The role of ANGPTL3 in controlling lipoprotein metabolism

Angiopoietin-like protein 3 (ANGPTL3) is a secretory protein regulating plasma lipid levels via affecting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of triglycerides and phospholipids. ANGPTL3-deficiency due to loss-of-function mutations in the ANGPTL3 gene causes familial combined hypobetalipoproteinemia (FHBL2, OMIM # 605019), a phenotype characterized by low concentration of all major lipoprotein classes in circulation. ANGPTL3 is therefore a potential therapeutic target to treat combined hyperlipidemia, a major risk factor for atherosclerotic coronary heart disease. This review focuses on the mechanisms behind ANGPTL3-deficiency induced FHBL2.Peer reviewe

In memoriam : Christian Ehnholm

Non peer reviewe

New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?

Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are at present the central molecular targets for therapies designed to reduce TRL, and there are new drugs emerging that suppress their expression or inhibit the function of these two key proteins. The medications targeting these components are biological, either human monoclonal antibodies or antisense oligonucleotides. In this article, we briefly review the mechanisms of action of ANGPTL3 and apoC-III, the reasons why they have been considered promising targets of novel therapies for CVD, as well as the current status and the most important results of their clinical trials. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Angiopoietin-like protein 3, an emerging cardiometabolic therapy target with systemic and cell-autonomous functions

Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.Peer reviewe

Lipoproteiini (a):n suurentunut pitoisuus on ateroskleroottisen valtimotaudin riskitekijä, jonka tehokas hoito mahdollistuu uusilla täsmälääkkeillä

Vertaisarvioitu. English abstract.Lipoproteiini (a) [Lp(a)] on LDL:n kaltainen kolesterolia kuljettava aterotromboottinen seerumin lipoproteiini ja ateroskleroottisen valtimotaudin itsenäinen riskitekijä. Ihmisten Lp(a)-pitoisuudet vaihtelevat suuresti ja määräytyvät pääosin perinnöllisesti. Suurentunut Lp(a)-pitoisuus liittyy sepelvaltimotautiin, sydän- ja aivoinfarktiin, perifeeriseen valtimotautiin ja aorttaläpän ahtaumaan. Seerumin Lp(a)-pitoisuuden mittaamista suositellaan erityisesti familiaalisen hyperkolesterolemian (FH) yhteydessä sekä silloin, kun potilaan suvussa on varhaisia valtimotautitapauksia tai potilaan valtimotautien kokonaisriski on suuri tai erittäin suuri. Statiinilääkitys ei pienennä Lp(a)-pitoisuutta. Sen sijaan LDL-kolesterolipitoisuutta voimakkaasti pienentävät PCSK9:n estäjät pienentävät Lp(a)-pitoisuutta noin 30 % ja näyttävät pienentävän valtimotautiriskiä myös tätä kautta. Lähivuosina markkinoille on tulossa seerumin Lp(a)-pitoisuutta erittäin tehokkaasti pienentäviä RNA:han kohdentuvia täsmälääkkeitä.Peer reviewe

Ateroskleroottisten sydän- ja verisuonitautien uudet hoitokohteet

English summaryPeer reviewe

Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Peer reviewe

Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors

In atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MO and GM-MO, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MO, the M-MO expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MO foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MO strongly suppressed the high baseline expression of CCL2, whereas in GM-MO the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.Peer reviewe