Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: insights on insulin resistance, inflammation, and atherogenic dyslipidemia
- 1 April 2016
- journal article
- review article
- Published by Springer Science and Business Media LLC in Endocrine
- Vol. 54 (3), 588-601
- https://doi.org/10.1007/s12020-016-0939-0
Abstract
Low-density lipoprotein (LDL) cholesterol plays a pivotal role in the pathogenesis of atherosclerotic cardiovascular disease (CVD). The discovery that proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a key regulator pathway for hepatic LDL receptor (LDLR) degradation sheds light on new uncovered issues regarding LDL-C homeostasis. Indeed, as confirmed by phase II and III clinical trials with monoclonal antibodies, targeting PCSK9 represents the newest and most promising pharmacological tool for the treatment of hypercholesterolemia and related CVD. However, clinical, genetic, and experimental evidence indicates that PCSK9 may be either a cause or an effect in the context of metabolic syndrome (MetS), a condition comprising a cluster of risk factors including insulin resistance, obesity, hypertension, and atherogenic dyslipidemia. The latter is characterized by a triad of hypertriglyceridemia, low plasma concentrations of high-density lipoproteins, and qualitative changes in LDLs. PCSK9 levels seem to correlate with many of these lipid parameters as well as with the insulin sensitivity indices, although the molecular mechanisms behind this association are still unknown or not completely elucidated. Nevertheless, this area of research represents an important starting point for a better understanding of the physiological role of PCSK9, also considering the recent approval of new therapies involving anti-PCSK9. Thus, in the present review, we will discuss the current knowledge on the role of PCSK9 in the context of MetS, alteration of lipids, glucose homeostasis, and inflammation.Keywords
Funding Information
- Fondazione Cariplo (2015-0552, 2012-0549)
This publication has 114 references indexed in Scilit:
- Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9Arteriosclerosis, Thrombosis, and Vascular Biology, 2015
- Selective Hepatic Insulin Resistance, VLDL Overproduction, and HypertriglyceridemiaArteriosclerosis, Thrombosis, and Vascular Biology, 2012
- Proprotein Convertase Subtilisin/Kexin Type 9 Interacts With Apolipoprotein B and Prevents Its Intracellular Degradation, Irrespective of the Low-Density Lipoprotein ReceptorArteriosclerosis, Thrombosis, and Vascular Biology, 2012
- Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemiaAtherosclerosis, 2012
- Lack of association between plasma PCSK9 and LDL-apoB100 catabolism in patients with uncontrolled type 2 diabetesAtherosclerosis, 2011
- Circulating Proprotein Convertase Subtilisin Kexin Type 9 Has a Diurnal Rhythm Synchronous With Cholesterol Synthesis and Is Reduced by Fasting in HumansArteriosclerosis, Thrombosis, and Vascular Biology, 2010
- Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humansJournal of Lipid Research, 2010
- Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genesProceedings of the National Academy of Sciences of the United States of America, 2003
- Insulin resistance and cardiovascular diseaseJCI Insight, 2000
- The role of the LDL receptor in apolipoprotein B secretionJCI Insight, 2000