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Pathophysiology of Diabetic Dyslipidaemia: Where Are We?

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Pathophysiology of Diabetic Dyslipidaemia: Where Are We? Diabetologia (2015) 58:886–899 DOI 10.1007/s00125-015-3525-8 REVIEW Pathophysiology of diabetic dyslipidaemia: where are we? Bruno Vergès Received: 25 November 2014 /Accepted: 19 January 2015 /Published online: 1 March 2015 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Cardiovascular disease is a major cause of morbid- retinol-binding protein 4, may also contribute to the ity and mortality in patients with type 2 diabetes mellitus, with development of dyslipidaemia in patients with type 2 a two- to fourfold increase in cardiovascular disease risk com- diabetes. pared with non-diabetic individuals. Abnormalities in lipid metabolism that are observed in the context of type 2 diabetes are among the major factors contributing to an increased car- Keywords Cardiovascular disease . Dyslipidaemia . diovascular risk. Diabetic dyslipidaemia includes not only HDL-cholesterol (HDL-C) . Insulin resistance . quantitative lipoprotein abnormalities, but also qualitative LDL-cholesterol (LDL-C) . Lipid metabolism . Review . and kinetic abnormalities that, together, result in a shift to- Triglycerides . Type 2 diabetes mellitus wards a more atherogenic lipid profile. The primary quantita- tive lipoprotein abnormalities are increased triacylglycerol (triglyceride) levels and decreased HDL-cholesterol levels. Abbreviations Qualitative lipoprotein abnormalities include an increase in ABCA1 ATP-binding cassette protein 1 large, very low-density lipoprotein subfraction 1 (VLDL1) ABCG1 ATP-binding cassette G1 and small, dense LDLs, as well as increased triacylglycerol Apo Apolipoprotein content of LDL and HDL, glycation of apolipoproteins and ARF-1 ADP ribosylation factor 1 increased susceptibility of LDL to oxidation. The main kinetic CETP Cholesteryl ester transfer protein abnormalities are increased VLDL1 production, decreased ChREBP Carbohydrate responsive element-binding VLDL catabolism and increased HDL catabolism. In addition, protein even though LDL-cholesterol levels are typically normal in ER Endoplasmic reticulum patients with type 2 diabetes, LDL particles show reduced FOXO1 Forkhead box protein O1 turnover, which is potentially atherogenic. Although the path- HMG-CoA 3-Hydroxy-3-methylglutaryl coenzyme A ophysiology of diabetic dyslipidaemia is not fully understood, LCAT Lecithin–cholesterol acyltransferase the insulin resistance and relative insulin deficiency ob- ICAM-1 Intercellular adhesion molecule 1 served in patients with type 2 diabetes are likely to IDL Intermediate-density lipoprotein contribute to these lipid changes, as insulin plays an LPL Lipoprotein lipase important role in regulating lipid metabolism. In addi- LRP LDL receptor–related protein tion, some adipocytokines, such as adiponectin or MTP Microsomal triacylglycerol transfer protein PERPP Post-ER presecretory proteolysis PI3K Phosphatidylinositol 3-kinase B. Vergès (*) Service Endocrinologie, Diabétologie et Maladies Métaboliques, PIP2 Phosphatidylinositol 4,5-bisphosphate Hôpital du Bocage, 2 bd Maréchal de Lattre de Tassigny, PIP3 Phosphatidylinositol 3,4,5-trisphosphate 21000 Dijon, France PLTP Phospholipid transfer protein e-mail: [email protected] RBP4 Retinol-binding protein 4 B. Vergès PTP-1B Protein-tyrosine phosphatase 1B INSERM CRI 866, Medicine University, Dijon, France SREBP Sterol regulatory element-binding protein Diabetologia (2015) 58:886–899 887 Introduction density, ranging from chylomicrons to VLDL, intermediate- density lipoprotein (IDL), LDL and HDL (Fig. 1). The risk of cardiovascular disease and cardiovascular mortal- ity is significantly increased in patients with type 2 diabetes Postprandial lipidaemia and chylomicrons mellitus relative to healthy individuals [1, 2]. A major contrib- utor to the increased cardiovascular risk associated with type 2 Dietary lipids are absorbed by the enterocytes via pas- diabetes is dyslipidaemia, which encompasses abnormalities sive diffusion or specific transporters (e.g. CD36 for in all lipoproteins [3–5]. Lipid abnormalities observed in type NEFA and Niemann-Pick C1-like 1 protein [NPC1L1] 2 diabetes are not only quantitative, but also qualitative and for cholesterol). Within the enterocytes, triacylglycerols kinetic in nature [6–8]. A number of factors may contribute to (triglycerides), cholesteryl esters and other lipids (phos- the changes in lipid metabolism in patients with type 2 pholipids and small amounts of unesterified cholesterol) diabetes, including insulin resistance and/or relative are associated with apolipoprotein (Apo)B-48 (as well insulin deficiency, adipocytokines (e.g. adiponectin), and as ApoA-IV and ApoA-I) to form chylomicrons in a hyperglycaemia [6–8]. The aim of this review is to briefly process involving microsomal triacylglycerol transfer describe normal lipoprotein metabolism, including the role protein (MTP) and fatty acid transport proteins. of insulin, to describe the pathophysiology of the lipid abnor- Chylomicrons are then exported into lymph and subse- malities observed in individuals with type 2 diabetes, and to quently into the blood. ApoB-48 synthesis by the gut discuss how these lipid abnormalities relate to the develop- occurs continuously; however, lipidation to form chylo- ment of cardiovascular disease. microns is dependent on the availability of lipids and occurs mainly after meals. Lipoprotein lipase (LPL), which is attached to the Overview of normal lipoprotein metabolism luminal surface of endothelial cells and present mostly in muscles, the heart and the adipose tissue, plays a Lipids are transported within body fluids in the form of lipo- major role in chylomicron clearance by hydrolysing tri- protein particles, which are classified according to their acylglycerols and liberating NEFA into the circulation. Chylomicrons ApoB-48 Insulin 3 + + 3 LPL NEFA LPL ApoB-48 VLDL IDL LDL ApoB-100 ApoB-100 ApoB-100 Chylomicron remnants NEFA 4 CE LDL-R Insulin LRP LDL-R – – + + 1 ABCG1 Peripheral cell HSL TAG Liver SR-B1 CETP NEFA ABCA1 ApoA-I ApoA-I HL LCAT 5 ApoA-I HDL2 HDL3 Adipose tissue 2 Insulin HDLn Fig. 1 An overview of human lipoprotein metabolism and the effects of Insulin increases LDL receptor (LDL-R) expression. CE, cholesterol ester; insulin on lipoprotein metabolism. (1) Insulin inhibits hormone-sensitive CETP, cholesteryl ester transfer protein; HDLn, nascent HDL HL, hepatic lipase. (2) Insulin inhibits hepatic VLDL production. (3) Insulin activates lipase; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase; SR-B1, LPL. (4) Insulin increases LRP expression on the plasma membrane. (5) scavenger receptor B1; TAG, triacylglycerol 888 Diabetologia (2015) 58:886–899 The chylomicron remnants produced by the lipolysis of As with chylomicrons, triacylglycerols from VLDLs are chylomicrons are taken up by the liver via the LDL hydrolysed by LPL in plasma, producing NEFA to be used receptor (Fig. 1) in conjunction with the LDL as fuel in the heart and skeletal muscle or for storage within receptor-related protein (LRP), both of which bind adipocytes (as triacylglycerols). The progressive triacylglyc- ApoE. erol depletion of VLDLs induces the transfer of a portion of the lipoprotein surface layer (including phospholipids, ApoC VLDLs and IDLs and ApoE) to HDLs and leads to the formation of IDLs [8]. Approximately 90% of IDLs are converted into LDL through Lipids are exported from the liver into the blood as VLDLs. further lipolysis involving hepatic lipase, which has both tri- The first step of VLDL assembly takes place in the rough acylglycerol lipase and phospholipase activities, whereas the endoplasmic reticulum (ER) where ApoB-100 is rest is cleared by the liver (via LRP or LDL receptors). cotranslationally and post-translationally lipidated by MTP, forming pre-VLDL [9, 10]. In the absence of adequate core LDLs lipids and/or MTP, partially translocated ApoB is exposed to the cytosol and subjected to degradation via the ubiquitin– LDL, the major transporter of cholesterol within the blood, proteasome system. During the second step, pre-VLDL is fur- comprises a core of esterified cholesterol molecules enclosed ther lipidated late in the ER compartment to form VLDL2, in a shell of phospholipids and unesterified cholesterol, to- exiting the ER compartment via Sar1 (a GTPase)/coat protein gether with a single molecule of ApoB-100. LDL is taken up II (COPII) vesicles that fuse to the cis side of the Golgi appa- into cells via receptor-mediated endocytosis, which involves, ratus. In the Golgi apparatus, VLDL2 can be converted into first, the binding of LDL–ApoB-100 to the LDL receptor on larger VLDL1 by the addition of lipids (Fig. 2). At this stage, the plasma membrane of hepatic and other tissues, then the VLDL particles may also be degraded via post-ER internalisation of the LDL-receptor complex via endocytosis, presecretory proteolysis (PERPP) [11]. The formation of followed by fusion with lysozymes, which contain a number VLDL1 depends on factors such as ADP ribosylation factor of catabolic enzymes. Proprotein convertase subtilisin/kexin 1 (ARF-1), phospholipase D1 and extracellular signal- type 9 (PCSK9) plays a key role in regulating LDL-receptor regulated kinase 2 (ERK2), which are involved in membrane activity by binding the LDL-receptor/LDL complex and trafficking between the ER and the Golgi apparatus or in the directing the receptor away from recycling back to the surface formation of cytosolic lipid droplets [10]. and into the lysosomal catabolic pathway. Fig. 2 An overview of VLDL VLDL assembly
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