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Atherosclerosis Supplements 16 (2015) 12–16 Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome Dipartimento di Medicina Interna e Specialità Mediche, UOS Centro Arteriosclerosi Università di Roma La Sapienza, Rome, Italy Diabetes and metabolic syndrome are associated with abnormal postprandial lipoprotein metabolism, with a significant delay in the clearance of many lipid parameters, including triglycerides and chylomicrons. Abnormal concentrations of plasma lipids can result fromchanges in the production, conversion, or catabolism of lipoprotein particles. Whereas the liver is involved in controlling serum lipid levelsthrough synthesis of liver derived triglyceride-rich lipoproteins and low-density lipoprotein metabolism, the intestine also has a major rolein lipoprotein production. Postprandial lipemia results from increases in apoB-48 availability, lipogenesis, and the synthesis and absorptionof cholesterol in the enterocytes. Increased intestinal lipoprotein production prolongs postprandial lipemia in patients with diabetes andMetS, and may contribute directly to atherogenesis in these patients.
2015 Elsevier Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus; Metabolic syndrome; Intestine; Cholesterol metabolism; Postprandial lipemia 1. Abnormalities of lipoprotein metabolism in diabetes density lipoprotein (VLDL)] to identify the mechanisms mellitus and metabolic syndrome responsible for AD. These studies have consistently re-ported that the major metabolic defects in AD are increased Dyslipidemia associated with diabetes mellitus and VLDL production, and reduced catabolism of LDL and its metabolic syndrome (MetS) is characterized by a clus- precursor, intermediate-density lipoprotein (IDL).
ter of metabolically interrelated lipoprotein abnormalities.
Overproduction of VLDL is particularly evident in Due to the elevated atherogenic potential of these abnor- patients with diabetes, where this abnormality is related malities they are usually comprehensively designated as to the plasma glucose level and indices of tissue insulin atherogenic dyslipidemia (AD). The phenotypic hallmarks sensitivity such as the HOMA index. In addition, intra- of AD are increased plasma triglycerides (TG), reduced abdominal and liver fat are also significant predictors of high-density lipoprotein cholesterol (HDL-C) and increased liver production of large TG-rich VLDL [1].
numbers of small, dense low-density lipoprotein (sdLDL) Assessment of HDL metabolism in subjects with dia- betes using a stable isotope method revealed a higher than Abnormal concentrations of plasma lipids can result normal mean fractional catabolic rate (FCR) of apoAI- from changes in the production, conversion, or catabolism HDL, strongly suggesting that HDL is catabolized more of lipoprotein particles. Therefore, several studies have rapidly in these patients. Therefore, the AD phenotype can investigated the kinetic parameters of apoB-containing result from: 1) increased production of VLDL, 2) a reduced lipoproteins [low-density lipoprotein (LDL) and very-low- catabolic rate of apoB-containing lipoproteins (IDL andLDL), and 3) an increased catabolic rate of HDL.
The liver plays a fundamental role in cholesterol home- * Department of Internal Medicine and Medical Specialties, UOS ostasis, because it processes cholesterol taken up from Atherosclerosis Center, La Sapienza University, Policlinico Umberto I, plasma lipoproteins and chylomicrons, and uses cholesterol Viale del Policlinico 155 - 00161 Rome, Italy. Tel.: +39 064450074;fax: +69 064440290.
to form bile acids that are subsequently secreted into the bile. As the major site of LDL catabolism, the liver also 1567-5688/ 2015 Elsevier Ireland Ltd. All rights reserved.
M. Arca / Atherosclerosis Supplements 16 (2015) 12–16 has a part in determining plasma LDL levels. As described More recent evidence indicates that the adipokine resistin elsewhere in this supplement [2], the liver is not the only is also involved in regulating chylomicron assembly. Plasma organ with an important role in this process: also the intes- resistin concentrations are elevated in MetS and associated tine plays an essential role. In diabetes mellitus or MetS, with insulin resistance [9]. In cultured hepatocytes, resistin chylomicrons produced in the intestine can accumulate in stimulates the overproduction of VLDL apo-B by increasing the circulation thereby influencing overall lipid and lipopro- the activity of the microsomal transfer protein (MTP), tein turnover. There are indications that chylomicrons and which plays a pivotal role in coupling triglycerides with cholesterol metabolism in the intestine are involved in apoB-48 in chylomicrons (Fig. 1), and by decreasing insulin regulating plasma LDL concentrations [3].
signaling [10].
Chylomicron assembly is also influenced by the avail- 2. Abnormalities in intestinal lipids and lipoprotein ability of cholesterol in enterocytes. Regulation of chy- metabolism in diabetes and metabolic syndrome lomicron cholesterol is depicted in Fig. 2. Cholesterol isabsorbed through a process facilitated by the Niemann- Patients with diabetes have abnormal post absorptive Pick C1-Like 1 (NPC1L1) protein, which plays the major lipoprotein metabolism, with a significant delay in the quantitative role in intestinal cholesterol absorption. In ad- postprandial clearance of many lipid parameters, including dition, ABCG5 and ABCG8 proteins regulate enterocyte triglycerides and chylomicrons, in spite of normal fasting cholesterol content by promoting its re-excretion into the levels [4]. Similar results have been observed in people with intestinal lumen throughout the intestinal villi.
MetS [5]. This is observed even if subjects are categorized NPC1L1 mRNA expression is elevated in patients with according to insulin resistance.
type 2 diabetes [11], suggesting that cholesterol absorption Chylomicrons are lipoprotein particles secreted by the is increased. Moreover, these patients also have increased intestine during the postprandial period. Their assembly expression of MTP, associated with reduced expression of is a complex, multistep process (Fig. 1), in which apoB- the cholesterol efflux transporters ABCG5 and ABCG8 48 synthesis of is one of the limiting factors [6]. Duez (Fig. 3). Taken together, this pattern strongly support the et al. hypothesized that abnormalities in the synthesis notion that diabetic patients have elevated amounts of of intestinally-derived apolipoproteins drive the prolonged enterocyte cholesterol available for chylomicron assembly.
postprandial phase in insulin-resistant subjects, and ex- Based on these observations, one could hypothesize that amined the relationship between insulin resistance and the modulating intestine cholesterol metabolism might be a the rate of production of intestinal lipoproteins [7]. They useful strategy for controlling the exaggerated postprandial found that ApoB-48 was produced at a significantly higher lipemia in insulin-resistant conditions (diabetes mellitus and rate in hyperinsulinemic, insulin-resistant subjects and that MetS). Ezetimibe is a compound that specifically reduces this correlated with fasting plasma insulin concentrations.
intestinal cholesterol absorption by inhibiting the activity Consistent with this observation, others have reported that of NPC1L1 [12]. Administration of ezetimibe to men with insulin administration decreases levels of circulating apoB- moderate primary hypercholesterolemia increases the frac- 48-containing lipoproteins [8] tional catabolic rate of apoB-100-containing lipoproteins, Fig. 1. Regulation of chylomicron synthesis. ApoB-48, apoproptein B-48; ABCG, ATP-binding cassette sub-family G member; ACAT, Acyl-CoA:cholesterol acyltransferase; HMGCoA, hydroxy-3-methyl-glutaryl-CoA. (Reproduced with permission from Diabetes Care 2008; 31(Suppl. 2):S241–8.) M. Arca / Atherosclerosis Supplements 16 (2015) 12–16 Fig. 2. Chylomicron cholesterol derives from dietary, biliary and intestinal de novo synthesized cholesterol. NPC1-L1 regulates its absorption andABCG5 and ABCG8 regulate its excretion. MTP assembles the apoB-48 protein, cholesterol and other lipids to form the chylomicron, which is thensecreted into the lymph. (Reproduced with permission from Diabetes Care 2008 Feb;31 Suppl 2:S241–8 [6].) Fig. 3. Comparison of mRNA expression of intestinal proteins regulating cholesterol absorption and chylomicron composition in diabetic (n = 15)(black bars) and non-diabetic control patients (n = 17) (white bars) not receiving statin treatment. a) microsomal triglyceride transfer protein (MTP) andNiemann-Pick C1-like 1 (NPC1-L1); b) ATP-binding cassette, transporters G5 and G8 (ABCG5/G8). Mean ± SE, *p < 0.05, **p < 0.02 compared tocontrol subjects. (Reproduced with permission from Diabetologia 2006 May;49(5):1008–16 [11].) with an associated decrease in this lipoprotein fraction fasting state, and this difference remained statistically [13], which is considered the major mechanism of action significant during the entire postprandial phase. Postpran- of this drug. However, several studies have demonstrated dial levels of chylomicron triglycerides and the choles- that ezetimibe has a beneficial effect also on postpran- terol/triglyceride ratio were also significantly lower with dial triglyceride-rich lipoproteins in patients with type 2 ezetimibe, compared to placebo, as were the levels of apoB.
diabetes. For example, postprandial chylomicron apoB-48concentrations were about 50% lower in subjects with type 3. Contribution of insulin resistance-related 2 diabetes and hypercholesterolemia receiving simvastatin perturbation of intestinal lipid metabolism to + ezetimibe, compared with simvastatin + placebo (Fig. 4) cardiovascular risk in patients with diabetes or [14]. This decrease suggests that ezetimibe reduces the metabolic syndrome number of intestinal particles, confirming the results fromthe kinetic study in men with mixed hyperlipidemia cited During the postprandial phase, triglyceride-rich lipopro- teins (chylomicrons and VLDL) are converted into partially Chylomicron cholesterol content was also significantly hydrolyzed lipoproteins known as remnant-like particles lower after ezetimibe compared to placebo, even in the (RLPs) which represent transient lipoprotein particles rel- M. Arca / Atherosclerosis Supplements 16 (2015) 12–16 to increased hepatic synthesis of liver derived triglyceride-rich lipoproteins (VLDL), these conditions are associatedwith increased intestinal lipoprotein production. This resultsfrom increases in apoB-48 availability, lipogenesis, and thesynthesis and absorption of cholesterol in the enterocytes.
Increased intestinal lipoprotein production prolongs post-prandial lipemia in patients with diabetes and MetS, andmay contribute directly to atherogenesis in these patients.
Dr. Arca received lecture honoraria, consultancy fees and research funding from Merck Sharp & Dohme, Pfizer,Asta Zeneca, Kowa, Sanofi, Regeneron, Roche, Genzyme,Abbott, Boheringer, Aegerion, Mediolanum, SigmaTau, Fig. 4. Postprandial cholesterol, triglycerides, cholesterol/triglyceride Menarini, ISIS, Amgen.
ratio, and apoB-48 concentrations in chylomicrons with ezetimibe and This work was funded by an unrestricted grant by placebo treatment in patients with type 2 diabetes. *p < 0.05 by paired MSD Italia Srl. The sponsor had no role in reviewing samples t-test. (Reproduced with permission from Atherosclerosis. 2011 the literature, drafting or reviewing the paper, or in the decision to submit the manuscript for publication. All viewsexpressed are solely those of the author. The author would atively enriched in apoB and cholesterol. Therefore, exag- like to thank Editamed Srl for editorial assistance in the gerated postprandial lipemia may favor the production of preparation of the manuscript.
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