The role of ANGPTL3 in controlling lipoprotein metabolism
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REVIEW
The role of ANGPTL3 in controlling lipoprotein metabolism Anna Tikka1 • Matti Jauhiainen1
Received: 30 October 2015 / Accepted: 16 December 2015 Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract 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. ANGPTL3deficiency 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 ANGPTL3deficiency induced FHBL2. Keywords Triglycerides Lipoprotein metabolism ANGPTL3 FHBL2 LPL
Introduction Dietary fats are transported in the circulation in lipoprotein particles, lipid-apolipoprotein complexes containing a surface of phospholipid monolayer together with free cholesterol and structural apolipoproteins (apo) and a hydrophobic core including cholesterol esters and triglycerides (TG) [1, 2]. In humans, TGs are packed and secreted in the small intestine in apoB-48-containing chylomicrons (CM) and in the liver in apoB-100 containing very low
& Anna Tikka [email protected] 1
National Institute for Health and Welfare. Genomics and Biomarkers Unit, Biomedicum, Haartmaninkatu 8, 00250 Helsinki, Finland
density lipoproteins (VLDL) [1, 2]. TG in CM and VLDL are hydrolyzed in circulation by lipoprotein lipase (LPL) [3]. The resulting free fatty acids are taken up by tissues primarily via the function of CD36 transporter [4]. After deprivation of TG, CM, and VLDL remnants are cleared via specific liver receptors. Some VLDL remnants are converted in circulation, via hepatic lipase (HL) function, into cholesterol-rich low density lipoproteins (LDL). LDL-receptors recognize LDL-bound apoB-100, resulting in the uptake of the circulating LDL, mainly by the liver and by the steroidogenic tissues [3]. Another class of lipoproteins, high density lipoproteins (HDL), are functionally important in reverse cholesterol transport, to clear excess accumulated cholesterol from the periphery, and transport it back to the liver for excretion [5]. Disturbances in lipoprotein metabolism by genetic variants in genes affecting LPL activity (ANGPTL3, APOC3, APOC2, APOA5), remnant clearance (APOE, LIPC, LRP1), LDL receptor activity (PCSK9, LDLR), lipoprotein secretion (APOB, MTP) and HDL (APOA1, ABCA1) have been detected in humans [6, 7]. High blood levels of saturated fat and cholesterol are major risk factors for coronary heart disease (CHD). Lipids within apoB-containing lipoproteins can accumulate in arterial intima and result in plaque formation and the development of atherosclerosis [8]. LDL-Cholesterol is a major cause for the generation o
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