cholesterol (TC) and low-density lipoprotein (LDL-C – often called ‘bad’ cholesterol) in people with moderately raised cholesterol levels. A specific strain of probiotic called Bifidobacterium longum BB536, may decrease TC and LDL-C by reducing the reabsorption of cholesterol from the intestine, and, combined with other natural supplements, may be useful to manage high cholesterol in people at low risk of heart disease. This study was conducted to evaluate the effect of a nutraceutical (Lactoflorene Colesterolo®), containing Bifidobacterium longum BB536 (1bn CFUs) combined with red yeast rice (RYR) extract (10 mg/day monacolin K), niacin (16mg) and coenzyme Q10 (20mg) on levels of cholesterol and fats in the blood. This was a 12-week randomised, parallel, double-blind, placebo-controlled study, in which 33 adults at low risk of heart disease were given either the Bifidobacterium combination, or a placebo. Treatment with the Bifidobacterium combination significantly reduced total cholesterol by 16.7%, LDL-C by 25.7%, non-HDL-C by 24% and apolipoprotein-B by 17%. Triglycerides, HDL-C, apolipoprotein AI, lipoprotein (a) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were unchanged. Markers of cholesterol synthesis and absorption suggested that a reduction in the synthesis of cholesterol had occurred without increased absorption of cholesterol. No adverse effects were reported in the study and the compliance rate was high at 97%. The use of nutraceuticals in the prevention of cardiovascular disease, as well as in other areas related to chronic diseases like cancer, is currently expanding.
Abstract
BACKGROUND Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. METHODS A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70 years) in primary CV prevention and low CV risk (SCORE 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200 mg/dL) were randomly allocated to either nutraceutical (N = 16) or placebo (N = 17). RESULTS Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (- 16.7%), LDL-C (- 25.7%), non-HDL-C (- 24%) (all p < 0.0001), apoB (- 17%, p = 0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. CONCLUSIONS A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. TRIAL REGISTRATION NCT02689934 .
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Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.
D'Erasmo, L, Minicocci, I, Nicolucci, A, Pintus, P, Roeters Van Lennep, JE, Masana, L, Mata, P, Sánchez-Hernández, RM, Prieto-Matos, P, Real, JT, et al
Journal of the American College of Cardiology. 2018;(3):279-288
Abstract
BACKGROUND Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.
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Appropriateness of statin prescription in the elderly.
Ruscica, M, Macchi, C, Pavanello, C, Corsini, A, Sahebkar, A, Sirtori, CR
European journal of internal medicine. 2018;:33-40
Abstract
Statins, the most widely used drugs in the Western world, have become a pivotal component in the primary and secondary prevention of vascular diseases. Although benefits have been well documented in younger-than-75-year-old individuals, the value of statins in people aged >75years and over is controversial. The CTT meta-analysis calculated an absolute risk reduction of 0.6%/year per 38.7mg/dl reduction in LDL-C levels in patients aged >75years, that would translate into a number needed to treat of 167. However, the absolute effect of a 38.7mg/dl cholesterol lowering on the rate of annual ischemic heart disease mortality is 10-fold larger in older vs younger patients. In order to advise physician prescription, three major Guidelines have been published over the last few years, i.e. the AHA/ACC and the NLA in the US, and the ESC/EAS in Europe. Moreover, statin prescription in the elderly should also consider the cardiovascular outcomes of elderly patients reported in classical statin preventive trials which give important clues on adherence and persistence of use, as well as on drug safety. The present review discusses benefits of intensive vs moderate statin therapy, justifications for the use of aggressive lipid management in the very old and the use of statins in frail elderlies. The final decision on the therapeutic strategy with statins in elderlies at higher risk to develop cardiovascular events should be always based on a careful analysis of the patient's general health and on the presence of metabolic abnormalities or drug interactions potentially leading to risk.
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10.
Nutraceutical approaches to metabolic syndrome.
Sirtori, CR, Pavanello, C, Calabresi, L, Ruscica, M
Annals of medicine. 2017;(8):678-697
Abstract
Metabolic Syndrome (MetS), affecting at least 30% of adults in the Western World, is characterized by three out of five variables, from high triglycerides, to elevated waist circumference and blood pressure. MetS is not characterized by elevated cholesterolemia, but is rather the consequence of a complex interaction of factors generally leading to increased insulin resistance. Drug treatments are of difficult handling, whereas well-characterized nutraceuticals may offer an effective alternative. Among these, functional foods, e.g. plant proteins, have been shown to improve insulin resistance and reduce triglyceride secretion. Pro- and pre-biotics, that are able to modify intestinal microbiome, reduce absorption of specific nutrients and improve the metabolic handling of energy-rich foods. Finally, specific nutraceuticals have proven to be of benefit, in particular, red-yeast rice, berberine, curcumin as well as vitamin D. All these can improve lipid handling by the liver as well as ameliorate insulin resistance. While lifestyle approaches, such as with the Mediterranean diet, may prove to be too complex for the single patient, better knowledge of selected nutraceuticals and more appropriate formulations leading to improved bioavailability will certainly widen the use of these agents, already in large use for the management of these very frequent patient groups. Key messages Functional foods, e.g. plant proteins, improve insulin resistance. Pro- and pre-biotics improve the metabolic handling of energy-rich foods. Nutraceutical can offer a significant help in handling MetS patients being part of lifestyle recommendations.