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We reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcomes. Here, we analysed a breast cancer xenograft with or without enforced expression of BMP4 to gain insight into the mechanisms by which BMP4 suppresses metastasis. Transcriptomic analysis of cancer cells recovered from primary tumours and phosphoproteomic analyses of cancer cells exposed to recombinant BMP4 revealed that BMP4 inhibits cholesterol biosynthesis, with many genes in this biosynthetic pathway being downregulated by BMP4. The treatment of mice bearing low-BMP4 xenografts with a cholesterol-lowering statin partially mimicked the anti-metastatic activity of BMP4. Analysis of a cohort of primary breast cancers revealed a reduced relapse rate for patients on statin therapy if their tumours exhibited low BMP4 levels. These findings indicate that BMP4 may represent a predictive biomarker for the benefit of additional statin therapy in breast cancer patients.

Objective: Some observational studies have unexpectedly reported the association of cholesterol metabolism with mental and psychological disorders, but a firm conclusion has not been drawn. The aim of this study was to further investigate the effects of peripheral cholesterol traits and cholesterol-lowering therapy on depression and schizophrenia using a Mendelian randomisation approach., Methods: Instrumental variables meeting the correlation, independence and exclusivity assumptions were extracted from one genome-wide association study for predicting total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and nonHDL cholesterol. Instrumental variables for total cholesterol and LDL cholesterol were also adopted to predict statin use (a type of cholesterol-lowering drug); these instrumental variables should not only satisfy the above assumptions but also be close to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR, the target gene of statins) on the chromosome. Three methods (including inverse variance weighted) were used to conduct causal inference of the above exposures with depression and schizophrenia. Sensitivity analyses were performed to assess horizontal pleiotropy., Results: Higher levels of peripheral nonHDL cholesterol were nominally associated with a decreased risk of depression ( P = 0.039), and higher levels of HMGCR-mediated total cholesterol and LDL cholesterol were nominally related to a decreased risk of depression ( P = 0.013 and P = 0.028, respectively). Moreover, these cholesterol traits cannot affect the risk of schizophrenia. Sensitivity analysis did not reveal any horizontal pleiotropy., Conclusion: The study provided some interesting, but less sufficient, evidence that nonHDL cholesterol may have a protective effect on depression, and lowering cholesterol using statins might increase the risk of the disease.

Hypercholesterolemia is frequently intertwined with hepatosteatosis, hypertriglyceridemia, and hyperglycemia. This study is designed to assess the therapeutic efficacy of miR-206 in contrast to statins in the context of managing hypercholesterolemia in mice. We previously showed that miR-206 is a potent inhibitor of de novo lipogenesis (DNL), cholesterol synthesis, and gluconeogenesis in mice. Given that these processes occur within hepatocytes, we employed a mini-circle (MC) system to deliver miR-206 specifically to hepatocytes (designated as MC-miR-206). A single intravenous injection of MC-miR-206 maintained high levels of miR-206 in the liver for at least two weeks, thereby maintaining suppression of hepatic DNL, cholesterol synthesis, and gluconeogenesis. MC-miR-206 significantly reduced DNA damage, endoplasmic reticulum and oxidative stress, and hepatic toxicity. Therapeutically, both MC-miR-206 and statins significantly reduced total serum cholesterol and triglycerides as well as LDL cholesterol and VLDL cholesterol in mice maintained on the normal chow and high-fat high-cholesterol diet. MC-miR-206 reduced liver weight, hepatic triglycerides and cholesterol, and blood glucose, while statins slightly increased hepatic cholesterol and blood glucose and failed to affect levels of liver weight and hepatic triglycerides. Mechanistically, miR-206 alleviated hypercholesterolemia by inhibiting hepatic cholesterol synthesis, while statins increased HMGCR activity, hepatic cholesterol synthesis, and fecal-neutral steroid excretion. MiR-206 facilitates the regression of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and hepatosteatosis. MiR-206 outperforms statins by reducing hyperglycemia, hepatic cholesterol levels, and hepatic toxicity., Competing Interests: Conflict of interests The authors involved in this study declared that they have nothing to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipoprotein(a) (Lp(a)) and Low-density lipoprotein cholesterol (LDLc) is an important risk factor for atherosclerotic cardiovascular disease. The objective of this study was to determine the impact of Lp(a) concentration both on the indirect analytical measurement of LDLc and on the efficacy of dyslipidaemia treatment using the atorvastatin statin. Two retrospective studies were conducted, one with 340 patients and another with 107 patients treated with atorvastatin. Lp(a) concentrations were measured by turbidimetry with an assay independent of the size of the apo(a) isoform. LDLc was calculated using the Friedewald equation and the corrected LDLc was calculated using the Dahlén equation. A strong positive correlation was observed between the serum Lp(a) concentration and the LDLc-overestimation percentage ( r  = 0.960, p  < .001). It was also observed that as the Lp(a) concentration rose there was no significant variation in the percentage decrease in corrected LDLc during atorvastatin treatment ( r  = 0.186, p  > .05). The concentration of LDLc obtained by using the Friedewald equation included Lp(a) cholesterol. The lowering of LDLc in patients treated with atorvastatin depended solely on accessible LDL cholesterol and not on Lp(a) cholesterol.

The interaction of the fluorescent probe 22-NBD-cholesterol with membranes of human peripheral blood mononuclear cells (PBMC) was tested by time- and spectrally resolved fluorescence imaging to monitor the disturbance of lipid metabolism in chronic kidney disease (CKD) and its treatment with statins. Blood samples from healthy volunteers (HV) and CKD patients, either treated or untreated with statins, were compared. Spectral imaging was done using confocal microscopy at 16 spectral channels in response to 458 nm excitation. Time-resolved imaging was achieved by time-correlated single photon counting (TCSPC) following excitation at 475 nm. The fluorescence of 22-NBD-cholesterol was mostly integrated into plasmatic membrane and/or intracellular membrane but was missing from the nuclear region. The presence of two distinct spectral forms of 22-NBD-cholesterol was uncovered, with significant variations between studied groups. In addition, two fluorescence lifetime components were unmasked, changing in CKD patients treated with statins. The gathered results indicate that 22-NBD-cholesterol may serve as a tool to study changes in the lipid metabolism of patients with CKD to monitor the effect of statin treatment.

Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR , APOB , PCSK9 , and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy ( N = 18; men = 8, age 55.4 ± 13.1 years) and patients under combined long-term LDL apheresis/hypolipidemic therapy ( N = 14; men = 7; age 58.0 ± 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p < 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p < 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation.

The infectious power of coronaviruses is dependent on cholesterol present in the membranes of their target cells. Indeed, the virus enters the infected cell either by fusion or by endocytosis, in both cases involving cholesterol-enriched membrane microdomains. These membrane domains can be disorganized in-vitro by various cholesterol-altering agents, including statins that inhibit cell cholesterol biosynthesis. As a consequence, numerous cell physiology processes, such as signaling cascades, can be compromised. Also, some examples of anti-bacterial and anti-viral effects of statins have been observed for infectious agents known to be cholesterol dependent. In-vivo, besides their widely-reported hypocholesterolemic effect, statins display various pleiotropic effects mediated, at least partially, by perturbation of membrane microdomains as a consequence of the alteration of endogenous cholesterol synthesis. It should thus be worth considering a high, but clinically well-tolerated, dose of statin to treat Covid-19 patients, in the early phase of infection, to inhibit virus entry into the target cells, in order to control the viral charge and hence avoid severe clinical complications. Based on its efficacy and favorable biodisposition, an option would be considering Atorvastatin, but randomized controlled clinical trials are required to test this hypothesis. This new therapeutic proposal takes benefit from being a drug repurposing, applied to a widely-used drug presenting a high efficiency-to-toxicity ratio. Additionally, this therapeutic strategy avoids any risk of drug resistance by viral mutation since it is host-targeted. Noteworthy, the same pharmacological approach could also be proposed to address different animal coronavirus endemic infections that are responsible for heavy economic losses., Competing Interests: Declaration of competing interest JJM has consulting activity for Mylan, Servier and Pfizer; AG has received personal fees for public speaking or consultancy support from Akcea Therapeutics, Amgen, MSD, Mylan, Novartis, Sanofi and Regeneron, Unilever; EB declares having received honoraria from Amgen, MSD, Sanofi and Regeneron, Danone, Aegerion, Chiesi, Rottapharm-MEDA, Servier, Ionis-pharmaceuticals, AKCEA, Mylan, GENFIT and Silence Therapeutic; the other author has no competing interests to declare., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the United States (U.S.) and incurs significant cost to the healthcare system. Management of cholesterol remains central for ASCVD prevention and has been the focus of multiple national guidelines. In this review, we compare the American Heart Association (AHA)/American College of Cardiology (ACC) and the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) Cholesterol guidelines. We review the evidence base that was used to generate recommendations focusing on 4 distinct themes: 1) the threshold of absolute 10-year ASCVD risk to start a clinician-patient discussion for the initiation of statin therapy in primary prevention patients; 2) the utility of coronary artery calcium score to guide clinician-patient risk discussion pertaining to the initiation of statin therapy for primary ASCVD prevention; 3) the use of moderate versus high-intensity statin therapy in patients with established ASCVD; and 4) the utility of ordering lipid panels after initiation or intensification of lipid lowering therapy to document efficacy and monitor adherence to lipid lowering therapy. We discuss why the VA/DoD and AHA/ACC may have reached different conclusions on these key issues., Competing Interests: Declaration of Competing Interest Salim S. Virani, Research support: Department of Veterans Affairs, World Heart Federation, Tahir and Jooma Family. Honorarium: American College of Cardiology (Associate Editor for Innovations, acc.org). Vijay Nambi, Site PI for study sponsored by AMGEN. Supported by VA MERIT award. Provisional patent along with BCM, Roche on use of biomarkers in prediction of Heart failure, (Published by Elsevier Inc.)

Cholesterol is being recognized as a molecule involved in regulating the entry of the SARS-CoV-2 virus into the host cell. However, the data about the possible role of cholesterol carrying lipoproteins and their receptors in relation to infection are scarce and the connection of lipid-associated pathologies with COVID-19 disease is in its infancy. Herein we provide an overview of lipids and lipid metabolism in relation to COVID-19, with special attention on different forms of cholesterol. Cholesterol enriched lipid rafts represent a platform for viruses to enter the host cell by endocytosis. Generally, higher membrane cholesterol coincides with higher efficiency of COVID-19 entry. Inversely, patients with COVID-19 show lowered levels of blood cholesterol, high-density lipoproteins (HDL) and low-density lipoproteins. The modulated efficiency of viral entry can be explained by availability of SR-B1 receptor. HDL seems to have a variety of roles, from being itself a scavenger for viruses, an immune modulator and mediator of viral entry. Due to inverse roles of membrane cholesterol and lipoprotein cholesterol in COVID-19 infected patients, treatment of these patients with cholesterol lowering statins needs more attention. In conclusion, cholesterol and lipoproteins are potential markers for monitoring the viral infection status, while the lipid metabolic pathways and the composition of membranes could be targeted to selectively inhibit the life cycle of the virus as a basis for antiviral therapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin's anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Bruiners et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)

A multiproduct approach toward method development is presented for a fast and reliable analysis of the eight most important cholesterol-lowering drugs via ultra-high-performance supercritical fluid chromatography. A two-step approach based on design of experiments was applied: (1) selection of the stationary phase, organic modifier, and diluent in the mobile phase through a multilevel categorical design and (2) optimization of the elution strength by varying the pressure, temperature, and gradient using a central composite design. Finally, the flow rate was adjusted. The first design selected UPC 2 Torus 1-AA as the column, ethanol:water as the organic modifier, and acetonitrile:ethanol 3:2 v/v as the diluent. The results led to a pressure, column temperature, and gradient elution of 14.83 MPa, 42°C, and 5-15.5% of ethanol:water in CO 2 , respectively. The flow rate was set at 1.8 mL/min, providing a total analysis time of 4 min. This multiproduct method was validated and applied to 11 different commercial products available in the Brazilian market, and it was found to be accurate, with r > 0.990, recoveries between 95 and 105%, and precision not higher than 5.4%. Therefore, this method was shown to be a greener alternative for the analysis of these pharmaceuticals., (© 2020 Wiley-VCH GmbH.)

Objective: Statins are a group of medications that reduce cholesterol synthesis by inhibiting the activity of HMG-CoA reductase, a key enzyme in the mevalonate pathway. The clinical use of statins to lower excess cholesterol levels has revolutionized the cardiovascular field and increased the survival of millions, but some patients have adverse side effects. A growing body of data suggests that some of the beneficial and adverse effects of statins, including their anti-inflammatory, anti-tumorigenic, and myopathic activities, are cholesterol-independent. However, the underlying mechanisms for these effects of statins are not well defined., Methods: Because Caenorhabditis elegans (C. elegans) lacks the cholesterol synthesis branch of the mevalonate pathway, this organism is a powerful system to unveil the cholesterol-independent effects of statins. We used genetic and biochemical approaches in C. elegans and cultured macrophage-derived murine cells to study the cellular response to statins., Results: We found that statins activate a conserved p38-MAPK (p38) cascade and that the protein geranylgeranylation branch of the mevalonate pathway links the effect of statins to the activation of this p38 pathway. We propose that the blockade of geranylgeranylation impairs the function of specific small GTPases we identified as upstream regulators of the p38 pathway. Statin-mediated p38 activation in C. elegans results in the regulation of programs of innate immunity, stress, and metabolism. In agreement with this regulation, knockout of the p38 pathway results in the hypersensitivity of C. elegans to statins. Treating cultured mammalian cells with clinical doses of statins results in the activation of the same p38 pathway, which upregulates the COX-2 protein, a major regulator of innate immunity in mammals., Conclusions: Statins activate an evolutionarily conserved p38 pathway to regulate metabolism and innate immunity. Our results highlight the cytoprotective role of p38 activation under statin treatment in vivo and propose that this activation underlies many of the critical cholesterol-independent effects of statins., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual crosstalk between the two cell types, particularly the transport of cholesterol from its site of synthesis to its target loci in neuronal cells, discussing the multiple mechanistic aspects and transporter systems involved. Statins are next analyzed from the point of view of their chemical structure and its impingement on their pharmacological properties and permeability through cell membranes and the blood-brain barrier in particular. The following section then discusses the transcriptional effects of statins and the changes they induce in brain cell genes associated with a variety of processes, including cell growth, signaling and trafficking, uptake and synthesis of cholesterol. We review the effects of statins at the cellular level, analyzing their impact on the cholesterol composition of the nerve and glial cell plasmalemma, neurotransmitter receptor mobilization, myelination, dendritic arborization of neurons, synaptic vesicle release, and cell viability. Finally, the role of statins in disease is exemplified by Alzheimer and Parkinson diseases and some forms of epilepsy, both in animal models and in the human form of these pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Breast cancer is the 2nd leading cause of cancer-related death among women. Increased risk of breast cancer has been associated with high dietary cholesterol intake. However, the underlying mechanisms are not known. The nuclear receptor, estrogen-related receptor alpha (ERRα), plays an important role in breast cancer cell metabolism, and its overexpression has been linked to poor survival. Here we identified cholesterol as an endogenous ligand of ERRα by purification from human pregnancy serum using a GST-ERRα affinity column and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We show that cholesterol interacts with ERRα and induces its transcriptional activity in estrogen receptor positive (ER+) and triple negative breast cancer (TNBC) cells. In addition, we show that cholesterol enhances ERRα-PGC-1α interaction, induces ERRα expression itself, augments several metabolic target genes of ERRα, and increases cell proliferation and migration in both ER+ and TNBC cells. Furthermore, the stimulatory effect of cholesterol on metabolic gene expression, cell proliferation, and migration requires the ERRα pathway. These findings provide a mechanistic explanation for the increased breast cancer risk associated with high dietary cholesterol and possibly the pro-survival effect of statins in breast cancer patients, highlighting the clinical relevance of lowering cholesterol levels in breast cancer patients overexpressing ERRα.

Huntington's disease is an autosomal-dominant, neurodegenerative disorder caused by a CAG repeat expansion in exon-1 of the huntingtin gene. Alterations in cholesterol metabolism and distribution have been reported in Huntington's disease, including abnormal interactions between mutant huntingtin and sterol regulatory element-binding proteins, decreased levels of apolipoprotein E/cholesterol/low-density lipoprotein receptor complexes, and alterations in the synthesis of ATP-binding cassette transporter A1. Plasma levels of 24S-hydroxycholestrol, a key intermediary in cholesterol metabolism and a possible marker in neurodegenerative diseases, decreased proportionally to the degree of caudate nucleus atrophy. The interaction of mutant huntingtin with sterol regulatory element-binding proteins is of particular interest given that sterol regulatory element-binding proteins play a dual role: They take part in lipid and cholesterol metabolism, but also in the inflammatory response that induces immune cell migration as well as toxic effects, particularly in astrocytes. This work summarizes current evidence on the metabolic and immune implications of sterol regulatory element-binding protein dysregulation in Huntington's disease, highlighting the potential use of drugs that modulate these alterations. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Non-high-density lipoprotein cholesterol (non-HDL-C) includes atherogenic cholesterol and low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. Patients with diabetes frequently have elevations in non-HDL-C., Objective: This study examines temporal trends in the levels of non-HDL-C in free-living subjects with diabetes but a negative history of atherosclerotic cardiovascular disease., Methods: National Health and Nutrition Examination Surveys conducted between 1999 and 2016 had data from 3,219 adults (aged 40-75 years) with diabetes. Temporal trends in changes in the distribution of total cholesterol, non-HDL-C, LDL cholesterol (LDL-C), and HDL-C were evaluated. Data were weighted to account for complex survey design., Results: Significant decreases were observed in non-HDL-C (20.1%; P < .0001) and total cholesterol (16.1%; P < .0001) levels between 1999 and 2016. No significant changes were noted in HDL-C levels. LDL-C was reduced by 29.6% in a subset of subjects. The reduction in non-HDL-C and LDL-C occurred simultaneously, with an increase of 4.4% of subjects per year taking cholesterol-lowering drugs and statins. In contrast, the fraction of subjects taking antihypertensives or hypoglycemia agents rose at a rate of 2.2% per year. There was also a significant trend for increases in weight gain (P ≤ .013)., Conclusions: In subjects with diabetes, non-HDL-C levels have declined over time in parallel with reported increases in cholesterol-lowering drugs. Nonetheless, treatment targets for lipids in subjects with diabetes lag behind current recommendations. Reported intakes for antihypertensive agents and hypoglycemia agents were relatively high throughout the period of study, with little change over time. However, there was a trend for weight increase in diabetic subjects, which may offset some of the benefits of pharmacotherapy., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O 2 compartments, such as bone marrow (BM) niches, are well-recognized hosts of drug-resistant leukaemic cells, standard in vitro studies are routinely performed under supra-physiologic (21% O 2 , ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O 2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy-induced vulnerability in AML cells under low O 2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high-potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher-potency statin (eg rosuvastatin)-based combination therapies to enhance targeting residual AML cells that reside in low O 2 environments., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Cancer is a multifaceted global disease. Transformation of a normal to a malignant cell takes several steps, including somatic mutations, epigenetic alterations, metabolic reprogramming and loss of cell growth control. Recently, the mevalonate pathway has emerged as a crucial regulator of tumor biology and a potential therapeutic target. This pathway controls cholesterol production and posttranslational modifications of Rho-GTPases, both of which are linked to several key steps of tumor progression. Inhibitors of the mevalonate pathway induce pleiotropic antitumor-effects in several human malignancies, identifying the pathway as an attractive candidate for novel therapies. In this review, we will provide an overview about the role and regulation of the mevalonate pathway in certain aspects of cancer initiation and progression and its potential for therapeutic intervention in oncology., Competing Interests: Declaration of Competing Interest The authors have received grants or honorarium for advisory boards or lectures to the individual or the institution by Amgen (MR, LCH, TDR), Biomedica (AG), Novartis (LCH, TDR), and Merck (LCH, TDR)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The association between hypocholesterolaemia and outcome of patients with coronary artery disease (CAD) remains controversial. We undertook this study to investigate whether there is an association between spontaneous or under statin therapy occurring hypocholesterolaemia and mortality in patients with CAD., Materials and Methods: This study included 14 952 patients with CAD undergoing percutaneous coronary intervention (PCI). Hypocholesterolaemia was defined as a total cholesterol (TC) <157 mg/dL (the upper limit of 1st quintile of TC). The study outcome was all-cause mortality at 30 days and 3 years after PCI., Results: Patients are categorized in four groups according to TC and statin therapy on admission: statin-naïve patients with hypocholesterolaemia (n = 1102), statin-naïve patients without hypocholesterolaemia (n = 7490), statin-treated patients with hypocholesterolaemia (n = 1824) and statin-treated patients without hypocholesterolaemia (n = 4536). In these groups, 30-day all-cause deaths occurred in 3.7%, 1.4%, 1.2% and 0.6% of the patients, respectively; 3-year deaths occurred in 18.0%, 8.4%, 10.9% and 7.2%, of the patients, respectively. After adjustment, hypocholesterolaemia remained independently associated with 30-day (adjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] 1.07 to 2.09; P < 0001) and 3-year (HR = 1.29 [1.12-1.47]; P < .001) mortality. Statin therapy on admission was independently associated with 30-day (HR = 0.61 [0.43-0.86]; P = .012) and 3-year (HR = 0.82 [0.72-0.94]; P = .017) mortality with no statin-by-cholesterol interaction with respect to 30-day (adjusted Pint = 0.669) or 3-year (adjusted Pint = 0.767) all-cause mortality suggesting that statins reduce the risk of mortality irrespective of cholesterol level., Conclusions: In patients with CAD, hypocholesterolaemia on admission was independently associated with increased risk of all-cause mortality at 30 days and 3 years after PCI., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques., Methods: Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry., Results: Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein., Conclusions: High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin., Trial Registration: ISRCTN16590640., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Familial hypercholesterolemia (FH) is a frequent disorder associated with premature atherosclerotic cardiovascular disease. Different clinical diagnosis criteria are available, and cost of genetic testing has been reduced in the last years; however, most cases are not diagnosed worldwide. Patients with FH are at high cardiovascular risk and the risk can be reduced with lifelong lifestyle and pharmacological treatment. Statins and ezetimibe are available as generic drugs in most countries reducing the cost of treatment. However, the use of high-intensity statins combined with ezetimibe and PCSK9 inhibitors, if necessary, is low for different reasons that contribute to a high number of patients not reaching LDL-C targets according to guidelines. On the other hand, cardiovascular risk varies greatly in families with FH; therefore, risk stratification strategies including cardiovascular imaging is another element to consider for improving care and management of FH. There are numerous barriers depending on the awareness, knowledge, perception of risk, management and care of patients living with FH that impact in the diagnosis and treatment of the disorder. In this contemporary review, we analyze different barriers in the diagnosis and care of patients to improve patients' care and prevention of atherosclerotic cardiovascular disease and describe recent advances and strategies to improve the gaps in the care of FH, including global collaboration and advocacy., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Alonso et al.)

Background: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis., Objective: To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis., Methods: We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3 months. The response was evaluated and patients photographed at every visit., Results: Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events., Limitations: Case series design with a small number of patients., Conclusion: Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors., (Copyright © 2019. Published by Elsevier Inc.)

Gallbladder cancer (GBC) is the common malignancy of the bile tract system with extremely poor clinical outcomes, owing to its metastatic property and intrinsic resistance to the first-line drugs. Although it is well-established that cholesterol abnormity contributes to gallstone formation, a leading risk factor for GBC, the link of cholesterol homeostasis with GBC has not been investigated. The present study systematically examined the genes implicated in cholesterol homeostasis, and revealed altered gene expressions of de novo cholesterol biosynthesis and sterol sulfonation (SULT2B1), reduced bile acid synthesis (CYP7B1 and CYP39A1) and impaired sterol efflux (ABCA1, ABCG5, LCAT, and CETP) in GBC tissues. Suppression of cholesterol biosynthesis by lovastatin inhibited GBC cell proliferation possibly through attenuating the DNA repair process. Further investigation revealed lovastatin sensitized GBC cells to cisplatin-induced apoptosis and suppressed the activation of CHK1, CHK2, and H2AX during DNA damage response. By using chemically distinct statins, HMGCR depletion or supplementing mevalonate, the product of HMGCR, we showed the inhibitory effects on DNA repair process of lovastatin were due to the blockage of the mevalonate pathway. Subcutaneous xenograft mice model suggested lovastatin promoted the therapeutic efficacy of cisplatin, and significantly prolonged the survival times of tumor-bearing mice. Moreover, HMGCR ablation repressed tumor growth in vivo , which can be rescued partially by restored expression of HMGCR, suggesting the on-target effects of lovastatin. Therefore, our study provides the clinical relevance of cholesterol homeostasis with GBC progression, and highlights a novel intervention of combined use of lovastatin and cisplatin for GBC.

Cholesterol dyshomeostasis in cancer cells leads to intracellular cholesterol accumulation, which imparts drug resistance and allows these cells to evade apoptotic signalling processes and maintain continuous cell division and proliferation. Therefore, cholesterol lowering in cancer cells has been envisaged as a potential anticancer strategy. In this direction, two therapeutic strategies have been proposed: (a) to inhibit the biosynthesis of cholesterol in the cells and (b) to deplete excess cholesterol from cancer cells. In the first phase of this review, we collate the cancer signalling pathways (particularly in breast cancer) that are perturbed by cholesterol dyshomeostasis and highlight recent drug discovery efforts to develop cholesterol-lowering compounds, some of which are currently under clinical trials. In the second phase, based on the analysis of the available scientific evidence, we conceptualize and argue that the depletion of excess cholesterol could sensitize cancer cells to available therapeutics and may also help to alleviate cancer drug resistance., (© 2019 Federation of European Biochemical Societies.)

Background: There is strong evidence of a rise in cardiovascular risk in patients suffering from autoimmune diseases, especially in those with Sistemic Lupus Erythematosus. Until now, there are a few trials that assess the potencial benefit of statins on the incidence of cardiovascular events and on lipid profile of patients with SLE. This evidence has not been synthesized and assessed altogether., Methods: We performed a search in databases of literature published until August of 2016 (Embase, MEDLINE, Cochrane Library, SciELO, Clinical Evidence, DynaMed, Cochrane Central Register of Controlled Trials, LILACS), identifying controlled clinical trials that could estimate the impact of statins on mortality, cardiovascular events, C-reactive protein and lipid profile in patients with Systemic Lupus Erythematosus. The quality of the information available was assessed with a meta-analysis, using a random effects model, employing the RevMan 5.3 software., Results: 6 trials and 412 patients were included in the analysis. The use of statins in patients with SLE was found to significantly reduce the levels of serum total cholesterol (mean difference [MD] -31,4 mg/dL; CI 95% -43,0; -19,9), and serum low density cholesterol (MD -31,4 mg/dL; IC 95% -43,0; -19,9), but had no impact on levels of serum triglycerides (MD 4 mg/dL; IC 95% 2,49; 6,21) and C-reactive protein (MD -0,78; IC 95% -1,43; -0,13). No evidence was found about the impact on the risk of mortality or cardiovascular events., Conclusion: Statins have a significant effect on the levels of serum total cholesterol, LDL cholesterol and C-reactive protein, however, more randomized controlled trials with long-term follow-up are necessary to assess the impact on mortality and cardiovascular risk., (Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline., Methods: The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14 weeks and whether these responses were predictive of eGFR decline during the subsequent 9 months of follow-up., Results: UPCR and TC response varied between individuals: mean UPCR response was -1.3% (5th-95th percentile -59.9 to 141.8) and mean TC response was -93.9 mg/dL (-169.1 to -26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) -1.6 to 0.9; P = 0.54] and TC responders (0.3; 95% CI -1.8 to 1.1; P = 0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6-3.0; P = 0.004 and 1.7; 95% CI 0.5-2.9; P = 0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5-3.7; P = 0.01). These findings were not different for rosuvastatin or atorvastatin., Conclusions: Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.)

The 2018 AHA/ACC cholesterol guideline builds on the 2013 ACC/AHA cholesterol guideline statin recommendations to provide more detailed recommendations for the use of nonstatin therapy risk stratification for primary prevention statin use. New information has become available after the development of the 2018 AHA/ACC cholesterol guideline that can further inform clinical practice. Proprotein convertase subtilisin kexin type-9 (PCSK9) monoclonal antibodies are now a reasonable or even good value following over 60% reductions in their acquisition price, and the identification of high risk patient groups most likely to benefit from further low-density lipoprotein cholesterol (LDL-C) lowering. Meta-analyses and clinical trial data now show that patients with LDL-C ≥ 100 mg/dl are more likely to experience progressively greater reductions in the risk of cardiovascular and total mortality and coronary heart disease events for progressively higher LDL-C levels. Icosapent ethyl, a highly concentrated form of modified EPA has been shown to reduce cardiovascular events in high risk patients with moderate hypertriglyceridemia on statin therapy. Comparisons with other statin guidelines revealed that statin initiation for those with ≥7.5% 10-year atherosclerotic cardiovascular disease (ASCVD) risk is the most effective strategy for reducing the most ASCVD events for the proportion of the population treated. Data from younger populations finally became available for coronary artery calcium (CAC) scoring (mean age of 51 years) which confirmed the value of CAC > 0 for identifying individuals at increased ASCVD risk most likely to benefit from statin initiation. This analysis also found that statins could keep CAC = 0 in those with risk factors. Epidemiologic pooling studies now clearly show that LDL-C and non-high-density lipoprotein cholesterol levels in young adulthood confer excess risk for ASCVD later in life. Accumulating data support earlier risk factor intervention trials as the next research priority., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy., Background: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH., Methods: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis., Results: A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001)., Conclusions: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The authors review more than three decades of progress in providing clinicians and patients with guidance on risk assessment, patient evaluation and cholesterol management. Beginning with the National Cholesterol Education Program's Initial Adult Treatment Panel report, the cholesterol guidelines increasingly reflect the progress made in understanding the benefits of improved lifestyle and nutrition to improve lipid profiles, major risk factors and reduce ASCVD risk. Moreover, they now provide qualitative and quantitative assessment tools to guide appropriate risk reduction LDL-C lowering therapy. Use of the Pooled Cohort Equations to determine Low, Borderline, Intermediate and High 10-year ASCVD risk is now joined by recognition of conditions and biomarkers that enhance ASCVD risk. This personalizes the risk discussion for the patient. An important addition is the selective use of coronary artery calcium (CAC) scoring to reclassify risk in patients at borderline or intermediate risk, but for whom a risk decision regarding statin therapy is uncertain. In secondary prevention, current guidelines provide criteria for determining a "very high" risk group in whom risk is especially high and in whom aggressive LDL-C lowering can be shown to provide increased absolute benefit. Current guidelines provide a comprehensive look at children and adolescents, young adults, elderly, women and issues specific to women through the life course. They provide guidance for those adults at risk due to severe hypercholesterolemia, persistent hypertriglyceridemia after secondary causes have been addressed, those with inflammatory disorders and HIV, those adults with chronic kidney disease, and those affected by issues of race/ethnicity. They conclude with a brief summary of recommendations emphasizing important concepts for providing safety with LDL-C lowering therapy. This combination of best external evidence and clinical expertise from the expert panel should provide a solid foundation for lipid management of patients at risk for or with clinical ASCVD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia and it is characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. However, the complete pathogenesis of the disease is still unknown. High level of serum cholesterol has been found to positively correlate with an increased risk of dementia and some studies have reported a decreased prevalence of AD in patients taking cholesterol-lowering drugs. Years of research have shown a strong correlation between blood hypercholesterolemia and AD, however cholesterol is not able to cross the Blood Brain Barrier (BBB) into the brain. Cholesterol lowering therapies have shown mixed results in cognitive performance in AD patients, raising questions of whether brain cholesterol metabolism in the brain should be studied separately from peripheral cholesterol metabolism and what their relationship is. Unlike cholesterol, oxidized cholesterol metabolites known as oxysterols are able to cross the BBB from the circulation into the brain and vice-versa. The main oxysterols present in the circulation are 24S-hydroxycholesterol and 27-hydroxycholesterol. These oxysterols and their catalysing enzymes have been found to be altered in AD brains and there is evidence indicating their influence in the progression of the disease. This review gives a broad perspective on the relationship between hypercholesterolemia and AD, cholesterol lowering therapies for AD patients and the role of oxysterols in pathological and non-pathological conditions. Also, we propose cholesterol metabolites as valuable targets for prevention and alternative AD treatments., (Copyright © 2019. Published by Elsevier Ltd.)

Background: This study examined the predictive value of remnant lipoprotein levels for cardiovascular events (CVEs) in patients with stable coronary artery disease (CAD) and low-density lipoprotein cholesterol (LDL-C) levels <70 mg/dL on statin treatment.Methods and Results:Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol: RLP-C) were measured by an immunoseparation method in 247 consecutive patients with CAD who had on-statin LDL-C levels <70 mg/dL. All the patients were followed prospectively for a period of ≤60 months or until the occurrence of the primary composite endpoint of cardiac death, nonfatal myocardial infarction, unstable angina requiring coronary revascularization, worsening heart failure, peripheral artery disease, aortic event, and ischemic stroke. During a mean follow-up period of 38 months, 33 CVEs occurred. Kaplan-Meier analysis demonstrated that higher RLP-C levels (≥3.9 mg/dL, determined by ROC curve) resulted in a significantly higher probability for the primary endpoint than did lower RLP-C levels (<3.9 mg/dL) (P<0.01 by log-rank test). Stepwise multivariate Cox proportional hazard analysis showed that RLP-C was a significant predictor of the primary endpoint after adjustment for known risk factors and lipid variables including triglycerides, and total apolipoprotein B (hazard ratio 1.62, 95% confidence interval 1.26-2.07, P<0.01)., Conclusions: RLP-C levels are a residual risk factor for future CVEs in patients with CAD and on-statin LDL-C <70 mg/dL.

In this study we attempted to verify the hypothesis that the mevalonate pathway affects amyloid beta precursor protein (AβPP) processing and regulates clusterin protein levels. AβPP expression was monitored by green fluorescence (FL) and Western blot (WB). WB showed soluble amyloid protein precursor alpha (sAβPPα) presence in AβPP -wt cells and Aβ expression in AβPP -sw cells. Nerve growth factor (NGF)-differentiated rat neuronal pheochromocytoma PC-12 cells were untreated/treated with statins alone or together with non-sterol isoprenoids. Co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol demonstrated statin-dependent neurotoxicity resulted from the attenuated activity of mevalonate pathway rather than lower cholesterol level. Atorvastatin (50 μM) or simvastatin (50 μM) as well as cholesterol chelator methyl-β-cyclodextrin (0.2 mM) diminished cell viability ( p < 0.05) and clusterin levels. Interestingly, co-treatment with mevalonate, dolichol, ubiquinol, farnesol, geranylgeraniol, or water-soluble cholesterol stimulated ( p < 0.05) clusterin expression. Effects of non-sterol isoprenoids, but not water soluble cholesterol (Chol-PEG), were the most significant in mock-transfected cells. Geranylgeraniol (GGOH) overcame atorvastatin (ATR)-dependent cytotoxicity. This effect does not seem to be dependent on clusterin, as its level became lower after GGOH. The novelty of these findings is that they show that the mevalonate (MEV) pathway rather than cholesterol itself plays an important role in clusterin expression levels. In mock-transfected, rather than in AβPP-overexpressing cells, GGOH/farnesol (FOH) exerted a protective effect. Thus, protein prenylation with GGOH/FOH might play substantial role in neuronal cell survival.

Coronary artery disease is characterised by the development of atherosclerotic plaques and is associated with significant morbidity and mortality on a global level. However, many patients with atherosclerosis are asymptomatic and the prediction of acute coronary events is challenging. The role of imaging studies in characterising plaque morphology and stability is emerging as a valuable prognostic tool, while providing evidence for the beneficial effects of cholesterol-lowering therapy on plaque burden. This review provides an overview of contemporary studies describing the value of imaging strategies for atherosclerotic plaques. Coronary angiography is commonly used in the clinical setting, but requires a significant radiation dose (similar to computed tomography). Magnetic resonance imaging evaluation of coronary vessels would avoid exposure to ionising radiation, but is not yet feasible due to motion artefacts. The roles of alternative imaging techniques, including grey-scale intravascular ultrasound, optical coherence tomography and near-infrared spectroscopy have emerged in recent years. In particular, grey-scale intravascular ultrasound has been effectively applied to detect changes in plaque burden and features of plaques predictive of rupture, as well as plaque characteristics during cholesterol-lowering therapy, providing novel insights into factors that may contribute to treatment effectiveness. Challenges and limitations to the use of imaging techniques are considered in this context, along with future imaging strategies.

Background: Circulating cholesterol levels have been linked to PD, but not directly to brain physiology., Objective: To assess whether brain cholesterol metabolism is related to PD., Methods: Sixty PD patients and 64 controls were recruited from an academic movement disorder clinic (2009-2012). Thirty-five PD patients and 33 controls returned approximately 36 months later. Fasting plasma (S)24-OH-cholesterol (brain-derived cholesterol metabolite) and 27-OH-cholesterol (peripheral cholesterol metabolite) were quantified. Odds ratios for PD were derived from logistic regression models, adjusting for potential confounders. Relationships between the oxysterols and clinical measurements were explored using Spearman correlation coefficients., Results: Mean age of PD subjects was 63.8 ± 8.3 years and disease duration was 5.0 ± 5.4 years. Plasma (S)24-OH-cholesterol levels were inversely associated with the odds of having PD, with an odds ratio of 0.92 (95% confidence interval: 0.87-0.97) for each 1-ng/mL increase (P = 0.004). Compared to the lowest tertile, the odds ratio was 0.34 (0.12-0.98) for the second tertile (P = 0.045) and 0.08 (0.02-0.31) for the highest tertile (P < 0.001). Higher (S)24-OH-cholesterol levels also were correlated with better sense of smell (r = 0.35; P = 0.01). No significant associations were found between clinical measures and 27-OH-cholesterol, a peripheral cholesterol metabolite. Furthermore, (S)24-OH-cholesterol levels were stable over time, whereas 27-OH-cholesterol decreased with time in both cases and controls., Conclusions: Results indicate that plasma (S)24-OH-cholesterol (possibly reflecting brain cholesterol metabolism) is inversely linked to PD, is relatively stable over time, and may serve as a new biomarker for PD. Further investigation is necessary to determine the mechanistic and clinical implications. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Reduction in cholesterol blood levels represents one of the therapeutic goals to achieve in order to reduce the occurrence of cardiovascular diseases. Commonly, this goal is attempted by promoting healthy lifestyle behaviors and low-fat diets. Recently, several nutraceuticals have been shown to possess cholesterol-lowering properties and are becoming common over the counter products. Among others, apple polyphenols efficiently lower total cholesterol levels in humans and impact overall lipid metabolism. Malus Pumila Miller cv Annurca is an apple native to Southern Italy presenting one of the highest content of procyanidin B2, a dimeric procyanidin. Tested in clinical trials, the oral consumption of an Annurca polyphenolic extract (AAE) exerted a cholesterol-lowering effect similar to the statins Atorvastatin and Simvastatin. Despite AAE activity, the analysis of the molecular mechanism behind its cholesterol-lowering effect is unclear. Using isotope labeling and high-resolution mass spectrometry approaches we here performed a metabolic profiling of in vitro cultured human hepatocytes treated with AAE to reveal its mechanism of action. The results show that AAE acts differently than statins. The extract reprograms hepatic cell metabolism and promotes mitochondrial respiration, lipolysis and fatty acid β-oxidation. Citrate and acetyl-CoA, both necessary for the production of cholesterol, are diverted to the Krebs Cycle by AAE, that, ultimately, lowers cholesterogenesis and fatty acid synthesis.

Background: It has been suggested that high cholesterol represents a risk factor for Graves' orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves' disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol., Methods: The design entailed the inclusion of consecutive patients with a GD of recent onset, with or without GO, who came to our observation to receive radioiodine over a period of 6 months, and a stratification aimed at having two homogeneous group of patients in terms of thyroid function. A total of 86 patients fulfilled the inclusion and evaded the exclusion criteria. All patients underwent an ophthalmological assessment and serum lipids were measured., Results: Serum levels of LDL-cholesterol were significantly higher in patients with GO (135.3 ± 41.3 mg/dL) compared with those without GO (106.6 ± 23.9 mg/dL, P = 0.0007). In a similar manner, serum levels of total cholesterol were higher in patients with GO (211.6 ± 44.0 mg/dL) than in those without GO (176.0 ± 27.2 mg/dL, P = 0.0001). There was no relationship between GO severity and activity and cholesterol. There was no relationship between GO and high-density lipoprotein-cholesterol or triglycerides., Conclusions: Our study confirms a relationship between the presence of GO and cholesterol in patients with GD of recent onset. Whether lowering of cholesterol ameliorates, GO remains to be established.

Millions of people worldwide receive agents targeting the renin-angiotensin system (RAS) to treat hypertension or statins to lower cholesterol. The RAS and cholesterol metabolic pathways in the brain are autonomous from their systemic counterparts and are interrelated through the cholesterol metabolite 27-hydroxycholesterol (27-OHC). These systems contribute to memory and dementia pathogenesis through interference in the amyloid-beta cascade, vascular mechanisms, glucose metabolism, apoptosis, neuroinflammation and oxidative stress. Previous studies examining the relationship between these treatments and cognition and dementia risk have produced inconsistent results. Defining the blood-brain barrier penetration of these medications has been challenging, and the mechanisms of action on cognition are not clearly established. Potential biases are apparent in epidemiological and clinical studies, such as reverse epidemiology, indication bias, problems defining medication exposure, uncertain and changing doses, and inappropriate grouping of outcomes and medications. This review summarizes current knowledge of the brain cholesterol and RAS metabolism and the mechanisms by which these pathways affect neurodegeneration. The putative mechanisms of action of statins and medications inhibiting the RAS will be examined, together with prior clinical and animal studies on their effects on cognition. We review prior epidemiological studies, analysing their strengths and biases, and identify areas for future research. Understanding the pathophysiology of the brain cholesterol system and RAS and their links to neurodegeneration has enormous potential. In future, well-designed epidemiological studies could identify potential treatments for Alzheimer's disease (AD) amongst medications that are already in use for other indications., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Statins are mainstream therapy in the treatment and prevention of cardiovascular disease through inhibitory effects on cholesterol synthesis. However, statins' beneficial effects in cardiovascular disease may also be attributable to their role as anti-inflammatory mediators. Here, we investigated the effects of simvastatin treatment on expression levels of interleukin (IL) 1β in both patient with hyperlipidemia and healthy human peripheral blood mononuclear cells (PBMCs) using cholesterol crystals (CC), a cardiovascular pathogenic stimulus for activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. Cholesterol crystal-induced NLRP3 inflammasome activation was used to trigger maturation and release of IL-1β in PBMCs. Specifically, isolated PBMCs from patients with hyperlipidemia at baseline and following 8 weeks of in vivo treatment with simvastatin (10-20 mg) daily were stimulated with lipopolysaccharide (LPS; 100 ng/mL) for 3 hours to induce proIL-Iβ expression followed by CC (2 mg/mL) stimulation for further 18 hours to activate the NLRP3 inflammasome complex to induce maturation/activation of IL-1β. Peripheral blood mononuclear cells were also isolated from healthy donors and stimulated in vitro with simvastatin (50, 25, 5, and 2 µmol/L) prior to stimulation with LPS and CC as described above. The effects of simvastatin treatment on levels of IL-1β expression were determined by enzyme-linked immunosorbent assay and western blot. Both in vitro and in vivo treatments with simvastatin led to a significant reduction in the levels of expression of IL-1β in response to stimulation with CC. Simvastatin inhibits the expression and activation of IL-1β induced by CC in PBMCs, which may contribute to its protective role in patients with cardiovascular disease.

Breast cancer​ is one of the most commonly diagnosed cancers in women. Accumulating evidence suggests that cholesterol plays an important role in the development of breast cancer. Even though the mechanistic link between these two factors is not well understood, one possibility is that dysregulated cholesterol metabolism may affect lipid raft and membrane fluidity and can promote tumor development. Current studies have shown oxysterol 27-hydroxycholesterol (27-HC) as a critical regulator of cholesterol and breast cancer pathogenesis. This is supported by the significantly higher expression of CYP27A1 (cytochrome P450, family 27, subfamily A, polypeptide 1) in breast cancers. This enzyme is responsible for 27-HC synthesis from cholesterol. It has been shown that 27-HC can not only increase the proliferation of estrogen receptor (ER)-positive breast cancer cells but also stimulate tumor growth and metastasis in several breast cancer models. This phenomenon is surprising since 27-HC and other oxysterols generally reduce intracellular cholesterol levels by activating the liver X receptors (LXRs). Resolving this paradox will elucidate molecular pathways by which cholesterol, ER, and LXR are connected to breast cancer. These findings will also provide the rationale for evaluating pharmaceutical approaches that manipulate cholesterol or 27-HC synthesis in order to mitigate the impact of cholesterol on breast cancer pathophysiology. In addition to cholesterol, epigenetic changes including non-coding RNAs, and microRNAs, DNA methylation, and histone modifications, have all been shown to control tumorigenesis. The purpose of this review is to discuss the link between altered cholesterol metabolism and epigenetic modification during breast cancer progression., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Patients with dyslipidemia are often treated with statins to reduce lipids and hence cardiovascular risk, but treatment response is variable, partly due to genetic factors., Methods: We studied the influence of 6 gene variants (APOE c.526C > T (APOE2), APOE c.388T > C (APOE4), SLCO1B1 c.521T > C, CYP3A4 c.-392G > A, HMGCR c.1564-106A > G, and LPA c.3947 + 467T > C) on statin efficacy assessing 2 indicators: the percent reduction in total cholesterol (TC) and non-HDL cholesterol (non-HDL), as well as the achievement of therapeutic goals. The study was performed in a group of patients (n = 100) without previous pharmacological treatment. Multiple regression models were used to calculate the percentage of explanation in response variability added by every variant to a basal model constructed with significant nongenetic control variables., Results: The most influential variant was HMGCR c.1564-106A > G (rs3846662), and carriers showed a significantly lower reduction in TC and non-HDL. This variant is related to an alternative splicing involving exon 13, which is also regulated by lipid concentrations in patients without the variant. Concerning therapeutic goals, HMGCR c.1564-106A > G hindered the achievement of TC targets on patients., Conclusions: The HMGCR c.1564-106A > G variant was associated with less statin efficacy to decrease cholesterol., (© 2018 Wiley Periodicals, Inc.)

Background: Statins are first-line for cholesterol lowering and prevention of atherosclerotic cardiovascular disease (ASCVD), but their use is complicated by side effects and potential for drug-drug interactions. Provider-patient communication is the basis of the recommended shared decision-making, but relatively little is known about this in the context of statin use., Methods: We surveyed 5014 US adults prescribed a statin for hypercholesterolemia to learn their perspectives on communication with their provider., Results: Ninety-four percent reported currently taking a statin while 6% had stopped. Past users vs current users were more likely to be female, age < 65 years, and to have fewer cardiovascular disease-related comorbidities (hypertension, type 2 diabetes mellitus, and coronary heart disease, respectively). Although 93% of current statin users were taking ≥1 other prescription medications (median of 4), 76% were "not at all"/"not very concerned" about potential drug-drug interactions with their statin, and fewer than one-quarter recalled mention of these from their provider. Ninety-five percent of subjects said it was "extremely"/"somewhat" important that their healthcare provider take "an individualized approach to selecting the right statin," but 73% and 76%, respectively, said their statin choice was made with little or no input from them. Only 25% were told that "some statins might be more likely than others to interact with other medications," and only 18% (and only 20% of past users) were told that "their particular statin might interact with other medications.", Conclusion: Provider-patient communication regarding statin therapy appears inadequate, by patient recall, and efforts to improve it are warranted., (© 2018 Wiley Periodicals, Inc.)

The US Preventive Services Task Force cholesterol guideline recommended statins for fewer adults than the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline by setting a higher 10-year atherosclerotic cardiovascular disease threshold (≥10.0% vs ≥7.5%) and requiring concomitant diabetes mellitus, hypertension, dyslipidemia, or cigarette smoking. The 2017 ACC/AHA hypertension guideline lowered the hypertension threshold, increasing 2016 guideline statin-eligible adults. Cross-sectional data on US adults aged 40 to 75 years enabled estimated numbers for the 2013 guideline and 2016 guideline with hypertension thresholds of ≥140/≥90 mm Hg and ≥130/80 mm Hg, respectively, on: (1) untreated, statin-eligible adults for primary atherosclerotic cardiovascular disease prevention (25.40, 14.72, 15.35 million); (2) atherosclerotic cardiovascular disease events prevented annually (124 000, 70 852, 73 199); (3) number needed to treat (21, 21, 21); and (4) number needed to harm (38, 143, 143) per 1000 patient-years for incident diabetes mellitus (42 800, 6700, 7100 cases per year). Despite the lower hypertension threshold, the 2013 cholesterol guideline qualifies approximately 10 million more adults for statins and prevents approximately 50 600 more primary atherosclerotic cardiovascular disease events but induces approximately 35 700 more diabetes mellitus cases annually than the 2016 guideline., (©2018 Wiley Periodicals, Inc.)

Background: Little information is available regarding prescribers' adherence rate to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guideline, especially that from a teaching versus a nonteaching setting., Objectives: We aim to evaluate adherence rates to the 2013 ACC/AHA cholesterol guideline in a teaching versus a nonteaching practice site. In addition, the impact of a pharmacist-led seminar on adherence rate to the guideline was assessed., Methods: This study is a 2-part retrospective chart review. Part 1 consists of patients who were initiated on statin therapy between December 2013 and November 2014. Patients were analyzed to determine if they received concordant statin therapy as recommended by the guideline. For the second part, we evaluated the impact of a seminar on the adherence rate to the guideline., Results: Of the 325 patients who received a statin prescription, 233 were included in the study. Prescriber adherence to the guideline was 42.9%, which was significantly lower than the 65.8% observed in a study previously conducted at a teaching outpatient clinic ( P < 0.0001). For the second part of our study, prescriber adherence to the guideline 3 months before the pharmacist-led seminar was 53.5%, and this adherence rate remained virtually unchanged at 54.2% at 3 months after the educational session., Conclusion: The overall adherence rate to the 2013 ACC/AHA cholesterol guideline from this nonteaching outpatient clinic was significantly lower than that previously observed in a teaching outpatient clinic. The single pharmacist-led seminar did not significantly affect prescribers' adherence rate to the guideline.

Background: Limited data suggest that treatment with statins is associated with a reduced risk of Graves' orbitopathy (GO) in patients with Graves' disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the relation between severity or activity (the clinical activity score [CAS]) of GO and LDL-cholesterol., Methods: A cross-sectional investigation was conducted in consecutive patients with GD who came under the authors' observation to undergo radioiodine treatment, a stratification aimed at forming two distinct groups of patients under the same conditions. A total of 250 patients were enrolled, 133 with and 117 without GO. Ophthalmological assessments and serum lipids measurements were performed., Results: In multivariate analyses with correction for the duration of hyperthyroidism, a variable that differed between patients with respect to the presence or absence of GO, a correlation between the presence of GO and both total (p = 0.01) and LDL-cholesterol (p = 0.02) was observed. In patients with hyperthyroidism lasting <44 months, total and LDL-cholesterol were higher (p = 0.01 and p = 0.008, respectively) among GO patients. In this subgroup, based on the presence/absence of GO, cutoff values were established for total (191 mg/dL) and LDL-cholesterol (118.4 mg/dL), above which an increased risk of GO was observed (total cholesterol relative risk: 1.47; p = 0.03; LDL-cholesterol relative risk: 1.28; p = 0.03). GO severity and CAS did not correlate with serum lipids. However, CAS was found to be higher (p = 0.02) in patients with high total cholesterol. When the analysis was restricted to untreated GO patients, a correlation was found between CAS and both total (p = 0.04) and LDL-cholesterol (p = 0.03), after adjustment for GO duration., Conclusions: In patients with a short duration of hyperthyroidism, total and LDL-cholesterol correlate with the presence of GO, suggesting a role of cholesterol in the development of GO. Depending on GO duration, total and LDL-cholesterol correlate with GO activity, suggesting a role of cholesterol in the clinical expression of GO.

Background: Vitamin D preparations reduce titers of thyroid antibodies in women with autoimmune thyroiditis. The same effect was induced by high-dose, but not moderate-dose-, statin therapy. No previous study has investigated the impact of concomitant treatment with a statin and vitamin D on thyroid autoimmunity., Methods: The study included three matched groups of women with Hashimoto's thyroiditis and low vitamin D status. Groups B (n=19) and C (n=20) were treated with vitamin D (2000 IU daily). Because of coexistent hypercholesterolemia, groups A (n=18) and B received simvastatin (40mg daily). Plasma lipids, serum levels of thyrotropin, free thyroid hormones and 25-hydroxyvitamin D, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later., Results: At baseline, 25-hydroxyvitamin D levels inversely correlated with titers of thyroid antibodies. In groups A and B, simvastatin reduced plasma levels of total and LDL cholesterol. Simvastatin produced no effect on thyroid antibody titers. Vitamin D decreased titers of thyroid peroxidase antibodies, as well as tended to decrease titers of thyroglobulin antibodies. Simvastatin-vitamin D combination therapy reduced serum titers of thyroid peroxidase and thyroglobulin antibodies and this effect was stronger than the effect of simvastatin and vitamin D administered alone. Treatment-induced changes in thyroid antibody titers correlated with baseline antibody titers, baseline levels of 25-hydroxyvitamin and treatment-induced changes in 25-hydroxyvitamin., Conclusions: The obtained results indicate that simvastatin may potentiate the impact of vitamin D on thyroid autoimmunity in vitamin D-deficient women with Hashimoto's thyroiditis., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

Purpose: Statins have been postulated to have chemopreventive activity against breast cancer. We evaluated whether germline genetic polymorphisms modified the relationship between statins and breast cancer risk using data from the Women's Health Initiative. We evaluated these interactions using both candidate gene and agnostic genome-wide approaches., Methods: To identify candidate gene-statin interactions, we tested interactions between 22 SNPS in nine candidate genes implicated in the effect of statins on lipid metabolism in 1687 cases and 1687 controls. We then evaluated statin use interaction with the remaining 30,380 SNPs available in this sample from the CGEMS GWAS study., Results: After adjusting for multiple comparisons, no SNP interactions with statin usage and risk of breast cancer were statistically significant in either the candidate genes or genome-wide approaches., Conclusions: We found no evidence of SNP interactions with statin usage for breast cancer risk in a population of 3374 individuals. These results suggest that genome-wide common genetic variants do not moderate the association between statin usage and breast cancer in the population of women in the Women's Health Initiative.

In individuals, heterogeneous drug-response phenotypes result from a complex interplay of dose, drug specificity, genetic background, and environmental factors, thus challenging our understanding of the underlying processes and optimal use of drugs in the clinical setting. Here, we use mass-spectrometry-based quantification of molecular response phenotypes and logic modeling to explain drug-response differences in a panel of cell lines. We apply this approach to cellular cholesterol regulation, a biological process with high clinical relevance. From the quantified molecular phenotypes elicited by various targeted pharmacologic or genetic treatments, we generated cell-line-specific models that quantified the processes beneath the idiotypic intracellular drug responses. The models revealed that, in addition to drug uptake and metabolism, further cellular processes displayed significant pharmacodynamic response variability between the cell lines, resulting in cell-line-specific drug-response phenotypes. This study demonstrates the importance of integrating different types of quantitative systems-level molecular measurements with modeling to understand the effect of pharmacological perturbations on complex biological processes., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)