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Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n  = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n  = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n  = 19). Fifty-one patients (males, n  = 27; females, n  = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 . The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.

Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene–diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile after weight loss and in response to a given diet, among overweight European adults participating in the Diet Obesity and Genes study. By multiple linear regressions, 240 SNPs in twenty-four candidate genes were investigated for SNP main and SNP–diet interaction effects on total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG after an 8-week low-energy diet (only main effect), and a 6-month ad libitum weight maintenance diet, with different contents of dietary protein or glycaemic index. After adjusting for multiple testing, a SNP–dietary protein interaction effect on TAG was identified for lipin 1 (LPIN1) rs4315495, with a decrease in TAG of − 0·26 mmol/l per A-allele/protein unit (95 % CI − 0·38, − 0·14, P= 0·000043). In conclusion, we investigated SNP–diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism pathways, and identified one significant interaction between LPIN1 rs4315495 and dietary protein for TAG concentration.

Searching for genes in which loss-of-function mutations confer protection against disease is a strategy to identity drug targets. This study reports an association between loss-of-function mutations in ANGPTL4 and protection against coronary artery disease. Although genomewide association studies have identified more than 56 loci associated with the risk of coronary artery disease, 1 – 3 the disease-associated variants are typically common (minor-allele frequency >5%) and located in noncoding sequences; this has made it difficult to pinpoint causal genes and affected pathways. This lack of a causal mechanism has in part hindered the immediate translation of the findings of genomewide association studies into new therapeutic targets. However, the discovery of rare or low-frequency coding-sequence variants that affect the risk of coronary artery disease has facilitated advances in the prevention and treatment of disease. The most recent example . . .

Aims/hypothesis Lipoprotein lipase (LPL) is produced by adipose tissue and skeletal muscle, but acts on plasma lipoproteins after being transported to endothelial binding sites. Insulin resistance is associated with decreased plasma LPL mass. We investigated the effects of insulin sensitisation on tissue-specific LPL expression and transport in patients with type 2 diabetes. Materials and methods Arterio-venous gradients of plasma LPL activity and mass across adipose tissue and skeletal muscle were measured in 16 type 2 diabetic patients in a double-blind, placebo-controlled, cross-over randomised trial of rosiglitazone. In vivo LPL rate of action was assessed by tissue-specific arterio-venous triglyceride concentration gradients. LPL mRNA was quantified in adipose tissue and skeletal muscle biopsies. Results Adipose tissue released large quantities of inactive LPL (p<0.001); skeletal muscle released small amounts of active LPL (p<0.01). Rosiglitazone increased adipose tissue release of LPL mass (+35%, p=0.04) and decreased the release of active LPL from skeletal muscle (-57%, p=0.03). Rosiglitazone increased adipose tissue and skeletal muscle LPL mRNA, but did not affect adipose tissue LPL rate of action or activity. Adipose tissue release of LPL mass correlated with systemic LPL mass concentrations (r=0.47, p=0.007), suggesting that the rate of adipose tissue release of LPL mass is a major determinant of systemic LPL mass concentrations. Conclusions/interpretation LPL transport from adipose tissue and skeletal muscle are regulated differently. In adipose tissue, rosiglitazone increases LPL mRNA abundance and LPL transport rate and possibly increases endothelial binding sites for LPL, but affects neither tissue LPL activity nor LPL rate of action.

The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.

The objective of this study was to test how the genetic polymorphisms located within the lipoprotein lipase (LPL) locus would modulate the relationship between a diet high in carbohydrate and insulin resistance related traits in metabolic syndrome adults. A one year nutritional intervention study focusing on education to increase dietary intake of whole grain, vegetable and fruit, and to reduce the intake of sodium, simple sugar and dietary fat (especially cooking oil and pork lard) was conducted. Two districts in Shanghai, China were randomly selected to be the intervention and control group, and patients (n=235) with metabolic syndrome within these two districts were selected based on a multistage sampling method. Fasting glucose was reduced in rs328 CC homozygotes (p=0.028) but not G carriers (p=0.686) within the intervention group. Also an ancillary study with greater statistical power by combining the baseline measurements across both the intervention and control groups was conducted to test the cross-sectional statistical interactions between carbohydrate/fat and lipoprotein lipase genotypes for homeostasis model assessment of insulin resistance/insulin/fasting glucose. Increased carbohydrate intakes were positively associated with homeostasis model assessment of insulin resistance and insulin in rs328 G carriers but not CC homozygotes (p for interaction was 0.025). These results indicate that diet high in carbohydrate may not be suitable for metabolic syndrome rs328 G carriers, calling for the development of personalized dietary intervention for metabolic syndrome subjects.

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. The present study was designed to determine whether 14-week CLA supplementation as triacylglycerols (3·76 g) with a 50 : 50 combination of the two main isomers (35 % cis-9, trans-11 and 35 % trans-10, cis-12) added to flavoured yoghurt-like products was able to alter body composition in healthy subjects and to alter the expression of several key adipose tissue genes (PPAR γ, lipoprotein lipase (LPL), hormone-sensitive lipase (HSL) and uncoupling protein 2 (UCP-2)). Forty-four healthy subjects were randomly assigned to consume daily either a CLA-supplemented yoghurt-like product or a placebo yoghurt for 98 d. There were no significant effects of CLA supplementation on body weight, fat mass or free fat mass. Basal energy expenditure expressed as kg free fat mass increased significantly in the CLA group (123·3 (sem 2·5) kJ/kg free fat mass per d on day 98 v. 118·7 (sem 2·3) kJ/kg free fat mass per d on day 0, P = 0·03). PPAR γ mRNA gene expression increased significantly with CLA supplementation (53 (sem 20) %, P < 0·01) and a significant reduction in mRNA levels of HSL was observed ( − 42 (sem 7) %, P = 0·01). The levels of UCP-2 and LPL mRNA were not affected. The present results suggest that a 98 d supplementation diet with a 50 : 50 mixture of the two CLA isomers cis-9, trans-11 and trans-10, cis-12 in a dairy product was unable to alter body composition, although a significant increase in the RMR has been induced. Moreover, changes in mRNA PPAR γ and HSL in adipose tissue were recorded.

In this study, investigators found that APOC3, a key regulator of triglyceride metabolism, had a profound and clinically relevant effect on triglyceride levels through a mechanism that is independent of lipoprotein lipase. The familial chylomicronemia syndrome is a rare autosomal recessive disease characterized by the buildup in the blood of fat particles called chylomicrons (chylomicronemia), severe hypertriglyceridemia, and the risk of recurrent and potentially fatal pancreatitis and other complications. 1 It is caused by mutations in the gene encoding LPL or, less frequently, by mutations in genes encoding other proteins necessary for LPL function. 2 Patients with this syndrome have plasma triglyceride levels ranging from 10 to 100 times the normal value (1500 to 15,000 mg per deciliter [17 to 170 mmol per liter]), eruptive xanthomas, arthralgias, neurologic symptoms, lipemia retinalis, and hepatosplenomegaly. 3 Nearly . . .

Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5-/- mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific mAbs, the binding of LPL Abs to heart and BAT capillaries (relative to CD31 or GPIHBP1 Abs) was reduced in Apoa5-/- mice. LPL levels in the postheparin plasma were also lower in Apoa5-/- mice. We suspected that a recent biochemical observation - that APOA5 binds to the ANGPTL3/8 complex and suppresses its capacity to inhibit LPL catalytic activity - could be related to the low intracapillary LPL levels in Apoa5-/- mice. We showed that an ANGPTL3/8-specific mAb (IBA490) and APOA5 normalized plasma triglyceride (TG) levels and intracapillary LPL levels in Apoa5-/- mice. We also showed that ANGPTL3/8 detached LPL from heparan sulfate proteoglycans and GPIHBP1 on the surface of cells and that the LPL detachment was blocked by IBA490 and APOA5. Our studies explain the hypertriglyceridemia in Apoa5-/- mice and further illuminate the molecular mechanisms that regulate plasma TG metabolism.