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The pregnancy of a patient with homozygous familial hypercholesterolemia (HoFH) represents a challenge in the clinical setting due to the high cardiovascular risk of the mother and maternal-fetal morbidity. The lipid lowering drugs are generally contraindicated and lipoprotein apheresis (LA) is the only accepted treatment in HoFH pregnant woman. Liposorber D, an LA technique on whole blood, has good efficacy, safety, and short operative time. We present a 31-year-old Caucasian pregnant woman with HoFH clinical phenotype on lipid-lowering treatment with Lomitapide and Evolocumab, discontinued during pregnancy. In multidisciplinary team it was decided to submit the patient to LA throughout the pregnancy. Liposorber D sessions (a whole blood technique) were performed on a strict weekly frequency. The treatment resulted in massive decrease of total cholesterol (TC) and LDL cholesterol (LDL-c), with no significant side effects. The pregnancy presented a normal course and a cesarean section was performed on clinical indications unrelated to the use of LA. She gave birth to a healthy male child at 37 weeks of gestation. LA is considered the only effective, safe and accepted therapy during HoFH pregnancy. This is the first reported case of successful pregnancy treated with Liposorber D, a whole blood LA technique. LA with dextran sulfate has been an effective and safe choice for the mother and fetus. Furthermore it was reasonably well tolerated from the beginning of pregnancy management to its conclusion., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Published by Elsevier Ltd.)

Background: Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides., Methods: In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis., Results: At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline., Conclusions: Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Aims: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the two main causes of severe hypertriglyceridemia (sHTG). FCS is a rare autosomal recessive form of sHTG, whereas MCS is mainly polygenic in nature with both common and rare variants accumulating and leading to sHTG. However, 30 to 50% of MCS patients have no identified genetic cause of sHTG. DNA methylation (DNAm) is a non-traditional heritable factor known to be associated with triglyceride (TG) levels. The aim of this study is to determine if DNAm level at three candidate genes for hypertriglyceridemia (ABCG1, CPT1A and SREBF1) could contribute to sHTG in MCS patients., Methods: A total of 114 MCS and 20 FCS patients were included in this retrospective study. DNAm levels were measured at ABCG1 (cg06500161), CPT1A (cg00574958), and SREBF1 (cg11024682) gene loci using pyrosequencing of bisulfite-treated DNA., Results: DNAm levels at ABCG1, CPT1A and SREBF1 were significantly associated with TG levels or minimal TG levels in MCS patients. Prevalence of patients with at least 2 loci with DNAm levels into the top tertile of DNAm associated with hypertriglyceridemia was significantly higher in MCS patients with genetically undefined sHTG compared to MCS patients with polygenic sHTG and FCS patients (57 % vs. 24 % vs. 0 %, respectively; p < 0.0001)., Conclusion: This study suggests for the first time that DNAm could contribute to sHTG in MCS patients. It suggests that further studies of epivariations may contribute to better understand the clinical heterogeneity seen in MCS patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AB received research grants from Akcea, Amgen, Astra Zeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi. He has participated in clinical research protocols from Acasti Pharma Inc., Akcea, Amgen, Arrowhead Pharmaceuticals, Astra Zeneca, Ionis Pharmaceuticals, Inc., ISIS Pharmaceuticals, The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. He has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. SBreceived research grants from Akcea, Fondation Leducq, and Fondation Yvan Morin. She has participated in clinical research protocols from Akcea, Amgen, Ionis Pharmaceuticals, Inc., The Medicines Company, Novartis, Pfizer, and Sanofi. She has served on advisory boards for Akcea, Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Sanofi, and received honoraria for symposia from Akcea, Amgen, Novo Nordisk, and Sanofi. SPG has served on advisory boards for Ultragenyx. MP, LB, LG, VD and AT have nothing to declare., (Copyright © 2025 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis. However, the risk of acute pancreatitis is very heterogenous in MCS. Previous studies suggested that inflammation might promote disease progression in hyperTG-induced acute pancreatitis., Objective: To determine if low-grade inflammation is associated with acute pancreatitis in MCS., Methods: This study included 102 subjects with MCS for whom high-sensitivity C-reactive protein (hsCRP) concentration was measured at their first visit at the Montreal Clinical Research Institute., Results: Patients with MCS who had a previous history of acute pancreatitis had a significant higher hsCRP concentration (4.62 mg/L vs 2.61 mg/L; P = .003), and high hsCRP concentration (≥ 3 mg/L) was independently associated with acute pancreatitis prevalence (P < .05). Up to 64% of the variability in acute pancreatitis prevalence was explained by the maximal triglycerides (TG) concentration, hsCRP concentration, the presence of rare variants in TG-related genes, and fructose intake, based on a stepwise multivariate regression model (P < .0001)., Conclusion: This retrospective study showed for the first time that hsCRP concentration is strongly associated with acute pancreatitis prevalence in MCS. It also suggests that low-grade inflammation may be a driver of acute pancreatitis in severe hypertriglyceridemia. Prospective studies could help determine the causality of this association and assess whether medication known to reduce low-grade inflammation could help prevent acute pancreatitis in individuals with severe hypertriglyceridemia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Familial chylomicronemia syndrome (FCS) is a severe type of hypertriglyceridemia (HTG). Despite its rarity, we have encountered more than 100 patients with FCS at our center. Therefore, we aimed to provide a useful resource for clinicians who may encounter such patients and help the scientific community accumulate knowledge to manage this disease., Methods: This retrospective study described the clinical characteristics and management of FCS patients at (King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia)., Results: In total, 29 pediatric patients were included, with a median age of 2.2 months [IQR: 1.3, 12]. Males predominated (62.0%). Key symptoms included a milky blood sample (72.4%), a family history of HTG (65.5%), hepatosplenomegaly (44.8%), acute pancreatitis (31.0%), and eruptive xanthoma (13.8%). Gemfibrozil (22 patients) reduced TG from 47.6 ± 55.7 to 9.4 ± 7.5 mmol/L (mean reduction 38.2 ± 54.5 mmol/L, P<0.001). Fenofibrate (19 patients) lowered TG from 45.4 ± 56.4 to 18.4 ± 13.1 mmol/L (mean difference 27.1 ± 52.0 mmol/L, P=0.001). While the Niacin-aspirin (4 patients) and diet alone (4 patients) had no significant effect (P=1.000) and (P=0.125), respectively., Discussion: The rarity of FCS makes it more challenging for scientists and clinicians to achieve advancements in its management. We observed that anti-TG medications, especially fibrate derivatives, can be used safely in pediatric patients. They displayed excellent ability to control TG levels in combination with diet restrictions, and treatment compliance was good. Among fibrate derivatives, gemfibrozil controlled TG levels better than fenofibrate, and neither drug had significant side effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al-Ashwal, AlHelal, AlSagheir, Alfattani, Ramzan, Imtiaz and Alhuthil.)

Background: Familial chylomicronemia syndrome (FCS) is a rare inherited condition due to lipoprotein lipase deficiency, characterized by hyperchylomicronemia and severe hypertriglyceridemia. Diagnosis is often delayed, thus increasing the risk of acute pancreatitis and hospitalization. Hypertriglyceridemia is a common finding in patients with type 2 diabetes (T2D), who may harbor FCS among the most severe forms. Aim of the Study: We investigated the prevalence and clinical characteristics associated with severe hypertriglyceridemia in a range indicative of FCS, in a large population of subjects with T2D. Methods: Within the large population of the AMD Annals Initiative, patients with T2D with a lipid profile suggestive of FCS [triglycerides >880 mg/dL and/or high-density lipoprotein (HDL)-cholesterol <22 mg/dL or non-HDL-cholesterol ≤70 mg/dL] and their clinical features have been identified. Results: Overall, 8592 patients had triglyceride values >880 mg/dL in a single examination, 613 in two examinations, and 34 in three or more measurements. Patients with high triglyceride levels were mostly male (80%), with a relatively young age (54 years), short duration of diabetes (6.3 years), and elevated hemoglobin A1c (HbA1c) levels (9.4%). By stratifying this group of patients according to the severity of hypertriglyceridemia, more severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL) was associated with an even younger age (52 vs. 54 years), even higher mean HbA1c values (10.0% vs. 9.4%), and significantly higher HDL-cholesterol levels (37.9 vs. 32.4 mg/dL; P < 0.0001). Patients with persistently elevated triglyceride levels ( n = 34), on three measurements, had a younger age; lower body mass index, HbA1c, and HDL-cholesterol levels; more frequent use of fibrates and insulin; and a higher prevalence of major cardiovascular events. Conclusions: Severe hypertriglyceridemia is a frequent condition in outpatients with T2D participating in the AMD Annals Initiative, and it is associated with male sex, young age, short disease duration, and a worse glycemic profile. Among patients with persistent severe hypertriglyceridemia, hidden FCS may be present.

Background and Aim: APO CII, one of several cofactors which regulate lipoprotein lipase enzyme activity, plays an essential role in lipid metabolism. Deficiency of APO CII is an ultra-rare autosomal recessive cause of familial chylomicronemia syndrome. We present the long-term clinical outcomes of 12 children with APO CII deficiency., Methods and Results: The data of children with genetically confirmed APO CII deficiency were evaluated retrospectively. Twelve children (8 females) with a mean follow-up of 10.1 years (±3.9) were included. At diagnosis, the median age was 60 days (13 days-10 years). Initial clinical findings included lipemic serum (41.6%), abdominal pain (41.6%), and vomiting (16.6%). At presentation, the median triglyceride (TG) value was 4341 mg/dL (range 1277-14,110). All patients were treated with a restricted fat diet, medium-chain triglyceride (MCT), and omega-3-fatty acids. In addition, seven patients (58.3%) received fibrate. Fibrate was discontinued in two patients due to rhabdomyolysis and in one patient because of cholelithiasis. Seven (58.3%) patients experienced pancreatitis during the follow-up period. One female experienced recurrent pancreatitis and was treated with fresh frozen plasma (FFP)., Conclusions: Apo CII deficiency is an ultra-rare autosomal recessive condition of hypertriglyceridemia associated with significant morbidity and mortality. Low-fat diet and MCT supplementation are the mainstays of therapy, while the benefit of TG-lowering agents are less well-defined., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Reducing the synthesis of apoC-III reduces fasting triglycerides in individuals lacking lipoprotein lipase activity. Recently, Stroes et al. 1 published a phase 3 trial on the effects of olezarsen, a third-generation antisense oligonucleotide that blocks apoC-III mRNA, on triglycerides and risk of acute pancreatitis., Competing Interests: Declaration of interests P.V. received honoraria for presentations and advisory boards from AMGEN, Sanofi, Servier, Novartis, MSD, Alexion, Sobi, Akcea, and PTB. P.V. also received research grants from Ferrer and Sobi and technology transfer contracts with Lipigon Pharmaceuticals and Capenergy Medical., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III., Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis., Results: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group., Conclusions: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.)., (Copyright © 2024 Massachusetts Medical Society.)

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation., Competing Interests: Declaration of competing interest SDdF received grants from the National Institutes of Health/National Heart, Lung, and Blood Institute of the National Institutes of Health, the Family Heart Foundation and holds a patent for UpToDate, with royalties paid. AG received grants and personal fees from Amgen, Sanofi and Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Servier, Novartis and Ultragenyx. SGP received study funding from Amgen. JH received a research grant from the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number K23HL145109. DI received advisory honoraria from Amryt, and honoraria for lectures from Sanofi, Sobi and Novartis. CPS received advisory honoraria from Baxter, Iperboreal and Stadapharma, lecturing honoraria from Fresenius and research funding from Baxter. MK received honoraria from Abbott, Abdi Ibrahim, Amryt, LIB Therapeutics, NovoNordisk, and TR-pharma; research funding from Amryt Pharma, and participated in clinical trials with Amgen, Ionis, LIB Therapeutics, Novo Nordisk, Sanofi. RK, as head of the Apheresis Research GmbH, Cologne, Germany received financial grants for scientific research projects, honoraria for consulting and presentation of lectures including travel expenses from the companies Diamed, Cologne, Germany, and Asahi Kasei Medical, Tokyo, Japan. GK has given talks, attended conferences, received consultancy fees and participated in trials sponsored by Amgen, Novartis, Sanofi, Servier, Amryt. AW received research grants from Amgen, Regeneron, Novartis, Silence Therapeutics, Esperion, and Ultragenyx and advisory honoraria from Amryt, and Novartis. KA, EJD, LMdB, JWG, LCH, GDK, JO, RNP, MDR, CS and CT have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG., Methods: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS., Results: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone., Conclusions: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS., Competing Interests: Declaration of competing interest AB received research grants from Akcea, Amgen, Astra Zeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi. He has participated in clinical research protocols from Acasti Pharma Inc., Akcea, Amgen, Arrowhead Pharmaceuticals, Astra Zeneca, Ionis Pharmaceuticals, Inc., ISIS Pharmaceuticals, The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. He has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. SB received research grants from Akcea, Fondation Leducq, and Fondation Yvan Morin. She has participated in clinical research protocols from Akcea, Amgen, Ionis Pharmaceuticals, Inc., The Medicines Company, Novartis, Pfizer, and Sanofi. She has served on advisory boards for Akcea, Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Sanofi, and received honoraria for symposia from Akcea, Amgen, Novo Nordisk, and Sanofi. SPG, MP, LB, LG, VD and AT have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by extremely high triglyceride levels due to impaired clearance of chylomicrons from plasma. This paper is the result of a panel discussion with Latin American specialists who raised the main issues on diagnosis and management of FCS in their countries. Overall FCS is diagnosed late on the course of the disease, is characterized by heterogeneity on the occurrence of pancreatitis, and remains a long time in care of different specialists until reaching a lipidologist. Pancreatitis and secondary diabetes are frequently seen, often due to late diagnosis and inadequate care. Molecular diagnosis is unusual; however, loss of function variants on the lipoprotein lipase gene are apparently the most frequent etiology. A founder effect of the glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 gene has been described in the northeast of Brazil. Low awareness of the disease amongst health professionals contributes to inadequate care and an inadequate patient journey., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to compare plasmapheresis and medical apheresis as lipid-lowering therapies in children with familial lipoprotein lipase (LPL) deficiency., Methods: The data of 13 patients who were followed up after a diagnosis of LPL deficiency were retrospectively analyzed. Plasma triglyceride, cholesterol, amylase, and lipase values and complications were recorded before and after each patient underwent plasmapheresis or medical apheresis., Results: The mean follow-up period of the patients was 99.64 ± 52.92 months in the medical apheresis group and 118 ± 16.97 months in the plasmapheresis group. While the mean triglyceride level before plasmapheresis was 1,875.38 ± 547.46 mg/dL, it was 617 ± 228.28 mg/dL after plasmapheresis. While the mean triglyceride level before medical apheresis was 1,756.86 ± 749.27 mg/dL, it was found to be 623.03 ± 51.36 mg/dL after medical apheresis. Triglyceride levels were decreased by 59.62% with medical apheresis and 65.57% with plasmapheresis. The cost of treatment for medical apheresis was found to be lower compared to plasmapheresis 296.93 ± 29.94 Turkish lira (USD 43.34 ± 4.01) vs. 3,845.42 ± 156.17 Turkish lira (USD 561.37 ± 20.93; p<0.001)., Conclusions: Although there is no standardized strategy for the acute treatment of hypertriglyceridemia due to LPL deficiency, medical apheresis is a safe and effective treatment with a low risk of side effects. Unlike plasmapheresis, medical apheresis can be performed in any center, which is another important advantage of the procedure., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

Background: The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low-density lipoproteins triglycerides (CM/VLDL-TG) ratio, the triglycerides to cholesterol ratio (TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS)., Methods: Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL-TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cut-offs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort., Results: Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL-TG, TG/TC and TG/APOB ratios, whereas their HDL-C, LDL-C and APOB levels were lower than in non-FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL-TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cut-off of 3.8 and 4.5., Conclusions: Our results suggest that in subjects at high risk of FCS a total serum TG/TC ratio or TG/APOB ratio are feasible to initially screen for HLPI; however, a CM/VLDL-TG ratio ≥4.5 is a better diagnostic criterion for HPLI., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Chylomicronemia syndrome (CS) is a metabolic condition characterized by severely elevated plasma triglycerides (>880 mg/dL) and high rates of morbidity and mortality. The syndrome can be classified into two major groups: monogenic familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS), the frequencies of which are ill-defined., Objective: The objective of the study was to characterize the prevalence of the most common and rarest subsets of this syndrome, MCS and FCS, respectively, in a single-center, real-world setting., Methods: This was a retrospective cross-sectional study of patients with plasma triglycerides ≥880 mg/dL. The criteria used for identification of patients with FCS were modeled after a Food and Drug Administration endorsed set of parameters. Less stringent criteria that removed the requirement for pancreatitis were used to classify MCS. Full criteria are described in detail in the article., Results: Of the 2,342,136 patient records queried, 578 had triglycerides ≥880 mg/dL (0.025%), of which 86 had a documented history of pancreatitis. Five patients who met the criteria for FCS were identified (three genetically confirmed), resulting in an estimated prevalence of ~1-2 per 1,000,000. On the other hand, MCS was identified in 186 patients, corresponding to an estimated prevalence of ~1 in 12,000. There were 5181 cases of pancreatitis (0.22% of the entire cohort), 86 of which occurred in subjects with triglycerides≥880 mg/dL (1.7% of cases of pancreatitis). Rates of pancreatitis in this subset were elevated at 6.5%, 100%, and 17.8%, among patients with MCS, FCS, and secondary hypertriglyceridemia, respectively., Conclusions: CS is an uncommon condition, but it is associated with significant complications, regardless of etiology. Among patients with CS, MCS was 40- to 60-fold more prevalent than FCS and associated with frequent morbidity. Therefore, disease recognition and treatment should extend to all forms of CS pursuant to the clinical presentation., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Familial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive lipid disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis. Because the disorder is often misdiagnosed or not diagnosed and because traditional triglyceride lowering medications are often ineffective, the disease leads to a tremendous physical, social and emotional burden on afflicted patients and their caretakers. Mutations in 5 different genes have been implicated in the development of FCS, all of which have an effect on the activity of lipoprotein lipase. Lipoprotein lipase(LPL) is responsible for removing triglycerides from chylomicrons and other triglyceride rich lipoproteins in the circulation, breaking them down into free fatty acids for use as energy. Patients with FCS have loss of function of their LPL leading to severely elevated chylomicrons in the circulation and hence, severe hypertriglyceridemia. The principle treatment for FCS is to reduce chylomicron formation in the gut by placing the patient on an extremely low fat diet. New medications in development hold significant promise for improving the quality of life for FCS patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Volanesorsen (previously known as ISIS 304801) is a 20-nucleotide partially 2'- O -(2-methoxyethyl) (2'-MOE)-modified antisense oligonucleotide (ASO) gapmer, which was recently approved in the European Union as a novel, first-in-class treatment in the reduction of triglyceride levels in patients with familial chylomicronemia syndrome. We characterized the absorption, distribution, metabolism, and excretion characteristics of volanesorsen in mice, rats, monkeys, and humans, in either radiolabeled or nonradiolabeled studies. This also included the characterization of all of the observed ASO metabolite species excreted in urine. Volanesorsen is highly bound to plasma proteins that are similar in mice, monkeys, and humans. In all species, plasma concentrations declined in a multiphasic fashion, characterized by a relatively fast initial distribution phase and then a much slower terminal elimination phase following subcutaneous bolus administration. The plasma metabolite profiles of volanesorsen are similar across species, with volanesorsen as the major component. Various shortened oligonucleotide metabolites (5-19 nucleotides long) were identified in tissues in the multiple-dose mouse and monkey studies, but fewer in the [ 3 H]-volanesorsen rat study, likely due to a lower accumulation of metabolites following a single dose in rats. In urine, all metabolites identified in tissues were observed, consistent with both endo- and exonuclease-mediated metabolism and urinary excretion being the major elimination pathway for volanesorsen and its metabolites. SIGNIFICANCE STATEMENT: We characterized the absorption, distribution, metabolism, and excretion (ADME) of volanesorsen, a partially 2'-MOE-modified antisense oligonucleotide, from mouse to man utilizing novel extraction and quantitation techniques in samples collected from preclinical toxicology studies, a 3 H rat ADME study, and a phase 1 clinical trial., (Copyright © 2019 by The Author(s).)

Background: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels., Methods: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months., Results: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began., Conclusions: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.)., (Copyright © 2019 Massachusetts Medical Society.)

Background and Aims: Chylomicronemia can be either monogenic or multifactorial. The monogenic form, namely familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease that strongly predisposes to pancreatitis. However, the clinical variables differentiating FCS from multifactorial chylomicronemia (MCM) are not well established. The aims of the present study were to describe a well-defined cohort of FCS subjects and to investigate the differences between patients with FCS and MCM., Methods: A total of 25 FCS and 36 MCM patients were included in the present study. FCS patients were genetically confirmed, whereas MCM patients had negative genetic testing, triglycerides above 10 mmol/L at least once and the presence of both chylomicrons and VLDL in plasma., Results: FCS patients presented a significant higher frequency of pancreatitis (60% vs. 6%), multiple pancreatitis (48% vs. 3%) and abdominal pain (63% vs. 19%) and a lower frequency of metabolic abnormalities than in the MCM group (p < 0.0001). In addition, the frequency of cardiovascular events was higher in the MCM group than in the FCS group (17% vs. 0%), although the difference was not statistically significant (p = 0.07). In a univariate regression model, the significant predictors of FCS were age at first manifestation (β = -2.11, p = 0.0005), body mass index (BMI) (β = -1.82, p < 0.001) and gamma-glutamyl transferase (GGT) (β = -1.64, p = 0.001)., Conclusions: Our study identified several variables that significantly differentiates FCS from MCM patients. These results need to be replicated in larger cohorts to identify the independent predictors of FCS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Type I hyperlipoproteinemia is an autosomal recessive disorder of lipoprotein metabolism caused by mutations in the LPL gene, with an estimated prevalence in the general population of 1 in a million. In this work, we studied the molecular mechanism of two known mutations in the LPL gene in ex vivo and in vitro experiments and also the effect of two splice site mutations in ex vivo experiments., Methods: Two patients with hypertriglyceridemia were selected from the Lipid Clinic in Vienna. The first patient was compound heterozygote for c.680T > C (exon 5; p.V200A) and c.1139+1G > A (intron 7 splice site). The second patient was compound heterozygote for c.953A > G (exon 6; p.N291S) and c.1019-3C > A (intron 6 splice site). The LPL gene was sequenced and post-heparin plasma samples (ex vivo) were used to test LPL activity. In vitro experiments were performed in HEK 293T/17 cells transiently transfected with wild type or mutant LPL plasmids. Cell lysate and media were used to evaluate LPL production, secretion, activity and dimerization by Western blot analysis and LPL enzymatic assay, respectively., Results: Our data show that in both patients, LPL activity is absent. V200A is a mutation that alters LPL secretion and activity whereas the N291S mutation affects LPL activity, but both mutations do not affect dimerization. The effect of these mutations in patients is more severe since they have splice site mutations on the other allele., Conclusions: We characterized these LPL mutations at the molecular level showing that are pathogenic., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels >10 mmol/L [885 mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (≥10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high-priority candidates for genotyping., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Patients with type 1 hyperlipoproteinemia (T1HLP), a rare genetic disorder, have extreme chylomicronemia and recurrent episodes of acute pancreatitis. Currently, the only therapeutic option is to consume an extremely low-fat diet because the triglyceride-lowering medications are not efficacious., Objective: To determine the efficacy of orlistat, a gastric and pancreatic lipase inhibitor, in reducing serum triglyceride levels in patients with T1HLP., Design and Setting: We conducted a randomized, open-label, clinical trial with a four-period, two-sequence ("orlistat" and "off orlistat" for 3 months), crossover study design., Patients: Two unrelated young Asian Indian males (11 and 9 years old) with T1HLP due to homozygous large GPIHBP1 deletions were enrolled at the UT Southwestern Medical Center. The patients were randomized to receive 3 months of orlistat or no therapy (off), then crossed over to the other arm, and this sequence was then repeated. Fasting serum triglyceride levels, fat-soluble vitamins, and gastrointestinal side effects were assessed., Results: Compared with the two off periods, orlistat therapy reduced serum triglycerides by 53.3% and 53.0% in patient 1 and 45.8% and 62.2% in patient 2. There was no deficiency of fat-soluble vitamin levels, and their growth continued. There were no serious adverse effects of orlistat; patient 1 had a mild increase in passage of gas and bloating, and patient 2 had constipation with mild stool leakage., Conclusion: Orlistat is safe and highly efficacious in lowering serum triglycerides in children with T1HLP and should be the first-line therapy in conjunction with an extremely low-fat diet.

Objective: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery., Approach and Results: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/G hi ). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density., Conclusions: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation., (© 2018 American Heart Association, Inc.)

Familial chylomicronemia syndrome is characterized by severe elevation in serum triglycerides and an increased risk of acute pancreatitis. Although familial chylomicronemia syndrome is mainly caused by mutations in the lipoprotein lipase (LPL) gene, few causal mutations in other genes (ie, APOC2, APOA5, LMF1, and GPIHBP1) have also been reported. In this case report, we present the discovery of a novel mutation in the glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) gene and discuss its pathogenicity through a familial segregation study., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Université de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Type I hyperlipoproteinemia, also known as familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disorder caused by variants in LPL, APOC2, APOA5, LMF1 or GPIHBP1 genes. The aim of this study was to identify novel variants in the LPL gene causing lipoprotein lipase deficiency and to understand the molecular mechanisms., Methods and Results: A total of 3 individuals with severe hypertriglyceridemia and recurrent pancreatitis were selected from the Lipid Clinic at Sahlgrenska University Hospital and LPL was sequenced. In vitro experiments were performed in human embryonic kidney 293T/17 (HEK293T/17) cells transiently transfected with wild type or mutant LPL plasmids. Cell lysates and media were used to analyze LPL synthesis and secretion. Media were used to measure LPL activity. Patient 1 was compound heterozygous for three known variants: c.337T > C (W113R), c.644G > A (G215E) and c.1211T > G (M404R); patient 2 was heterozygous for the known variant c.658A > C (S220R) while patient 3 was homozygous for a novel variant in the exon 5 c.679G > T (V227F). All the LPL variants identified were loss-of-function variants and resulted in a substantial reduction in the secretion of LPL protein., Conclusion: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations., Methods: Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG., Results: A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed., Conclusions: These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL)., Objective: Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood., Methods: We performed the parallel sequencing of 20 plasma TG-related genes., Results: Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant., Conclusions: Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

We report a case of severe type I hyperlipoproteinemia caused by autoimmunity against lipoprotein lipase (LPL) in the context of presymptomatic Sjögren's syndrome. A 7-year-old mixed race (Caucasian/African American) girl was admitted to the intensive care unit at Vanderbilt Children's Hospital with acute pancreatitis and shock. She was previously healthy aside from asthma and history of Hashimoto's thyroiditis. Admission triglycerides (TGs) were 2191 mg/dL but returned to normal during the hospital stay and in the absence of food intake. At discharge, she was placed on a low-fat, low-sugar diet. She did not respond to fibrates, prescription fish oil, metformin, or orlistat, and during the following 2 years, she was hospitalized several times with recurrent pancreatitis. Except for a heterozygous mutation in the promoter region of LPL, predicted to have no clinical significance, she had no further mutations in genes known to affect TG metabolism and to cause inherited type I hyperlipoproteinemia, such as APOA5, APOC2, GPIHBP1, or LMF1. When her TG levels normalized after incidental use of prednisone, an autoimmune mechanism was suspected. Immunoblot analyses showed the presence of autoantibodies to LPL in the patient's plasma. Autoantibodies to LPL decreased by 37% while patient was on prednisone, and by 68% as she subsequently transitioned to hydroxychloroquine monotherapy. While on hydroxychloroquine, she underwent a supervised high-fat meal challenge and showed normal ability to metabolize TG. For the past 3 years and 6 months, she has had TG consistently <250 mg/dL, and no symptoms of, or readmissions for, pancreatitis., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The heterogeneity and mechanisms of multifactorial chylomicronemia (MCM) remain poorly understood. To gain new insights, post heparin lipolysis measured at 60 min (PHLA60), in addition to the more commonly used 10 min (PHLA10), was assessed in patients with history of MCM., Methods: 62 consecutive MCM patients were studied. The evaluation included LPL, APOC2, APOA5, GPIHBP1, LMF1 and APOE gene sequencing, as well as pre- and post-heparin injection biochemical analysis, including lipid profiles, determination of apolipoprotein B, B-48, CII, CIII, lipoprotein lipase (LPL) concentrations (LPLC0, LPLC10 and LPLC60) and post-heparin LPL activity (PHLA10 and PHLA60)., Results: In controls, PHLA60 did not differ from PHLA10, while in MCM patients, PHLA60 was significantly lower than PHLA10 (p<0.001). PHLA60 showed a bimodal distribution in MCM patients (p=0.03). One subgroup exhibited PHLA60 similar to controls, with persistent lipoprotein remodeling and, paradoxically, the highest basal plasma TG concentration. APOE ε4 was over-represented compared to the European population (p<0.05) and Apo CIII/Apo B ratio was increased (p<0.01). The other subgroup exhibited low PHLA60 (p<0.001) compared to both controls and the other MCM subgroup with a lipoprotein profile consistent with fast and transient remodeling. LMF1 p. Arg364Gln was over-represented compared to the European population (p<0.05)., Conclusions: The study showed that PHLA60 identifies a subgroup of MCM with a defect in lipolysability and/or hepatic clearance of triglycerides-rich lipoproteins, and a larger one with a defect in LPL availability. These findings provide new insights into the heterogeneity of MCM and might contribute to adjust treatment targeting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: GPIHBP1, a glycolipid-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) in the interstitial spaces and transports it to the capillary lumen. GPIHBP1 deficiency prevents LPL from reaching the capillary lumen, resulting in low intravascular LPL levels, impaired intravascular triglyceride processing, and severe hypertriglyceridemia (chylomicronemia). A recent study showed that some cases of hypertriglyceridemia are caused by autoantibodies against GPIHBP1 ("GPIHBP1 autoantibody syndrome")., Objective: Our objective was to gain additional insights into the frequency of the GPIHBP1 autoantibody syndrome in patients with unexplained chylomicronemia., Methods: We used enzyme-linked immunosorbent assays to screen for GPIHBP1 autoantibodies in 33 patients with unexplained chylomicronemia and then used Western blots and immunocytochemistry studies to characterize the GPIHBP1 autoantibodies., Results: The plasma of 1 patient, a 36-year-old man with severe hypertriglyceridemia, contained GPIHBP1 autoantibodies. The autoantibodies, which were easily detectable by Western blot, blocked the ability of GPIHBP1 to bind LPL. The plasma levels of LPL mass and activity were low. The patient had no history of autoimmune disease, but his plasma was positive for antinuclear antibodies., Conclusions: One of 33 patients with unexplained chylomicronemia had the GPIHBP1 autoantibody syndrome. Additional studies in large lipid clinics will be helpful for better defining the frequency of this syndrome and for exploring the best strategies for treatment., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies., Methods: Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1., Results: We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents., Conclusions: In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency., Competing Interests: The authors have declared that no competing interests exist.

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disease that leads to severe hypertriglyceridemia often associated with recurrent episodes of pancreatitis. The recognition and correct diagnosis of the disease is challenging due to its rarity, and to the lack of specificity of signs and symptoms. Lipid experts, endocrinologists, gastroenterologists, pancreatologists, and general practitioners may encounter patients who potentially have FCS. Therefore, cooperation between experts and improved knowledge of FCS is essential in improving the diagnosis. Currently, a consensus on best practice for the diagnosis of FCS is lacking., Methods: Aiming to define a diagnostic algorithm for FCS, a board of European experts was instituted. Such an algorithm for FCS is important to guide practitioners in the diagnosis of suspected FCS and to optimize therapeutic strategies., Results: The multidisciplinary views were merged, leading to a diagnostic algorithm, proposed here., Conclusion: This diagnostic algorithm represents a potentially useful tool to support primary and secondary care practitioners in the recognition of signs and clinical manifestations in individuals potentially affected by FCS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Type 1 hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme elevations in serum triglyceride (TG) levels. Despite considerable progress in identifying several causal genes for T1HLP, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1, the molecular basis of some extremely rare patients presenting with T1HLP remains obscure., Case Description: We report a 58-year-old Hispanic female who initially presented with serum TG of 4740 mg/dL at age 23 years when she was 3 weeks postpartum and was taking an oral contraceptive for 2 weeks. Over a period of 35 years, she has had recurrent episodes of extreme hypertriglyceridemia (fasting serum TG exceeding 2000 mg/dL), which responded to a reduction of dietary fat, fibrates, and fish oil therapy. Sanger sequencing of the known T1HLP genes in this patient did not reveal any disease-causing mutations. Whole-exome sequencing revealed compound heterozygous rare variants (p.Val103Met and p.Arg540Gln) in the glucokinase regulator (GCKR) gene., Conclusions: GCKR encodes glucokinase regulatory protein, which is an inhibitor of glucokinase, an enzyme that drives glucose uptake in the liver. Loss of function GCKR variants, by enhancing glucose uptake in hepatocytes, may induce de novo lipogenesis and TG biosynthesis, resulting in extreme hypertriglyceridemia. We conclude that compound heterozygous rare variants in GCKR cause an extremely rare unique T1HLP, most likely by inducing excessive hepatic lipogenesis.

Background/objective: Subjects suffering from lipoprotein lipase (LPL) deficiency show very severe hypertriglyceridemia, often accompanied by recurrent bouts of pancreatitis. Dietary intervention is currently considered first-line treatment of this condition in paediatric age. The aim of our study was to compare the effects of dietary treatment with a low-fat diet alone and a low-fat diet enriched with omega-3-fatty acids., Subjects/methods: The data of 11 patients with LPL deficiency who were diagnosed in our lipid clinic between October 1997 and October 2007 were summarised. All patients had been treated with a low-fat diet, and in addition a group of five patients received supplements of omega-3-fatty acids over a period of at least 5 months., Results: After adjustment for pre-intervention TG concentration, there was a statistically significant difference in post-intervention TG concentrations between the interventions, F(1,8)=13.529, P=0.006, partial η 2 =0.628. Post-intervention-adjusted TG concentrations were statistically significantly greater in the low-fat diet group vs the w3 diet group (P <0.05)., Conclusions: We provide first evidence that a low-fat diet supplemented with omega-3-fatty acids results in a pronounced decrease in TG in paediatric patients affected with LPL deficiency. However, further studies are necessary to evaluate the long-term effects and safety of omega-3-fatty acids.

Background: Type 1 hyperlipoproteinemia is a rare autosomal recessive disorder most often caused by mutations in the lipoprotein lipase (LPL) gene resulting in severe hypertriglyceridemia and pancreatitis., Objectives: The aim of this study was to identify novel mutations in the LPL gene causing type 1 hyperlipoproteinemia and to understand the molecular mechanisms underlying the severe hypertriglyceridemia., Methods: Three patients presenting classical features of type 1 hyperlipoproteinemia were recruited for DNA sequencing of the LPL gene. Pre-heparin and post-heparin plasma of patients were used for protein detection analysis and functional test. Furthermore, in vitro experiments were performed in HEK293 cells. Protein synthesis and secretion were analyzed in lysate and medium fraction, respectively, whereas medium fraction was used for functional assay., Results: We identified two novel mutations in the LPL gene causing type 1 hyperlipoproteinemia: a two base pair deletion (c.765&#95;766delAG) resulting in a frameshift at position 256 of the protein (p.G256TfsX26) and a nucleotide substitution (c.1211 T > G) resulting in a methionine to arginine substitution (p.M404 R). LPL protein and activity were not detected in pre-heparin or post-heparin plasma of the patient with p.G256TfsX26 mutation or in the medium of HEK293 cells over-expressing recombinant p.G256TfsX26 LPL. A relatively small amount of LPL p.M404 R was detected in both pre-heparin and post-heparin plasma and in the medium of the cells, whereas no LPL activity was detected., Conclusions: We conclude that these two novel mutations cause type 1 hyperlipoproteinemia by inducing a loss or reduction in LPL secretion accompanied by a loss of LPL enzymatic activity., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 ± 281.2 mg/dl) and low HDL cholesterol (31.4 ± 14.7 mg/dl) compared with wild-type mice (TG, 55.9 ± 13.3 mg/dl; HDL cholesterol, 55.9 ± 14.3 mg/dl). TGs were found in light (density < 1.063 g/ml) lipoproteins in the size range of very-low-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 μmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 ± 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency., (U.S. Government work not protected by U.S. copyright.)

During pregnancy physiological changes occur in the lipid metabolism due to changing hormonal conditions: the LDL cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) [Lp(a)] increase throughout pregnancy. Common lipoprotein disorders are associated in pregnancy with two major clinical disorders: severe hypertriglyceridemia (SHTG) is a potent risk factor for development of acute pancreatitis and elevated cholesterol due to greater concentrations of LDL and remnant lipoproteins and reduced levels of HDL promote atherosclerosis. The combination of homozygous Familial Hypercholesterolemia (HoFH) and pregnancy can be a fatal condition. Therapeutic plasma exchange (TPE) may be used for an urgent need of a fast and effective lowering of TG levels in order to prevent a severe pancreatitis episode or hypertriglyceridemia-induced complications during pregnancy. LDL apheresis can decrease LDL-C and prevent complications and can be considered in the treatment of pregnancies complicated by high LDL-C. These conditions are configured in patients with HeFH who were taking statins before pregnancy (selected cases), patients already receiving apheresis before pregnancy suffering from HoFH, patients suffering from hypertriglyceridemia due to familial hyperlipoproteinemia types I and V, and cases of hypertriglyceridemia secondary to diabetes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport., Objective: We set out to examine the association between FGF21 and LDLR mediated transmembrane cholesterol transport, by comparing FGF21 levels in patients with genetically impaired LDLR function and unaffected relatives. Secondly, we explored whether the severity of the LDLR mutation was associated with FGF21 levels., Methods: We performed a cross-sectional study in carriers of an LDLR mutation and their unaffected relatives. Subjects were eligible if they participated in the Dutch national screening program for familial hypercholesterolemia (FH), were 18-55 years old, and were carrier of a pathogenic LDLR mutation with an untreated LDL-C level below the 75(th) or above the 90(th) percentile of the general population, or did not carry an FH mutation. The outcome measure was the level of FGF21, which was assessed using ELISA., Results: We included 224 carriers of an LDLR mutation and 148 unaffected relatives. FGF21 levels were lower in LDLR mutation carriers compared to unaffected relatives (median [interquartile range]: 96.92 [60.80-174.05] versus 136.98 [77.34-219.47] pg/mL, respectively; p = 0.08), but after adjusting for potential confounders, there was no association between LDLR mutations and FGF21 levels (p = 0.70). Neither, did we find a relationship between the severity of LDLR mutations and FGF21 levels (p = 0.51, after adjustment for potential confounders)., Conclusions: We showed that levels of FGF21 are not different in patients with and without LDLR mutations, which suggests that decreased LDLR expression does not have a negative effect on FGF21 levels. Given the potential beneficial effects of FGF21 analogs on lipids and lipoproteins in a phase 1 study, we deem this of great interest for future treatment options for FH patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Monogenic hypertriglyceridemia (HTG) may result from mutations in some genes which impair the intravascular lipolysis of triglyceride (TG)-rich lipoproteins mediated by the enzyme Lipoprotein lipase (LPL). Mutations in the LPL gene are the most frequent cause of monogenic HTG (familial chylomicronemia) with recessive transmission., Methods: The LPL gene was resequenced in 149 patients with severe HTG (TG > 10 mmol/L) and 106 patients with moderate HTG (TG > 4.5 and <10 mmol/L) referred to tertiary Lipid Clinics in Italy., Results: In the group of severe HTG, 26 patients (17.4%) were homozygotes, 9 patients (6%) were compound heterozygotes and 15 patients (10%) were simple heterozygotes for rare LPL gene variants. Single or multiple episodes of pancreatitis were recorded in 24 (48%) of these patients. There was no difference in plasma TG concentration between patients with or without a positive history of pancreatitis. Among moderate HTG patients, six patients (5.6%) were heterozygotes for rare LPL variants; two of them had suffered from pancreatitis. Overall 36 rare LPL variants were found, 15 of which not reported previously. Systematic analysis of close relatives of mutation carriers led to the identification of 44 simple heterozygotes (plasma TG 3.2 ± 4.1 mmol/L), none of whom had a positive history of pancreatitis., Conclusions: The prevalence of rare LPL variants in patients with severe or moderate HTG, referred to tertiary lipid clinics, was 50/149 (33.5%) and 6/106 (5.6%), respectively. Systematic analysis of relatives of mutation carriers is an efficient way to identify heterozygotes who may develop severe HTG., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Familial hypercholesterolemia (FH) is the world's most abundant and the most common heritable disorder of lipid metabolism. The prevalence of the disease in general population is 1:500. Therefore the approximate number of FH patients all over the world is 14 million. From the genetic point of view the disease originates as a result of mutations in genes affecting the processing of LDL particles from circulation, resulting in an increase in LDL cholesterol and hence total cholesterol. These are mutations in genes encoding LDL receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 and LDL receptor adaptor protein 1. Cholesterol depositing in tissues and blood vessels of individuals creates tendon xanthoma, xanthelesma and arcus lipoides cornae. Due to the increased deposition of cholesterol in blood vessels, atherosclerosis process is accelerated, what leads to a significantly higher risk of premature cardiovascular diseases. Therefore, early clinical diagnosis confirmed by the DNA analysis, and effective treatment are crucial to reduce the mortality and high risk of premature atherosclerotic complications.

Background and Objective: Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, is under development to treat familial chylomicronemia syndrome. The potential impact of hepatic impairment on the pharmacokinetics of pradigastat was evaluated in this study., Methods: In this study, a single oral dose of 20 mg pradigastat was administered first to patients with mild and moderate hepatic impairment (n = 10/group) and subsequently to patients with severe hepatic impairment (n = 6). The pharmacokinetics of pradigastat were compared between each patient group and the respective matched healthy subjects., Results: As compared with the respective matched healthy groups, the geometric mean ratios of the area under the plasma concentration-time curve from time zero to infinity (AUC inf) (h · ng/mL) were 1.49, 1.06 and 1.99 in mild, moderate and severe hepatic impairment patients, respectively; the observed maximum plasma concentration (C max) (ng/mL) values were 0.97, 1.28 and 2.74, respectively; and the total body clearance of the drug from plasma (CL/F) (L/h) values were 0.67, 0.95 and 0.50, respectively. The elimination half-life and plasma protein binding of pradigastat were comparable among all the patients. There were no apparent relationships between AUC inf or C max and albumin or bilirubin levels (R (2) < 0.3; p > 0.05). Overall, 19 adverse events (AEs) were reported in 13 patients. The incidence of AEs appeared to increase with increasing severity of hepatic impairment., Conclusion: No clinically significant differences in the pharmacokinetics of pradigastat were observed in mild and moderate hepatic impairment patients compared with healthy subjects. However, the systemic exposure of pradigastat doubled while the clearance decreased by half in patients with severe hepatic impairment compared with healthy subjects. All treatments were well tolerated in the study.

Background: Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS., Methods: Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored., Results: Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events., Conclusion: The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease., Trial Registration: ClinicalTrials.gov identifier NCT01146522 .

Apolipoprotein A-I (apoA-I) mimetic peptides are currently being developed as possible new agents for the treatment of cardiovascular disease based on their ability to promote cholesterol efflux and their other beneficial antiatherogenic properties. Many of these peptides, however, have been reported to cause transient hypertriglyceridemia due to inhibition of lipolysis by lipoprotein lipase (LPL). We describe a novel bihelical amphipathic peptide (C-II-a) that contains an amphipathic helix (18A) for binding to lipoproteins and stimulating cholesterol efflux as well as a motif based on the last helix of apolipoprotein C-II (apoC-II) that activates lipolysis by LPL. The C-II-a peptide promoted cholesterol efflux from ATP-binding cassette transporter ABCA1-transfected BHK cells similar to apoA-I mimetic peptides. Furthermore, it was shown in vitro to be comparable to the full-length apoC-II protein in activating lipolysis by LPL. When added to serum from a patient with apoC-II deficiency, it restored normal levels of LPL-induced lipolysis and also enhanced lipolysis in serum from patients with type IV and V hypertriglyceridemia. Intravenous injection of C-II-a (30 mg/kg) in apolipoprotein E-knockout mice resulted in a significant reduction of plasma cholesterol and triglycerides of 38 ± 6% and 85 ± 7%, respectively, at 4 hours. When coinjected with the 5A peptide (60 mg/kg), the C-II-a (30 mg/kg) peptide was found to completely block the hypertriglyceridemic effect of the 5A peptide in C57Bl/6 mice. In summary, C-II-a is a novel peptide based on apoC-II, which promotes cholesterol efflux and lipolysis and may therefore be useful for the treatment of apoC-II deficiency and other forms of hypertriglyceridemia., (U.S. Government work not protected by U.S. copyright.)

The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.