Apolipoprotein B-100 Synthesis Research Articles

Dose-dependent effects of rumen-protected choline on hepatic metabolism during induction of fatty liver in dry pregnant dairy cows.

Objectives were to determine the effects of supplementing increasing amounts of choline ion on hepatic composition and mRNA abundance in pregnant dry cows subjected to a fatty liver induction protocol. Holstein cows (35 primiparous and 41 multiparous) at mean (± standard deviation) of 211 ± 9.9 days of gestation were blocked by body condition (3.59 ± 0.33) and assigned to receive 0, 6.45, 12.90, 19.35, and 25.80 g/day of choline ion as rumen-protected choline (RPC) as a top-dress for 14 days. Cows were fed for ad libitum intake on days 1 to 5 and restricted to 30% of the required net energy for lactation from days 6 to 14 of the experiment. Hepatic tissue was sampled on days 5 and 14 and analyzed for concentrations of triacylglycerol and glycogen, and mRNA abundance was investigated. Orthogonal contrasts evaluated the effects of supplementing RPC (0 g/day vs. rest), and the linear, quadratic, and cubic effects of increasing intake of choline ion from 6.45 to 25.80 g/day. Results are depicted in sequence of treatments from 0 to 25.8. During feed restriction, RPC reduced the concentration of hepatic triacylglycerol by 28.5% and increased that of glycogen by 26.1%, and the effect of increasing RPC intake on triacylglycerol was linear (6.67 vs. 5.45 vs. 4.68 vs. 5.13 vs. 3.81 ± 0.92% wet-basis). Feeding RPC during feed restriction increased abundance of transcripts involved in choline metabolism (CHKA, PLD1), synthesis of apolipoprotein-B100 (APOB100), and antioxidant activity (GPX3), and decreased the abundance of transcripts involved in hepatic lipogenesis (DGAT2, SREBF1) and acute phase response (SAA3). Most effects were linear with amount of choline fed. Changes in hepatic mRNA abundance followed a pattern of reduced lipogenesis and enhanced lipids export, which help explain the reduced hepatic triacylglycerol content in cows fed RPC. Choline exerts lipotropic effects in dairy cows by altering transcript pathways linked to hepatic lipids metabolism.

Abstract 116: Angptl3 Regulates Hepatic Lipoprotein Production: A New Model For Lipid Lowering?

Background: Angiopoietin-like protein 3 (ANGPTL3 ) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein cholesterol (LDL). Although ANGPTL3 modulates lipolytic pathways in lipoprotein metabolism, its potential intra-hepatocyte role in very low-density lipoprotein (VLDL) assembly and secretion remains unknown. Furthermore, although ANGPTL3 inhibition reduces low-density lipoprotein cholesterol (LDL), humans with complete LDL receptor (LDLR) deficiency exhibit LDLR-independent LDL lowering. Methods: We established hepatocyte cell culture systems, including CRISPR/Cas9-edited HepG2 cells with ANGPTL3 “knocked out” (KO). We also generated hepatocyte-like cells from patient-derived isogenic pluripotent stem cells (iPSCs) with and without ANGPTL3 KO. Radiolabeling was used to quantify apolipoprotein and triglyceride synthesis. Negative stain electron microscopy (NS-EM) was used to quantify the size of secreted lipoproteins. Results: We observed reduction of both apolipoprotein B100 and triglyceride synthesis and secretion in ANGPTL3 KO HepG2 cells. NS-EM demonstrated ANGPTL3-deficient HepG2 cells secrete significantly smaller lipoprotein particles compared to WT control cells. Together, these three findings suggest ANGPTL3 deficiency in hepatocytes results in the production of fewer, smaller, underlipidated lipoprotein particles. Conclusion: Our results point to an important intracellular role for ANGPTL3 within hepatocytes, suggesting that ANGPTL3 modifies the assembly and remodeling, as well as clearance, of hepatically secreted lipoproteins. Further experiments are planned to identify and characterize mechanistic mediators of this process. These studies have potential to identify additional targets for reducing plasma lipids via LDLR-independent pathways.

The Effect of Mipomersen in the Management of Patients with Familial Hypercholesterolemia: A Systematic Review and Meta-Analysis of Clinical Trials.

Background: Familial hypercholesterolemia (FH) lead to significant adverse effects in coronary arteries. Mipomersen is a second-generation antisense oligonucleotide that inhibits the synthesis of apolipoprotein B-100, an essential component of low density lipoprotein (LDL), and thus decreases the production of LDL. We aimed to determine the effect of mipomersen in patients with FH. Methods: We searched Ovid Medline, Ovid EMBASE, WHO ICTRP search portal, ISI database, the reference lists of relevant articles, and also Google Scholar to retrieve articles. All randomized controlled trials (RCTs) comparing patients with FH receiving mipomersen as an add-on and a parallel group receiving a placebo or no intervention were selected. Results: Five studies with more than 500 patients were included. All had low risk of bias. Pooling data showed that mipomersen probably reduces LDL compared with placebo [mean difference: −24.79, 95% CI (−30.15, −19.43)] but with a moderate level of certainty. There was a high level of evidence for injection site reactions [RR = 2.56, CI (1.47–4.44)] and a low level for increased serum alanine transaminase (ALT) > 3 times upper limit of normal (ULN) [RR = 5.19, CI (1.01–26.69)]. Conclusion: A moderate level of evidence in decreasing serum LDL indicates that we are uncertain if this drug provides benefit in any outcome important to patients. Although a low level of evidence for an increase in serum ALT leaves uncertainty about this adverse effect, injection site reactions in 10% or more of patients can be an important concern.

Riboflavin deficiency alters cholesterol homeostasis partly by reducing apolipoprotein B100 synthesis in HepG2 cells.

Riboflavin deficiency led to lower blood cholesterol level and higher content of hepatic cholesterol in rats and the mechanisms are not clarified yet. We hypothesized that riboflavin deficiency might alter cholesterol homeostasis via apolipoprotein B100, one of the important proteins in cholesterol transport. To test this hypothesis, HepG2 cells were cultured in riboflavin-deficient media for 4 days to develop riboflavin deficiency. Compared to riboflavin-sufficient cells, the mRNA (0. 37±0.04 vs 1.03±0.29 relative expression level, n=3) and protein expressions of apolipoprotein B100 (intracellular: 173.7±14.4 vs 254.8±47.2μg/mg protein; extracellular: 93.8±31.1 vs 161.6±23.9μg/mg protein; n=3) were significantly reduced in riboflavin-deficient cells (P<0.05). Endoplasmic reticulum oxidoreductin 1 and protein disulfide isomerase, two enzymes involved in the oxidative folding of apolipoprotein B100, were also lower remarkably in expression at both mRNA and protein levels. Meanwhile, intracellular cholesterol was increased (256.3±17.1μM/g protein vs 181.4±23.9μM/g protein, n=4) and extracellular cholesterol decreased (110.0±23.2μM/g protein vs 166.2±34.6μM/g protein, n=4) significantly in riboflavin-deficient cells (P<0.05). Very low-density lipoprotein was also diminished (29.0±6.1μM/g protein vs 67.0±11.0μM/g protein, n=4) in the culture media (P<0.05). These findings suggest that riboflavin deficiency alters cholesterol homeostasis partly by reducing apolipoprotein B100 synthesis in HepG2 cells.

Riboflavin deficiency affects lipid metabolism partly by reducing apolipoprotein B100 synthesis in rats

Lipid metabolism is dependent on riboflavin status. Apolipoprotein B100 plays an important role in lipids transportation. This study was aimed to investigate the effect of riboflavin status on lipid metabolism and explore its association with apolipoprotein B100 synthesis in vivo. Riboflavin deficiency was developed in rats by feeding riboflavin-deficient diets. Compared to the control rats, the mRNA and protein expressions of apolipoprotein B100 were significantly reduced in riboflavin-deficient rats. Endoplasmic reticulum oxidoreductin 1 (ERO1) and protein disulfide isomerase (PDI), two enzymes involved in the oxidative folding of apolipoprotein B100, were also lowered remarkably in expression at protein level. Meanwhile, total cholesterol and triglyceride levels were decreased in the plasma and increased in the liver of riboflavin-deficient rats. The plasma very low-density lipoprotein cholesterol (VLDL-c) and low-density lipoprotein cholesterol (LDL-c) were also reduced in riboflavin-deficient rats. Our findings demonstrate that riboflavin deficiency affects lipid metabolism partly by reducing apolipoprotein B100 synthesis.

Comparison of effects of anagliptin and alogliptin on serum lipid profile in type 2 diabetes mellitus patients.

IntroductionAnagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase‐4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients.Materials and MethodsThe study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase‐4 inhibitors for ≥8 weeks and had a low‐density lipoprotein cholesterol (LDL‐C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks.ResultsThere was no significant difference in percentage change in LDL‐C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL‐C levels, one of the secondary end‐points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B‐100 levels, and the percentage change in LDL‐C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B‐100 levels in the ANA group.ConclusionsThe LDL‐C‐lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL‐C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B‐100 synthesis.

The Effects of Mipomersen on Inhibiting Hepatic VLDL Apolipoprotein B100 Synthesis and Propensity for Hepatic Steatosis

Mipomersen is a 20-nucleotide, second-generation, antisense oligonucleotide that inhibits human apolipoprotein B (apo B)–1003 production by binding to and preventing translation of apo B messenger RNA. As apo B–100 is an essential structural component of VLDL, intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a), decreased hepatic production of apo B by mipomersen should lead to reduced circulating concentrations of all of these atherogenic lipoprotein particles (1). However, Reyes-Soffer et al., in a stable isotope study of 17 healthy volunteers without hyperlipidemia and presumably on a restricted fat diet, reported that mipomersen 200 mg weekly for 7 weeks, although reducing VLDL and its apo B and triglyceride content, did not reduce the production rates of VLDL apo B but surprisingly increased its clearance (2). The study did, however, find modest reductions in IDL- and LDL apo B–associated production and postulated that these lipoproteins were decreased independently and directly rather than being a consequence of reduced VLDL production. The authors postulated that, due to the partial inhibition of apo B synthesis by mipomersen, compensation occurred by increasing the proportion of newly synthesized apo B directed to VLDL production, which in turn helped maintain hepatic lipid homeostasis (2). In addition, there was increased loading of triglyceride onto VLDL …

Abstract 52: Efficacy and Safety of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled LDL-C Levels

Aim: Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein B-100 synthesis, FDA-approved to treat homozygous familial hypercholesterolemia. The primary objective of this study was to determine whether mipomersen significantly reduced atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (HeFH). Methods: This was a randomized, double-blind, placebo-controlled, parallel-group study comprised of two cohorts (NCT01475825). Cohort 1 had severe HeFH (LDL-C ≥200 mg/dL + coronary heart disease, or LDL-C ≥300 mg/dL) and Cohort 2 had milder HeFH (LDL-C ≥160 and &lt;200 mg/dL). For each cohort, patients were randomized 1:1 to 200 mg SC once weekly or 70 mg SC thrice weekly, then 2:1 to receive mipomersen or placebo for 60 weeks. The primary outcome was percent change from baseline in LDL-C in Cohort 1. The % change from baseline in LDL-C at Week 61 for mipomersen treated patients was compared to placebo using a mixed model for repeated measures (MMRM), as well as by ANCOVA on the value closest to 7 days post last treatment (LOCF). Results: Mean baseline LDL-C levels were 265 mg/dL in Cohort 1 (N=200) and 176 mg/dL in Cohort 2 (N=109). In Cohort 1, mipomersen 200 mg weekly reduced LDL-C levels by -29.7% (vs -7.9% placebo, P &lt;.001) in the mixed model, and by -36.3% (vs -7.6% placebo, P &lt;.001) using the LOCF. Analysis of LDL-C over time (Figure) showed a mean absolute reduction of 138 mg/dL in mipomersen patients who completed the blinded treatment period (n=32), achieving a mean level of 147 mg/dL from a mean 285 mg/dL baseline level. Tolerability to treatment and adverse events were similar between dose regimens. Adverse events were consistent with the drug’s known safety and tolerability profile. Conclusions: The primary analysis showed a significant reduction in LDL-C levels in patients with severe HeFH who received mipomersen 200 mg once weekly versus placebo. A highly relevant absolute reduction in LDL-C was achieved over time.

Management of patients with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is an autosomal inherited disorder characterized by markedly elevated LDL-cholesterol (LDL-C) levels and an increased risk of premature atherosclerotic cardiovascular disease. Although FH is one of the most common genetic disorders, this disorder remains mostly undetected and its management is often suboptimal. High-intensity statins are standard treatment for patients with FH, but LDL-C levels in most patients treated with statin monotherapy remain above those recommended by guidelines. Combination therapy to lower LDL-C levels further-such as treatment with statins plus ezetimibe-has been successful, and combination of apheresis with high-intensity statin treatment is used in patients with homozygous FH and in those with heterozygous FH who are statin-refractory. Mipomersen, an inhibitor of apolipoprotein B-100 synthesis, and lomitapide, a microsomal triglyceride transfer protein inhibitor, reduce LDL-C levels further when added to high-intensity statin treatment in homozygous FH, but both have important adverse effects, such as increasing liver fat content. At present, PCSK9 inhibition (with alirocumab or evolocumab) is well tolerated and reduces LDL-C levels considerably in patients receiving the maximally tolerated statin treatment, and seems the most promising emerging treatment option. Nevertheless, data from outcome trials with hard end points for PCSK9 inhibitors, mipomersen, and lomitapide are still needed before these therapies become standard for patients with FH.

Efficacy and safety of mipomersen in treatment of dyslipidemia: A meta-analysis of randomized controlled trials

Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. We identified 8 randomized controlled trials (n=462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55-39.18; P<.00001), total cholesterol by 24.18% (18.54-29.83; P<.00001), very low-density lipoprotein cholesterol by 21.59% (9.16-34.02; P=.0007), non-high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92-37.74; P<.00001), and triglycerides by 36.26% (22-50.54; P<.00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39-3.04; P=.0003), flu-like symptoms (1.63; 1.22-2.17; P=.0008), alanine aminotransferase ≥3X upper limit of normal (4.44; 1.67-11.86; P=.003), and hepatic steatosis (3.85, 1.39-10.67; P=.01). The risks of alanine aminotransferase ≥10X upper limit of normal did not reach statistical significance (1.57; 0.32-7.6, P=.58). Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo.

Abstract 1: Role of MicroRNAs in Postranscriptional Regulation of Apolipoprotein B-100 mRNA

Hepatic apolipoprotein B-100 (apoB) synthesis and secretion appears to be regulated largely at the posttranscriptional and posttranslational levels. MicroRNAs (miRNAs) are among posttranscriptional regulators of gene expression that bind to complementary sequences on target messenger RNA (mRNA) transcripts, usually resulting in translational repression or degradation. It is unknown whether specific miRNAs are involved in posttranscriptional regulation of apoB mRNA. We performed bioinformatic analysis, showing that two specific miRNAs with satisfactory E-values level (with levels indicating greater similarity between the input and its match) namely, miR-544 (E-value = 0.91) and miR-1202 (E-value=0.86) have potential to interact with 3’ and 5’ UTR of apoB, respectively. We hypothesized that the interaction of these specific miRNAs (miR-544 and miR-1202) with the 3’ and 5’UTR of apoB mRNA leads to apoB mRNA translational repression and/or activation. Using a human hepatoma cell line model, HepG2, the effects of overexpressed miRNAs and inhibition of endogenous miRNAs on the expression of apoB mRNA and apoB protein synthesis were investigated. We further examined the effect of these miRNAs on apoB mRNA traffic into cytoplasmic P-bodies. Transfection of HepG2 cells with miR-544 led to a significant reduction in apoB mRNA expression and protein synthesis and induced an increase in the co-localization of apoB mRNA into P-bodies. The opposite effect was observed when anti-miR-544 was employed to inhibit the endogenous miR-544. Results from luciferase reporter assays indicated that the effects of miR-544 may be mediated via interaction with the 3’UTR of apoB mRNA. In contrast to miR-544, miR-1202 overexpression induced an increase in apoB mRNA expression and protein synthesis. Similarly, the opposite effect was observed when using anti-miR-1202. Data from luciferase reporter assays showed an increased expression of the reporter gene in constructs carrying 5’UTR of apoB mRNA suggesting that miR-1202 may function via the 5’UTR. In summary, these data demonstrate that specific miRNAs are involved in the regulation of expression and translational control of apoB mRNA in hepatocytes. However, these miRNAs do not appear to mediate insulin regulation.

DIFFERENTIAL DIAGNOSIS OF HEREDITARY SYNDROME OF HYPOCHOLESTEROLEMIA BY USING EXOMIC SEQUENCING

Clinical case study is described. Patient D, 55 years old, applied to the Lipid clinic of State Research Centre for Preventive Medicine because of low blood cholesterol level. Results of the differential diagnosis of the hypocholesterolemia syndrome by using exomic sequencing are presented. This method allows to sequence the majority of regions of genome containing exons, protein-coding parts of genes. Heterozygous mutation in the gene for APOB (5 nucleotides deletion) was found out in the patient by using exomic sequencing. This mutation leads to a premature stop codon with violation of apolipoprotein B-100 synthesis and causes inherited monogenic disease - family hypobetalipoproteinemia.

Recent advances in the treatment of homozygous familial hypercholesterolaemia

To review publications in the English literature over the past 18 months relating to the management of homozygous familial hypercholesterolaemia. Experience with plasmapheresis has been summarized, guidelines are being introduced to enhance patient care and registries are under consideration to improve analysis of management in this rare but serious disorder. Liver transplantation has been reviewed for its biochemical efficacy, but still does not ensure freedom from vascular complications. For patients without access to plasmapheresis, there is now evidence that high-dose statins do improve the prognosis, but combination therapy with additional agents should still be considered for better outcome. Promising new agents that inhibit LDL production by limiting apolipoprotein B100 synthesis by means of antisense oligonucleotides (mipomersen) or by inhibition of microsomal triacylglycerol transfer protein (lomitapide) have made significant additional LDL reduction possible but are associated with hepatic fat accumulation and long-term safety data is still required. Several other lipid modulating agents and gene therapy are still being explored. The management of homozygous familial hypercholesterolaemia by pharmacological means is improving with agents that limit lipoprotein production but plasmapheresis, generally in combination with additional pharmacological treatment, remains the proven option. Liver transplantation is now less likely to be undertaken owing to improved pharmacological options and prognosis.

Lomitapide, mipomersen: Two novel agents for homozygous familial hypercholesterolemia

Lomitapide, mipomersen: Two novel agents for homozygous familial hypercholesterolemia

Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism that is characterized by a significant elevation in levels of low-density lipoprotein cholesterol (LDL-C), and patients are at very high risk for premature coronary heart disease (CHD). The etiology of FH includes known mutations in the gene of the LDL receptor, LDLR; the gene of apolipoprotein B, apo B; and the proprotein convertase subtilisin/kexin type 9 gene, PCSK9. The National Lipid Association Expert Panel on Familial Hypercholesterolemia has provided recommendations for the screening and treatment of patients with FH. Early identification and aggressive treatment of FH in individual patients, as well as screening of all first-degree relatives, are recommended to minimize the risk for premature CHD. Similar to patients with conventional hypercholesterolemia, patients with FH should receive statins as initial treatment, but patients with FH may require higher doses of statins, more potent statins, statin-based combination therapy, or adjunctive therapies. Patients with FH who have additional risk factors for, or existing, cardiovascular disease or those with an inadequate response to initial statin therapy should have access to higher doses of the most efficacious statins; statins used in combination with other LDL-C-lowering agents should also be supported by formularies; additional treatments, such as LDL-C apheresis or novel therapies, may also be required to achieve acceptable LDL-C levels. New treatment approaches include mipomersen, which was approved by the FDA in January 2013. Mipomersen is an oligonucleotide inhibitor of apolipoprotein B-100 synthesis (called an antisense inhibitor) indicated as an adjunct to lipid-lowering medications and diet to reduce LDL-C, apolipoprotein B, total cholesterol, and non-high density lipoprotein-cholesterol (non-HDL-C) levels in patients with homozygous FH (HoFH). The microsomal transfer protein lomitapide has also received FDA approval for use only in patients with HoFH. Other novel treatments currently in development include PCSK9 inhibitors. Therapies such as apheresis are likely more expensive than simple therapy with a statin but may be needed to achieve long-term reductions in complications from nonfatal and fatal cardiovascular events and hospitalizations related to myocardial infarction, cardiac revascularization, and stroke in FH patients. The cost-effectiveness of this more aggressive therapy has not been determined and should be studied. Utilization of published guidelines and the recommendations from the National Lipid Association will help to optimize the management of patients with FH.

Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial

AimsA randomized, double-blind, placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, in patients who are statin intolerant and at high risk for cardiovascular disease (CVD).Methods and resultsThirty-three subjects, not receiving statin therapy because of statin intolerance, received a weekly subcutaneous dose of 200 mg mipomersen or placebo (2:1 randomization) for 26 weeks. The primary endpoint was per cent change in LDL cholesterol (LDL-c) from the baseline to Week 28. The other efficacy endpoints were per cent change in apoB and lipoprotein a [Lp(a)]. Safety was determined using the incidence of treatment-emergent adverse events (AEs) and clinical laboratory evaluations. After 26 weeks of mipomersen administration, LDL-c was reduced by 47 ± 18% (P < 0.001 vs. placebo). apoB and Lp(a) were also significantly reduced by 46 and 27%, respectively (P < 0.001 vs. placebo). Four mipomersen (19%) and two placebo subjects (17%) discontinued dosing prematurely due to AEs. Persistent liver transaminase increases ≥3× the upper limit of normal were observed in seven (33%) subjects assigned to mipomersen. In selected subjects, liver fat content was assessed, during and after treatment, using magnetic resonance spectroscopy. Liver fat content in these patients ranged from 0.8 to 47.3%. Liver needle biopsy was performed in two of these subjects, confirming hepatic steatosis with minimal inflammation or fibrosis.ConclusionThe present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD. The long-term follow-up of liver safety is required.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00707746

Nutritional Repletion of Children with Severe Acute Malnutrition Does Not Affect VLDL Apolipoprotein B-100 Synthesis Rate ,

VLDL apo B-100 is essential for the secretion of liver fat. It is thought that synthesis of this lipoprotein is impaired in childhood severe acute malnutrition (SAM), especially in the edematous syndromes, and that this contributes to the common occurrence of hepatic steatosis in this condition. However, to our knowledge, it has not been confirmed that VLDL apo B-100 synthesis is slower in edematous compared with nonedematous SAM and that it is impaired in the malnourished compared with the well-nourished state. Therefore, VLDL apo B-100 kinetics were measured in 2 groups of children with SAM (15 edematous and 7 nonedematous), aged 4–20 mo, at 3 stages during treatment. Measurements were done at 4 ± 1 d postadmission, mid- catch-up growth in weight, and at recovery (normal weight-for-length). VLDL apo B-100 synthesis was determined using stable isotope methodology to measure the rate of incorporation of 2H3-leucine into its apoprotein moiety. The fractional and absolute synthesis of VLDL apo B-100 did not differ between the groups or from the initial malnourished stage to the recovery stage. Concentrations of VLDL apo B-100 were greater in the edematous than in the nonedematous group (P < 0.04) and did not differ from the initial stage to recovery. The data indicate that VLDL apo B-100 synthesis is not reduced when children develop either edematous or nonedematous SAM.

Apolipoprotein B synthesis inhibition: results from clinical trials

Mipomersen is a second-generation antisense oligonucleotide developed to inhibit the synthesis of apolipoprotein B-100 in the liver. In this review we will summarize the results of recent preclinical and clinical studies addressing safety and low-density lipoprotein-cholesterol (LDL-c) lowering efficacy of this new compound. In phase 3 clinical trials, mipomersen has been shown to significantly reduce LDL-c in patients with homozygous and heterozygous familial hypercholesterolemia on maximally tolerated lipid-lowering therapy. Injection site reactions, flu-like symptoms and increases in liver transaminases were the main adverse events. A recent safety study, designed to investigate the effects of mipomersen on intrahepatic triglyceride content, failed to show evidence of clinically relevant hepatic steatosis after 13 weeks of treatment. Mipomersen is a new agent to lower LDL-c in patients at increased risk of cardiovascular disease and/or intolerant to statins. Whereas safety concerns have focused on hepatic fat accumulation, to date no evidence of clinically relevant increases of intrahepatic triglyceride content are reported. Ongoing and future studies are eagerly awaited to assess the impact of mipomersen on hepatic triglyceride content after prolonged exposure.

Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia

To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change -0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound.

LDL-C-Lowering therapy: Current and future therapeutic targets

Recent trials have emphasized that more intensive low-density lipoprotein cholesterol (LDL-C) lowering results in a further reduction in cardiovascular disease risk. Uptitration of statins has limited incremental LDL-C-lowering effects and leads to an increased incidence of side effects. Therefore, attention has shifted toward alternative LDL-C-lowering modalities. Several promising compounds have entered the clinical trial arena, although with mixed results. Acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) inhibitors failed to show benefit. Microsomal triglyceride transfer protein and squalene synthase inhibitors, in spite of beneficial lipid profile changes, have shown adverse event profiles. In contrast, inhibitors of intestinal cholesterol absorption have shown LDL-C-lowering efficacy associated with few side effects. The inhibition of apolipoprotein B100 synthesis by antisense oligonucleotides has now been tested in phase 2 clinical trials, with promising results. Finally, compounds modifying protein convertase subtilisin/kexin type 9 levels are currently in the preclinical phase. In the present article, we discuss these LDL-C-lowering strategies.