Lipoprotein Lipase Deficiency Research Articles

Characteristics of Lipid Profile of LPL Deficiency in Japan – Comparison with Non-LPL Deficiency

Characteristics of Lipid Profile of LPL Deficiency in Japan – Comparison with Non-LPL Deficiency

New approaches to address dyslipidemia.

Although lipid-lowering treatment with statins, ezetimibe, and PCSK9 inhibitors is a very successful strategy to prevent cardiovascular events, there is a need for further drug developments. Not all patients respond sufficiently to the available therapy (very high baseline values, intolerance). Furthermore, patients may be characterized by dyslipidemias not accessible to available drugs such as patients with homozygous familial hypercholesterolemia, chylomicronemia syndrome, or elevated lipoprotein(a). A number of drugs are being developed to close these gaps. The focus is on new antibodies, antisense oligonucleotides, and small molecules that address different aspects of lipid metabolism. Many of these developments are promising as they decrease LDL-cholesterol and/or non-HDL-cholesterol and/or triglycerides and/or lipoprotein(a) in patients who so far cannot be treated sufficiently. These drugs are currently in different stages of development and being tested in clinical trials. Some of the new lipid-lowering drugs have a very promising profile. However, eventually phase 3 and outcome trials will be required to prove the usefulness of these compounds in clinical practice. Furthermore, it is unlikely that they will change the primary lipidological approach (statin and ezetimibe) even if they prove successful.

Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia

Background and aimsType 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 resultsA 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. ConclusionWe characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.

Molecular and functional characterization of familial chylomicronemia syndrome

Background and aimsFamilial 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. MethodsEight 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. ResultsA 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. ConclusionsThese results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.

Reduced psychological distress in familial chylomicronemia syndrome after patient support group intervention

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder that is associated with severe hypertriglyceridemia and complications that often include recurrent pancreatitis beginning in childhood. Patients with FCS frequently struggle to maintain normality in their lives as a consequence of the necessity to severely restrict their intake of dietary fat coupled with the constant threat of recurrent pancreatitis. Patients typically face a high level of psychological stress and anxiety in association with reduced measures of quality of life. Routine medical care for affected patients usually does not adequately address the day-to-day struggles that accompany a diagnosis of FCS, resulting in ongoing suffering for many patients. We describe herein the highly beneficial effects of a support group interaction for a patient with FCS.

ApoCIII as a Cardiovascular Risk Factor and Modulation by the Novel Lipid-Lowering Agent Volanesorsen.

Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus. Conversely, loss-of-function mutations in ApoCIII are associated with lower levels of plasma triglycerides (TG), attenuation of vascular inflammatory processes such as monocyte adhesion and endothelial dysfunction, and potentially, a reduction in the incidence and progression of atherosclerosis and cardioprotection. Evidence is now emerging that volanesorsen, a second-generation antisense oligonucleotide drug targeting ApoCIII messenger RNA resulting in decreases in TG in patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and metabolic dyslipidemia with type 2 diabetes giving support to the hypothesis that ApoCIII is a powerful inhibitor of LPL, and when reduced, endogenous clearance of TRLs can result in substantial reductions in TG levels. Discovery of the ApoCIII inhibitor volanesorsen opens a new era of lipid-lowering drugs for reduction in TG and potentially for reduction in LDL-C. Herein, this review will provide an update on the pathophysiology of ApoCIII-linked atherosclerosis and the development of the first drug to target ApoCIII, volanesorsen, as a promising lipid-lowering agent.

Exchange transfusions for extreme hypertriglyceridemia in a 7-week-old infant with multi-organ failure

Severe hypertriglyceridemia is the third most common cause of acute pancreatitis and is strongly associated with an increased risk of cardiovascular disease. In infants, the most common cause of severe hypertriglyceridemia is lipoprotein lipase deficiency. We describe a 7-week-old infant with severe hypertriglyceridemia, who presented with frequent gastrointestinal bleeding, respiratory distress, a decreased level of consciousness and lipemia retinalis. Triglycerides were reduced from 734 to 2 mmol/L (64,956–177 mg/dL), by exchange transfusions. The infant made a remarkable recovery with no sequelae. This case highlights atypical, protean presentations and a potential treatment when established therapies are unavailable.

Cell therapy could be a potential way to improve lipoprotein lipase deficiency

BackgroundLipoprotein lipase (LPL) deficiency is an autosomal recessive genetic disorder characterized by extreme hypertriglyceridemia, with no cure presently available. The purpose of this study was to test the possibility of using cell therapy to alleviate LPL deficiency.MethodsThe LPL coding sequence was cloned into the MSCV retrovirus vector, after which MSCV-hLPL and MSCV (empty construct without LPL coding sequence) virion suspensions were made using the calcium chloride method. A muscle cell line (C2C12), kidney cell line (HEK293T) and pre-adipocyte cell line (3 T3-L1) were transfected with the virus in order to express recombinant LPL in vitro. Finally, each transfected cell line was injected subcutaneously into nude mice to identify the cell type which could secret recombinant LPL in vivo. Control cells were transfected with the MSCV empty vector. LPL activity was analyzed using a radioimmunoassay.ResultsAfter virus infection, the LPL activity at the cell surface of each cell type was significantly higher than in the control cells, which indicates that all three cell types can be used to generate functional LPL. The transfected cells were injected subcutaneously into nude mice, and the LPL activity of the nearby muscle tissue at the injection site in mice injected with 3 T3-L1 cells was more than 5 times higher at the injection sites than at non-injected control sites. The other two types of cells did not show this trend.ConclusionThe subcutaneous injection of adipocytes overexpressing LPL can improve the LPL activity of the adjacent tissue of nude mice. This is a ground-breaking preliminary study for the treatment of LPL deficiency, and lays a good foundation for using cell therapy to correct LPL deficiency.

Treatment of Dyslipidemia in Diabetes: Recent Advances and Remaining Questions.

This article reviews current knowledge concerning diabetic dyslipidemia and cardiovascular disease (CVD). It reviews strategies to reduce diabetes-associated CVD, including reducing low-density lipoprotein levels, lowering triglycerides, and increasing high-density lipoproteins (HDL). Special considerations, such as the multifactorial chylomicronemia syndrome and partial lipodystrophy, and the role of glucose-lowering strategies in the management of diabetic dyslipidemia are discussed. The strongest evidence to date for reducing CVD in diabetes comes from the use of statins. While triglyceride lowering remains inconclusive, an ongoing trial might provide some finality to this question. The role of increasing HDL remains elusive, and HDL cholesterol appears to be an unsatisfactory metric for monitoring therapy. The use of statins offers the best current way to reduce diabetes-associated CVD. However, several novel and promising approaches for the management of diabetic dyslipidemia aimed at reducing CVD are in the pipeline.

The impact of lipoprotein lipase deficiency on health-related quality of life: a detailed, structured, qualitative study

BackgroundLipoprotein lipase deficiency (LPLD) is an autosomal recessive inherited disorder caused by loss-of-function mutations in genes involved in the lipoprotein lipase pathway. It is characterised by chylomicronaemia, severe hypertriglyceridaemia and an increased risk of recurrent pancreatitis that often requires hospitalisation. This research aimed to improve our understanding of the debilitating impact that LPLD has on the daily lives of patients and their families.MethodsThe research comprised a 2-h interview with the patient and, where possible, a 1-h interview with a family member; a 1-week pre- and post-interview task (written and/or video diary); and a 30–45-min follow-up telephone interview. Feelings and thoughts at each stage of the disease journey were captured on a 0–10 rating scale, while the impact of disease on overall health status was measured via the EuroQoL 5 domains, 3 levels (EQ-5D-3L) questionnaire (descriptive and visual analogue scale).ResultsOf four patients identified, three (two female, one male) were recruited to participate in the study; the male patient did not complete the pre-interview task or consent to a family member interview. Demographics and medical history differed among patients in terms of age at symptom onset, their journey to LPLD diagnosis, treatments, the number of attacks of pancreatitis and lengths of hospitalisations. Health-related quality of life, assessed by the EQ-5D-3L, was poor during acute attacks of pancreatitis but was minimally impacted by their condition at interview. Patients described feeling apprehensive, frightened, anxious, depressed or frustrated during and after hospitalisations; spouses of the two female patients also reported being worried or afraid. LPLD affected many aspects of daily living, including diet; socialising and building relationships; state of mind (fear of another attack of pancreatitis or lack of disease control); college and working life (through absenteeism and consequent financial implications); and being reliant on family and friends for support.ConclusionsThe interviews of the three patients with LPLD highlighted several concerns and emphasised the need for improved education, support, dietary advice and appropriate disease management. Additional support services would ease the fear and uncertainty surrounding attacks of pancreatitis, and would allow for improved treatment during hospitalisations.

The burden of familial chylomicronemia syndrome from the patients’ perspective

ABSTRACTBackground: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives.Methods: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS.Results: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS.Conclusions: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.

Incidental finding of severe hypertriglyceridemia in children. Role of multiple rare variants in genes affecting plasma triglyceride

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). Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. We performed the parallel sequencing of 20 plasma TG-related genes. 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. Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG.

The impact of lipoprotein lipase deficiency on quality of life: A detailed structured qualitative study

The impact of lipoprotein lipase deficiency on quality of life: A detailed structured qualitative study

Severe hypertriglyceridemia in Japan: Differences in causes and therapeutic responses

Severe hypertriglyceridemia (>1000mg/dL) has a variety of causes and frequently leads to life-threating acute pancreatitis. However, the origins of this disorder are unclear for many patients. We aimed to characterize the causes of and responses to therapy in rare cases of severe hypertriglyceridemia in a group of Japanese patients. We enrolled 121 patients from a series of case studies that spanned 30years. Subjects were divided into 3 groups: (1) primary (genetic causes); (2) secondary (acquired); and (3) disorders of uncertain causes. In the last group, we focused on 3 possible risks factors for hypertriglyceridemia: obesity, diabetes mellitus, and heavy alcohol intake. Group A (n=20) included 13 patients with familial lipoprotein lipase deficiency, 3 patients with apolipoprotein CII deficiency, and other genetic disorders in the rest of the group. Group B patients (n=15) had various metabolic and endocrine diseases. In Group C (uncertain causes; n=86), there was conspicuous gender imbalance (79 males, 3 females) and most male subjects were heavy alcohol drinkers. In addition, 18 of 105 adult patients (17%) had histories of acute pancreatitis. The cause of severe hypertriglyceridemia is uncertain in many patients. In primary genetic forms of severe hypertriglyceridemia, genetic diversity between populations is unknown. In the acquired forms, we found fewer cases of estrogen-induced hypertriglyceridemia than in Western countries. In our clinical experience, the cause of most hypertriglyceridemia is uncertain. Our work suggests that genetic factors for plasma triglyceride sensitivity to alcohol should be explored.

The approach study: a randomized, double-blind, placebo-controlled, phase 3 study of volanesorsen administered subcutaneously to patients with familial chylomicronemia syndrome (FCS)

The approach study: a randomized, double-blind, placebo-controlled, phase 3 study of volanesorsen administered subcutaneously to patients with familial chylomicronemia syndrome (FCS)

FIrst interim results of the global, longitudinal, pharmaco-epidemiologic, observational registry on gene therapy in the management of lipoprotein lipase deficiency (geniall)

Aim: Background: Lipoprotein Lipase Deficiency (LPLD) is a rare genetic disease resulting in chylomicronemia and increased risk of pancreatitis. Alipogene tiparvovec (Glybera®) is a gene therapy approved for treatment of LPLD that decreases the incidence and severity of pancreatitis for up to 6 years. A 15-year, international, multicenter, observational Registry was launched in 2014 to collect further data on epidemiology of LPLD and to continue the evaluation of long-term safety and clinical response to gene therapy.

Natural history and gene expression signature of platelet count in lipoprotein lipase deficiency

Natural history and gene expression signature of platelet count in lipoprotein lipase deficiency

A New Start for Triglycerides and Remnant Cholesterol-Nonfasting.

Featured Article: Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308.3 My first independent scientific project was to understand why patients with lipoprotein lipase (LPL) deficiency, the chylomicronemia syndrome, and severely increased plasma triglycerides did not develop cardiovascular disease. At the time this was a great mystery, one that led to the belief that triglycerides, unlike cholesterol, were not important for the development of atherosclerosis and cardiovascular disease. This belief was supported by studies by George Lyman Duff and others, published in the late 1940s, showing that the alloxan-diabetic, cholesterol-fed rabbit with severely increased triglycerides likewise did not develop atherosclerosis. I started my studies in the mid-1980s at the University of Copenhagen together with Dr. and later Professor Steen Stender, and continued in the laboratory of Professor Donald Zilversmit at Cornell University in New York. Using the alloxan-diabetic, cholesterol-fed rabbit we showed that, at severely increased triglycerides, most lipoproteins were chylomicron-like with diameters above 75 nm and that these lipoproteins were unable to enter into the arterial intima, explaining the lack of atherosclerosis development …

Disruption of Lipid Uptake in Astroglia Exacerbates Diet-Induced Obesity.

Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to have little relevance for such neuroendocrine control, we investigated whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required to centrally regulate energy homeostasis. Ex vivo studies with hypothalamus-derived astrocytes showed that LPL expression is upregulated by oleic acid, whereas it is decreased in response to palmitic acid or triglycerides. Likewise, astrocytic LPL deletion reduced the accumulation of lipid droplets in those glial cells. Consecutive in vivo studies showed that postnatal ablation of LPL in glial fibrillary acidic protein-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet. Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation, and glucose metabolism.

Gene Therapy 2017: Progress and Future Directions.

Gene therapy has changed dramatically in the 28 years since the first human gene transfer experiment in 1989. Alipogene tiparvovec, GlyberaR®, a recombinant adeno‐associated virus (rAAV) product for lipoprotein lipase deficiency, and Strimvelis®, a lentivirus vector for severe combined immune deficiency are approved in Europe. An rAAV2 product for a congenital form of blindness is currently under review in the United States, likely to be followed by numerous other gene therapies. Nonviral gene transfer The success of gene therapy has largely been driven by improvements in nonviral and viral gene transfer vectors. An array of physical and chemical nonviral methods have been used to transfer DNA and mRNA to mammalian cells and a substantial number of these have been developed as clinical stage technologies for gene therapy, both ex vivo and in vivo. Cationic liposome technology is based on the ability of amphipathic lipids, possessing a positively charged head group and a hydrophobic lipid tail, to bind to negatively charged DNA or RNA and form particles that generally enter cells by endocytosis. Some cationic liposomes also contain a neutral co‐lipid, thought to enhance liposome uptake by mammalian cells.4, 5, 6, 7 Similarly, other polycations, such as poly‐l‐lysine and polyethylene‐imine, complex with nucleic acids via charge interaction and aid in the condensation of DNA or RNA into nanoparticles, which are then substrates for endosome‐mediated uptake.8 Several of these cationic‐nucleic acid complex technologies have been developed as potential clinical products, including complexes with plasmid DNA (pDNA), oligodeoxynucleotides, and various forms of synthetic RNA.9, 10, 11 Modified (and unmodified or “naked”) DNA, RNA, and oligonucleotides have also been shown to mediate successful gene transfer in a number of circumstances. These include the use of pDNA by direct intramuscular injection for DNA vaccines, the use of intratumoral injection of pDNA to deliver cytokine and/or suicide genes, systemic (s.c. or i.v.) injection of antisense nucleotides to induce RNAse H1 or exon‐skipping.12, 13, 14 The most recent of these developed for induction of RNAi are discussed in a later section. Ex vivo introduction of pDNA and/or other nucleotides using physical methods has been well developed for certain cell types, including T lymphocytes.15 Electroporation techniques have become the standard with T cells for the introduction of a variety of molecular cargoes, including ribonucleoproteins composed of Cas9 and short‐guide RNAs for genome editing (see section below) and transposons for long‐term integration of transgenes.