Publications by authors named "Marina Cuchel"

68 Publications

HDL and reverse cholesterol transport in humans and animals: Lessons from pre-clinical models and clinical studies.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Oct 9;1867(1):159065. Epub 2021 Oct 9.

Division of Translational Medicine & Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104, USA.

The ability to accept cholesterol from cells and to promote reverse cholesterol transport (RCT) represents the best characterized antiatherogenic function of HDL. Studies carried out in animal models have unraveled the multiple mechanisms by which these lipoproteins drive cholesterol efflux from macrophages and cholesterol uptake to the liver. Moreover, the influence of HDL composition and the role of lipid transporters have been clarified by using suitable transgenic models or through experimental design employing pharmacological or nutritional interventions. Cholesterol efflux capacity (CEC), an in vitro assay developed to offer a measure of the first step of RCT, has been shown to associate with cardiovascular risk in several human cohorts, supporting the atheroprotective role of RCT in humans as well. However, negative data in other cohorts have raised concerns on the validity of this biomarker. In this review we will present the most relevant data documenting the role of HDL in RCT, as assessed in classical or innovative methodological approaches.
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http://dx.doi.org/10.1016/j.bbalip.2021.159065DOI Listing
October 2021

Familial hypercholesterolaemia: too many lost opportunities.

Lancet 2021 Sep 7. Epub 2021 Sep 7.

Division of Cardiology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; The FH Foundation, Pasadena, CA, USA.

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http://dx.doi.org/10.1016/S0140-6736(21)01372-6DOI Listing
September 2021

A proof-of-concept study of cascade screening for Familial Hypercholesterolemia in the US, adapted from the Dutch model.

Am J Prev Cardiol 2021 Jun 11;6:100170. Epub 2021 Mar 11.

Division of Nutrition and Metabolic Disease, Department of Internal Medicine, UT Southwestern Medical Center, 5232 Harry Hines Blvd, MC 8537, Dallas, TX 75390, United States.

Background: The Dutch cascade screening model for FH was the most successful of such programs in the world. It remains unclear whether aspects of the Dutch model (i.e. direct engagement with FH probands and relatives outside usual healthcare settings) are feasible in the US. This is especially important since prior attempts at cascade screening in the US have had very low screening rates (<10% of families screened).

Methods: We conducted a multi-site single-arm proof-of-concept study in which the US-based FH Foundation (a 501c3 research and advocacy organization) directly engaged with FH probands and relatives similar to the approach taken by the Dutch "Foundation for Tracing FH."

Results: Eleven unrelated probands with genetically confirmed FH were enrolled. Mean age was 43 years; 82% were women, and 82% were of European ancestry. Prior to enrolling into the study, only 2 families (18% screening rate) were screened for FH with both lipid measurements and genetic testing. Two probands declined cascade screening due to fear over genetic discrimination. Nine total relatives engaged with the FH Foundation. Mean age was 43 years and 44% were women. Seven of those relatives (from 6 families; 55% screening rate) consented to be screened for FH with lipid measurement and genetic testing. The two additional relatives - men ages 39 and 49 - agreed to lipid measurements but not genetic testing, each noting he would like to think more about genetic testing.

Conclusions: Our proof-of-concept study demonstrates the feasibility of the FH Foundation engaging FH probands and their relatives outside the usual healthcare settings for cascade screening, similar to the Dutch model. We found only 18% of families had already been screened, and after engaging with the FH Foundation, 55% of families were willing to participate in cascade screening. These findings suggest the methods described here may improve cascade screening rates in the US.
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http://dx.doi.org/10.1016/j.ajpc.2021.100170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315349PMC
June 2021

A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

Genet Med 2021 09 26;23(9):1697-1704. Epub 2021 May 26.

Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown.

Methods: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results.

Results: Proband median age was 59 (47-67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04).

Conclusion: We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH.

Clinical Trial Number: NCT04526457.
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http://dx.doi.org/10.1038/s41436-021-01192-zDOI Listing
September 2021

ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report.

Arterioscler Thromb Vasc Biol 2021 05 11;41(5):1753-1759. Epub 2021 Mar 11.

Division of Translational Medicine and Human Genetics, Department of Medicine (J.S.M., L.W., D.J.R., M.C.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057526PMC
May 2021

Case report: 68 yo Chinese-American woman with high HDL-C and ischemic stroke attributed to intracranial atherosclerotic stenosis.

J Clin Lipidol 2021 Mar-Apr;15(2):248-254. Epub 2021 Jan 28.

Perelman School of Medicine at the University of Pennsylvania. Electronic address:

Atherosclerotic cardiovascular disease (ASCVD) events are the most common cause of death in the United States and for most individuals who experience these events, may be predicted by risk identification tools. ASCVD risk calculators enable a clinician-patient discussion and the presence of risk-enhancing factors may further inform decision-making with respect to preventive pharmacotherapy, especially statin prescription. In cases where the decision of whether to treat with medicine is unclear, coronary artery calcium scoring by computed tomography offers enhanced risk stratification and may allow both clinicians and patients to feel more at ease with the decision to withhold statin therapy. Despite this thoughtful approach, individual risk may still be underestimated. We present a case of a woman whose family history suggested increased short- and long-term ASCVD risk due to intracranial atherosclerosis, but whose tests suggested a more equivocal indication for treatment. Neither she nor her clinician appreciated the presence of significant enough risk to persevere through minor statin side effects for primary prevention, but she was lucky to have survived without appreciable harm from an acute cerebrovascular event and is now able to pursue an appropriate secondary preventive strategy. We discuss how exceptional characteristics may mislead clinicians, including misperception about lower risk due to gender, East Asian predisposition to intracranial more than coronary atherosclerosis, high levels of high density lipoprotein cholesterol (HDL-C), and CACS = 0.
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http://dx.doi.org/10.1016/j.jacl.2021.01.006DOI Listing
January 2021

Controversial Role of Lecithin:Cholesterol Acyltransferase in the Development of Atherosclerosis: New Insights From an LCAT Activator.

Arterioscler Thromb Vasc Biol 2021 01 23;41(1):377-379. Epub 2020 Dec 23.

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1161/ATVBAHA.120.315496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901727PMC
January 2021

Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis.

J Clin Endocrinol Metab 2020 10;105(10)

Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Context: Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established.

Objective: To delineate the mechanism(s) underlying OGTT-related hypoglycemia.

Design And Setting: We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response.

Main Outcome Measure: OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+].

Results: Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (P < 0.01).

Conclusions: OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.
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http://dx.doi.org/10.1210/clinem/dgaa448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755140PMC
October 2020

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association.

J Clin Lipidol 2020 Jul - Aug;14(4):398-413. Epub 2020 May 7.

Professor of Medicine and Biochemistry, Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address:

The genetic basis for more than 2 dozen monogenic dyslipidemias has largely been defined. Genetic technologies, such as DNA sequencing, can detect both rare and common DNA variants underlying dyslipidemias, and these methods are increasingly available. Although patients with extreme abnormalities in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol may be considered for genetic testing, it is only in a minority of patients that the results will alter treatment or outcomes. Currently, there is potential clinical utility of genetic testing for familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia, lysosomal acid lipase deficiency, and a few other rare disorders, and this will increase the demand for reliable genetic diagnostic methods at lower cost. Clinical indications for genetic testing for most dyslipidemias are not clearly established and currently no guidelines exist. A shared decision-making model between the patient and the provider is essential as patient values and preferences play a very strong role. Potential benefits of genetic testing include providing a firm diagnosis in many cases, guiding optimal management and prevention strategies, advancing care strategies beyond currently available treatments, and contributing to overall scientific progress. Understanding the limitations and risks of genetic testing techniques is also important, as is careful interpretation of genetic test results to achieve the greatest benefit. Here we review laboratory methods, as well as technical, biological, clinical, and ethical implications and applications of genetic testing in dyslipidemias.
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http://dx.doi.org/10.1016/j.jacl.2020.04.011DOI Listing
August 2021

Homozygous familial hypercholesterolemia: what treatments are on the horizon?

Curr Opin Lipidol 2020 06;31(3):119-124

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose Of Review: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy.

Recent Findings: Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development.

Summary: LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.
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http://dx.doi.org/10.1097/MOL.0000000000000677DOI Listing
June 2020

Different β-cell secretory phenotype in non-obese compared to obese early type 2 diabetes.

Diabetes Metab Res Rev 2020 07 17;36(5):e3295. Epub 2020 Feb 17.

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Background: Type 2 diabetes (T2D) is characterized by impaired tissue sensitivity to insulin action (ie, insulin resistance) and impaired β-cell insulin secretion. Because obesity contributes importantly to the development of insulin resistance, we sought to determine whether insulin secretory defects would predominate in non-obese compared to obese T2D.

Methods: We measured β-cell function and secretory capacity using the glucose-potentiated arginine test in T2D subjects early in the disease course classified as non-obese (BMI <30; n = 12) or obese (BMI ≥30 kg/m ; n = 28) and additionally compared responses from non-obese T2D with a non-diabetic control group (n = 12).

Results: The acute insulin response to glucose potentiation of arginine-induced insulin release was less in non-obese T2D than in controls and associated with impaired β-cell sensitivity to glucose (PG ). Proinsulin secretory ratios were increased in non-obese T2D when compared to obese T2D. Obese T2D subjects had reduced insulin sensitivity (M/I) while non-obese T2D subjects had insulin sensitivity that was comparable to controls.

Conclusions: In non-obese T2D, insulin secretory defects predominate with impaired β-cell sensitivity to glucose and proinsulin processing in the absence of insulin resistance. Future studies should consider whether different β-cell secretory phenotypes and tissue sensitivity to insulin explain the varying responsiveness to T2D interventions.
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http://dx.doi.org/10.1002/dmrr.3295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864552PMC
July 2020

Proceedings of the Ninth HDL (High-Density Lipoprotein) Workshop: Focus on Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2019 12 10;39(12):2457-2467. Epub 2019 Oct 10.

Montreal Heart Institute, Montreal and Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada (C.M.).

The HDL (high-density lipoprotein) Workshop was established in 2009 as a forum for candid discussions among academic basic scientists, clinical investigators, and industry researchers about the role of HDL in cardiovascular disease. This ninth HDL Workshop was held on May 16 to 17, 2019 in Boston, MA, and included outstanding oral presentations from established and emerging investigators. The Workshop featured 5 sessions with topics that tackled the role of HDL in the vasculature, its structural complexity, its role in health and disease states, and its interaction with the intestinal microbiome. The highlight of the program was awarding the Jack Oram Award to the distinguished professor emeritus G.S. Getz from the University of Chicago. The tenth HDL Workshop will be held on May 2020 in Chicago and will continue the focus on intellectually stimulating presentations by established and emerging investigators on novel roles of HDL in cardiovascular and noncardiovascular health and disease states.
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http://dx.doi.org/10.1161/ATVBAHA.119.313340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937204PMC
December 2019

Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement.

Lancet Diabetes Endocrinol 2020 01 30;8(1):50-67. Epub 2019 Sep 30.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Milan, Italy.

Genome sequencing and gene-based therapies appear poised to advance the management of rare lipoprotein disorders and associated dyslipidaemias. However, in practice, underdiagnosis and undertreatment of these disorders are common, in large part due to interindividual variability in the genetic causes and phenotypic presentation of these conditions. To address these challenges, the European Atherosclerosis Society formed a task force to provide practical clinical guidance focusing on patients with extreme concentrations (either low or high) of plasma low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol. The task force also recognises the scarcity of quality information regarding the prevalence and outcomes of these conditions. Collaborative registries are needed to improve health policy for the care of patients with rare dyslipidaemias.
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http://dx.doi.org/10.1016/S2213-8587(19)30264-5DOI Listing
January 2020

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry.

Atherosclerosis 2019 10 19;289:85-93. Epub 2019 Aug 19.

Stanford University, Stanford, CA, USA.

Background And Aims: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH).

Methods: CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics.

Results: The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ± 15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ± 68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ± 11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors.

Conclusions: With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.08.007DOI Listing
October 2019

Is Low-Density Lipoprotein Cholesterol the Key to Interpret the Role of Lecithin:Cholesterol Acyltransferase in Atherosclerosis?

Circulation 2018 09;138(10):1008-1011

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (C.V., M.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035358DOI Listing
September 2018

JCL roundtable: High-density lipoprotein function and reverse cholesterol transport.

J Clin Lipidol 2018 Sep - Oct;12(5):1086-1094. Epub 2018 Oct 9.

Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. Electronic address:

High-density lipoproteins (HDL) have been known since the 1960s to be associated with protection from atherosclerotic cardiovascular disease. However, the mechanisms of this protection are unclear. The extent to which HDL per se vs other correlated metabolic factors may mitigate atherosclerosis has been seriously questioned. In fact, new epidemiologic studies have found that in some clinical settings, very high HDL cholesterol levels correlate with increased atherosclerotic risk. Most importantly, over the past 2 decades, randomized clinical trials targeting HDL have failed to reproduce the usual epidemiologic inverse relation of HDL cholesterol to atherosclerotic events. In this roundtable discussion, we bring together 3 expert investigators working in the HDL field to elucidate questions of HDL function. One area of agreement is that reverse cholesterol transport remains a primary hypothesis for an anti-atherogenic role of HDL. Bioassays that measure cholesterol efflux capacity of HDL (or of apolipoprotein [apo] B-depleted plasma) have emerged as potentially accurate surrogates for reverse cholesterol transport. ApoA-I is the major functional apoprotein of HDL, but apoE- and apoC-III-containing subpopulations of HDL may have significant roles. Anti- and pro-inflammatory functions of various HDL particles, as well as the role of oxidative and other modifications, are gaining attention.
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http://dx.doi.org/10.1016/j.jacl.2018.09.005DOI Listing
October 2019

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma.

J Lipid Res 2018 11 2;59(11):2084-2097. Epub 2018 Oct 2.

Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY

Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (-69%) and SM (-40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (-79%) and SM (-85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.
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http://dx.doi.org/10.1194/jlr.M087502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210916PMC
November 2018

Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

J Am Coll Cardiol 2018 08;72(6):662-680

The Familial Hypercholesterolemia Foundation, Pasadena, California.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.
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http://dx.doi.org/10.1016/j.jacc.2018.05.044DOI Listing
August 2018

Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia.

Orphanet J Rare Dis 2018 06 20;13(1):96. Epub 2018 Jun 20.

Aegerion Pharmaceuticals Ltd, Uxbridge, UK.

Background: Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown.

Methods: We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306).

Results: Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) - equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively.

Conclusions: Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further.

Trial Registration: NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).
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http://dx.doi.org/10.1186/s13023-018-0841-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011273PMC
June 2018

Cholesterol metabolism in humans: a review of methods and comparison of results.

Curr Opin Lipidol 2018 02;29(1):1-9

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose Of Review: Cholesterol metabolism has been the object of intense investigation for decades. This review focuses on classical and novel methods assessing in vivo cholesterol metabolism in humans. Two factors have fueled cholesterol metabolism studies in the last few years: the renewed interest in the study of reverse cholesterol transport (RCT) as an atheroprotective mechanism and the importance of the gut microbiome in affecting cholesterol metabolism.

Recent Findings: Recent applications of these methods have spanned from the assessment of the effect on cholesterol synthesis, absorption or excretion of drugs (such as ezetimibe, PCSK9 inhibitors and plant sterols) and the gut microbiome to the more complex assessment of transintestinal cholesterol excretion (TICE) and RCT.

Summary: These methods continue to be a valuable tool to answer novel questions and investigate the complexity of in-vivo cholesterol metabolism.
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http://dx.doi.org/10.1097/MOL.0000000000000475DOI Listing
February 2018

Paradoxical coronary artery disease in humans with hyperalphalipoproteinemia is associated with distinct differences in the high-density lipoprotein phosphosphingolipidome.

J Clin Lipidol 2017 Sep - Oct;11(5):1192-1200.e3. Epub 2017 Jul 8.

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Background: Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with risk of coronary artery disease (CAD) in epidemiologic studies. Despite this, the directionality of this relationship and the underlying biology behind it remain to be firmly established, especially at the extremes of HDL-C levels.

Objective: We investigated differences in the HDL phosphosphingolipidome in a rare population of subjects with premature CAD despite high HDL-C levels to gain insight into the association between the HDL lipidome and CAD disease status in this unusual phenotype. We sought to assess differences in HDL composition that are associated with CAD in subjects with HDL-C >90th percentile. We predicted that quantitative lipidomic analysis of HDL particles would reveal novel differences between CAD patients and healthy subjects with matched HDL-C levels.

Methods: We collected plasma samples from 25 subjects with HDL-C >90th percentile and clinically manifest CAD and healthy controls with HDL-C >90th percentile and without self-reported CAD. More than 140 individual HDL phospholipid and sphingolipid species were analyzed by LC/MS/MS.

Results: Significant reductions in HDL phosphatidylcholine (-2.41%, Q value = 0.025) and phosphatidylinositol (-10.7%, Q value = 0.047) content, as well as elevated sphingomyelin (+10.0%, Q value = 0.025) content, and sphingomyelin/phosphatidylcholine ratio (+12.8%, P value = .005) were associated with CAD status in subjects with high HDL-C.

Conclusions: These differences may lay the groundwork for further analysis of the relationship between the HDL lipidome and disease states, as well as for the development of biomarkers of CAD status and HDL function.
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http://dx.doi.org/10.1016/j.jacl.2017.06.018DOI Listing
May 2018

A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels.

Nat Med 2017 Sep 21;23(9):1086-1094. Epub 2017 Aug 21.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.
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http://dx.doi.org/10.1038/nm.4390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669375PMC
September 2017

Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia.

Circulation 2017 07;136(3):332-335

From University of Cape Town, South Africa (D.J.B.); Università di Palermo, Italy (M.R.A.); University of Pennsylvania, Philadelphia (E.A.M., D.J.R. M.C.); Netcare Private Hospital, Bloemfontein, South Africa (H.d.T.T.); Ospedale Niguarda, Milano, Italy (R.A.H.); University of Western Ontario, London, Canada (R.A.H.); Cedars-Sinai Heart Institute, Los Angeles, CA (P.K.S.); Université de Montreal, Chicoutimi, Quebec, Canada (D.G.); Università di Roma Sapienza, Italy (C.S.); Università di Ferrara, Italy (G.B.V.); CHRU Montpellier, France (D.L.); and Aegerion Pharmaceuticals, Cambridge, MA (L.T.B., P.F.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028208DOI Listing
July 2017

Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress.

Cell Rep 2017 05;19(7):1456-1466

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.
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http://dx.doi.org/10.1016/j.celrep.2017.04.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555078PMC
May 2017

ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion.

EBioMedicine 2017 Apr 14;18:139-145. Epub 2017 Mar 14.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles. ABCA1-deficient HLCs failed to mediate lipid efflux or nascent HDL formation, but had elevated triglyceride (TG) secretion. Global transcriptome analysis revealed significantly increased ANGPTL3 expression in ABCA1-deficient HLCs. Angiopoietin-related protein 3 (ANGPTL3) was enriched in plasma of TD relative to control subjects. These results highlight the required role of ABCA1 in cholesterol efflux and nascent HDL formation by hepatocytes. Furthermore, our results suggest that hepatic ABCA1 deficiency results in increased hepatic TG and ANGPTL3 secretion, potentially underlying the elevated plasma TG levels in TD patients.
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http://dx.doi.org/10.1016/j.ebiom.2017.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405159PMC
April 2017

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans.

J Lipid Res 2017 04 6;58(4):752-762. Epub 2017 Feb 6.

Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA.

Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophage-specific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using H-cholesterol nanoparticles to selectively trace macrophage-specific RCT in vivo in humans. Use of H-cholesterol nanoparticles was initially tested in mice to assess the distribution of tracer and response to interventions known to increase RCT. Thirty healthy subjects received H-cholesterol nanoparticles intravenously, followed by blood and stool sample collection. Tracer counts were assessed in plasma, nonHDL, HDL, and fecal fractions. Data were analyzed by using multicompartmental modeling. Administration of H-cholesterol nanoparticles preferentially labeled macrophages of the reticuloendothelial system in mice, and counts were increased in mice treated with a liver X receptor agonist or reconstituted HDL, as compared with controls. In humans, tracer disappeared from plasma rapidly after injection of nanoparticles, followed by reappearance in HDL and nonHDL fractions. Counts present as free cholesterol increased rapidly and linearly in the first 240 min after nadir; counts in cholesteryl ester increased steadily over time. Estimates of fractional transfer rates of key RCT steps were obtained. These results support the use of H-cholesterol nanoparticles as a feasible approach for the measurement of macrophage RCT in vivo in humans.
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http://dx.doi.org/10.1194/jlr.M075226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392750PMC
April 2017

Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance.

Diabetes 2017 Jan 5;66(1):134-144. Epub 2016 Aug 5.

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA

Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF.
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http://dx.doi.org/10.2337/db16-0394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204312PMC
January 2017

Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.

Lancet Diabetes Endocrinol 2016 10 27;4(10):850-61. Epub 2016 May 27.

Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Familial hypercholesterolaemia is common in individuals who had a myocardial infarction at a young age. As many as one in 200 people could have heterozygous familial hypercholesterolaemia, and up to one in 300 000 individuals could be homozygous. The phenotypes of heterozygous and homozygous familial hypercholesterolaemia overlap considerably; the response to treatment is also heterogeneous. In this Review, we aim to define a phenotype for severe familial hypercholesterolaemia and identify people at highest risk for cardiovascular disease, based on the concentration of LDL cholesterol in blood and individuals' responsiveness to conventional lipid-lowering treatment. We assess the importance of molecular characterisation and define the role of other cardiovascular risk factors and advanced subclinical coronary atherosclerosis in risk stratification. Individuals with severe familial hypercholesterolaemia might benefit in particular from early and more aggressive cholesterol-lowering treatment (eg, with PCSK9 inhibitors). In addition to better tailored therapy, more precise characterisation of individuals with severe familial hypercholesterolaemia could improve resource use.
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http://dx.doi.org/10.1016/S2213-8587(16)30041-9DOI Listing
October 2016
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