ERICH4 is not involved in the assembly and secretion of intestinal lipoproteins.

Background And Aims: The small intestine plays a central role in lipid metabolism, most notably the uptake of dietary fats that are packaged into chylomicrons and secreted into the circulation for utilisation by peripheral tissues. While microsomal triglyceride transfer protein (MTP) is known to play a key role in this pathway, the intracellular assembly, trafficking, and secretion of chylomicrons is incompletely understood.

Methods And Results: Using human transcriptome datasets to find genes co-regulated with MTTP, we identified ERICH4 as a top hit.

A suite of genome-engineered hepatic cells provides novel insights into the spatiotemporal metabolism of apolipoprotein B and apolipoprotein B-containing lipoprotein secretion.

Aims: Apolipoprotein B (APOB)-containing very LDL (VLDL) production, secretion, and clearance by hepatocytes is a central determinant of hepatic and circulating lipid levels. Impairment of any of the aforementioned processes is associated with the development of multiple diseases. Despite the discovery of genes and processes that govern hepatic VLDL metabolism, our understanding of the different mechanistic steps involved is far from complete.

VLDL Biogenesis and Secretion: It Takes a Village.

The production and secretion of VLDLs (very-low-density lipoproteins) by hepatocytes has a direct impact on liver fat content, as well as the concentrations of cholesterol and triglycerides in the circulation and thus affects both liver and cardiovascular health, respectively. Importantly, insulin resistance, excess caloric intake, and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. Cholesterol and triglycerides in remnant particles generated by VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease and have garnered increasing attention over the last few decades.

Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice.

The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is a pentameric protein complex localized at endosomes, where it facilitates the transport of numerous receptors from endosomes toward the plasma membrane. Recent studies have shown that the WASH complex plays an essential role in cholesterol and glucose homeostasis in humans and mice. To investigate the physiological importance of intestinal WASH, we ablated the WASH component WASHC1 specifically in murine enterocytes.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

Background: The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear.

Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.

Background And Aims: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.

Variants in the Gene Are Associated With a Favorable Cardiometabolic Risk Profile.

Background: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown.

Methods: Common and rare genetic variants in the gene locus were used as research instruments in the UK Biobank.

A novel role for GalNAc-T2 dependent glycosylation in energy homeostasis.

Objective: GALNT2, encoding polypeptide N-acetylgalactosaminyltransferase 2 (GalNAc-T2), was initially discovered as a regulator of high-density lipoprotein metabolism. GalNAc-T2 is known to exert these effects through post-translational modification, i.e.

Managing of Dyslipidaemia Characterized by Accumulation of Triglyceride-Rich Lipoproteins.

Purpose Of Review: The accumulation of triglyceride-rich lipoproteins (TRLs) in plasma in patients with familial chylomicronaemia syndrome (FCS) or severe hypertriglyceridemia is associated with an increased risk of potentially life-threatening pancreatitis. Elevated TRL levels have also been suggested to contribute to atherosclerotic cardiovascular disease (ASCVD). This review provides the latest progress that has been made in this field of research.

Large HDL particles negatively associate with leukocyte counts independent of cholesterol efflux capacity: A cross sectional study in the population-based LifeLines DEEP cohort.

Background And Aims: Leukocytosis, the expansion of white blood cells, is associated with increased cardiovascular risk. Studies in animal models have shown that high-density lipoprotein cholesterol (HDL-c) suppresses leukocytosis by mediating cholesterol efflux from hematopoietic stem and progenitor cells. HDL-c showed a moderate negative association with leukocyte numbers in the UK Biobank and Multi-Ethnic Study of Atherosclerosis.

Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates.

Programs to screen for Familial hypercholesterolemia (FH) are conducted worldwide. In Western societies, these programs have been shown to be cost-effective with hit/detection rates of 1 in 217-250. Thus far, there is no published data on genetic FH in the Gulf region.

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles.

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism.

Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.

Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.

Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells.

Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings.

LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967.

Taking One Step Back in Familial Hypercholesterolemia: Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans.

Objective: , encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of is absent in liver but mainly observed in immune cells. In this study, we set out to validate as a familial hypercholesterolemia gene.

Sharing lessons learnt across European cardiovascular research consortia.

Research consortia in Europe often compete with each other for skills, human and technical resources and, eventually, recognition of the scientific impact of their work. In response to the same EU Horizon2020 call, we received funding for our research project proposals to identify and validate novel drug targets for cardiovascular disease treatment. Each consortium followed a unique and independent research strategy.

Reduced CETP glycosylation and activity in patients with homozygous B4GALT1 mutations.

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls.

GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis.

Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice.

A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor.

Aims: Genome-wide association studies have previously identified INSIG2 as a candidate gene for plasma low-density lipoprotein cholesterol (LDL-c). However, we suspect a role for CCDC93 in the same locus because of its involvement in the recycling of the LDL-receptor (LDLR).

Methods And Results: Characterization of the INSIG2 locus was followed by studies in over 107 000 individuals from the general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, for associations of genetic variants with plasma lipids levels, with risk of myocardial infarction (MI) and with cardiovascular mortality.

The Future of Lipid-lowering Therapy.

The recent introduction of inhibitors of proprotein convertase subtilisin/kexin 9 to lower low-density lipoprotein (LDL) cholesterol on top of statins or as monotherapy is rapidly changing the landscape of treatment of atherosclerotic cardiovascular disease (ASCVD). However, existing lipid-lowering drugs have little impact on lipoprotein(a) (Lp(a)) or plasma triglycerides, two other risk factors for ASCVD. This review summarizes the evidence and the rationale to target Lp(a) and triglycerides and provides an overview of currently tested strategies to lower Lp(a), apolipoprotein C-III and angiopoietin-like protein 3.

The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance.

The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism.

N-Glycosylation Defects in Humans Lower Low-Density Lipoprotein Cholesterol Through Increased Low-Density Lipoprotein Receptor Expression.

Background: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation.

Methods: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)-deficiency CDG and PMM2 (phosphomannomutase 2)-deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels.

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred.

Rationale & Objective: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD.