Abstract
Low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and chylomicrons are referred to as apolipoprotein B (apoB)-containing lipoproteins and exhibit pro-atherogenic characteristics. VLDL, which transport endogenous lipids, are produced by the liver, while chylomicrons, which transport diet-derived lipids, are produced by the intestine. After lipoprotein secretion, triglycerides are hydrolyzed by lipoprotein lipase, and fatty acids are taken up by the cells to provide energy (in the muscle) or to be stored (in adipose tissue). The resulting remnant lipoproteins become enriched in cholesterol and can be taken up by cells.
Insulin plays a regulatory key role in the metabolism of these triglyceride (TG)-rich lipoproteins. Insulin resistance is a condition of reduced responsiveness of tissues (liver, muscle, and adipose tissue) to normal circulating levels of insulin, and is a feature of several diseases, including type 2 diabetes, obesity, dyslipidemia, and hypertension. As a result, insulin production increases to maintain normal levels of blood glucose. Insulin resistance can generate lipoprotein abnormalities, such as increased plasma levels of VLDL triglyceride and apoB100, reduced plasma levels of HDL and apoA-I, and relatively normal LDL levels with increase of small dense LDL particles.
TG-rich lipoproteins induce vascular dysfunction: endothelial function becomes impaired in the presence of hypertriglyceridemia, with increased expression of adhesion molecules and chemotactic factors involved in the inflammatory process; moreover, lipid deposition within arterial macrophages is enhanced, thus contributing to the generation of foam cells. These findings are in line with the idea that TG-rich lipoproteins may play a key role in the early stages of atherogenesis.
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Keywords
- Insulin Resistance
- Microsomal Triglyceride Transfer Protein
- Chylomicron Remnant
- Remnant Lipoprotein
- VLDL Secretion
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Apolipoprotein B (apoB)-containing lipoproteins are believed to be atherogenic and include chylomicrons, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL). Chylomicrons, which transport lipids derived from diet, are produced by the intestine, while VLDL, which transport endogenous lipids, are produced by the liver. Both are produced at the surface of the endoplasmic reticulum (ER). After secretion of these lipoproteins, triglycerides are hydrolyzed by lipoprotein lipase, and fatty acids are taken up by the cells to provide energy (in the muscle) or to be stored (in adipose tissue). Remnant lipoproteins are enriched in cholesterol and can be taken up by cells, and VLDL can be converted to LDL. Plasma triglycerides are mainly produced in the liver and the intestine.
TG-Rich Lipoproteins Secretion by Liver and Intestine
TG-rich lipoproteins (TGRLs) comprise both hepatically derived apoB100-containing very low-density lipoprotein (VLDL) and intestinally derived apoB48-containing chylomicrons [1, 2]. TGRLs are assembled in the liver by hepatocytes and in the intestine by jejunal enterocytes. These lipoproteins are spherical particles, consisting of a neutral lipid core (mainly cholesteryl esters and TG) surrounded by a monolayer of lipids (phospholipids and free cholesterol) and apolipoproteins. Apolipoprotein B (apoB) is the main protein in both VLDL and chylomicrons; each particle contains a single apoB molecule. Human apoB100 is secreted exclusively by the liver in VLDL, while apoB48 is secreted exclusively by the intestine in chylomicrons. ApoB is synthesized in two isoforms: apoB100 in the liver and apoB48 (deriving from the same gene of apoB100) in the intestine [3, 4]. ApoB is synthesized in coordination with MTP (microsomal triglyceride transfer protein) expression and activity [5]. In the presence of lipids, nascent apoB is quickly lipidated by MTP; in the absence of lipids, nascent apoB is ubiquitinylated and degraded. ApoB levels are in fact highly regulated by multiple distinct degradative pathways [6]. When lipid availability is low or MTP activity is reduced, apoB is cotranslationally targeted for ubiquitinylation and degradation by the proteasome [7–9]. Alternatively, fully assembled apoB particles can undergo reuptake by cells through interaction with the LDL receptor or with specific proteoglycans [10]. In addition, dietary polyunsaturated fatty acids (PUFAs) induce the degradation of newly synthesized apoB through a non-proteasome, post-ER pathway [6]; this process occurs in the presence of normal triglyceride levels, resulting in reduced VLDL secretion.
Lipoprotein assembly starts with apoB transcription and translocation into the lumen of the endoplasmic reticulum (ER). Here, lipid droplets are added to apoB, facilitated by the activity of MTP, thus resulting in a premature form of apoB-containing particle. Next, the addition of neutral lipids increases the size of the nascent particle that is then transported through the Golgi and secreted into the hepatic vein for the hepatic lipoproteins and in the lymphatic system for intestinal lipoproteins.
VLDL Assembly and Secretion
ApoB100 is the major structural protein of VLDL, exhibits a highly lipophilic nature, and contains two domains able to interact irreversibly with the neutral lipids present in the lipoprotein core [11]. The intrahepatic assembly of apoB into VLDL can be divided into two steps (Fig. 6.1). Due to its lipophilic nature, apoB folding and stability depends upon the simultaneous addition of lipids; this process is related to the activity of MTP [12, 13]. MTP is an ER-resident protein that, following heterodimerization with the small subunit protein disulfide isomerase (PDI), catalyzes the transfer of polar (phospholipids) and neutral (triglycerides) lipids to nascent apoB during its translocation through a protein channel in the membrane of the rough ER [14, 15]. MTP is also expressed in the intestine and plays a key role in the lipidation of apoB48 during chylomicron assembly [16, 17]. This lipidation step results in the formation of a relatively small (max 25 nm), dense particle. Maturation of these precursors to VLDL particles with 30–80 nm diameter involves the post-translational acquisition of the bulk of triglycerides by fusion of the apoB-containing precursor with large triglyceride droplets produced in the smooth endoplasmic reticulum [18], giving rise to TG-rich VLDL. The size of the VLDL particles secreted by the liver is determined by the size of the TG pool [19], which mainly derives from lipolytic mobilization of the hepatic storage pool [20] rather than from newly formed TG [21].
VLDL assembly and secretion is a process highly regulated by the availability of triglycerides in the liver [22]; TG may derive from different sources, including uptake of albumin-bound fatty acids, uptake of circulating remnants of VLDL and chylomicrons, and de novo hepatic synthesis. Beside apoB and MTP, TG availability determines the efficiency of apoB-lipoprotein formation. In fact, reduced lipid availability results in targeting of apoB for degradation and decreased VLDL secretion [23]. Fatty acids derived from diet or released from adipose tissue enter the liver where they are re-esterified, forming triglyceride droplets [24]. Not all mobilized TGs enter into the secretory pool to contribute to VLDL formation; a relatively large proportion (determined by MTP and insulin activity) is returned back to the cytosolic pool. Newly synthesized VLDL contain little apoC; after secretion in the circulation, they acquire apoE and additional apoC from HDL (Fig. 6.2).
Two major subfractions of VLDL exist, large VLDL1 and smaller VLDL2. VLDL1 secretion is dependent on fatty acid availability, and insulin inhibits VLDL1 secretion [25]; this does not seem to be true for VLDL2. After secretion, VLDL1 are delipidated, following hydrolysis of TG through lipoprotein lipase; the delipidation process of VLDL1 is not complete, and only a minor fraction is converted to LDL, most remnants being directly removed from plasma [26]. On the contrary, most VLDL2 particles are delipidated and converted to LDL [27].
Chylomicron Assembly and Secretion
Three proteins play a key role in the process of chylomicron assembly: apoB48, MTP, and apoA-IV. ApoB48 is produced from the same gene of apoB100 in the small intestine and is formed by post-transcriptional mRNA editing in intestinal enterocytes; it lacks the LDLR-binding domain and is essential for the assembly of chylomicrons. MTP is a lipid-transfer protein that transports ER membrane-bound lipid (mainly TG) to newly synthesized apoB48, a step that prevents apoprotein degradation; moreover, MTP facilitates the successive lipidation of chylomicron precursors. ApoA-IV is a lipid-binding protein expressed mainly in the small intestine and incorporated early into nascent chylomicrons; after chylomicron secretion, apoA-IV dissociates from the particles to circulate as lipid-free protein.
Chylomicrons are responsible for the transport of dietary cholesterol and medium- and long-chain fatty acids from the intestinal lumen to the liver. The main lipids in chylomicrons are triacylglycerols. They are assembled mainly in the ER and then transported to the Golgi via specialized vesicles (PCTVs, prechylomicron transport vesicles). During the first assembly step, apoB48, synthesized by the small intestine, is translated into the ER lumen and immediately lipidated through the action of intestinal MTP (Fig. 6.1), resulting in the formation of a precursor particle. The lipidation can occur both by transfer of lipid from the ER membrane to apoB48 or by binding of MTP to apoB48 to facilitate the protein folding and lipid acquisition. During the second step, MTP mediates further addition of lipids to the precursor. In this phase apoA-IV is added at the particle surface; apoA-IV increases MTP activity and increases chylomicron lipidation [28].
Lipoprotein Lipase-Mediated Lipolysis
VLDL and chylomicrons leave the liver and intestine and enter the circulation where they acquire apoC-II and apoE from plasma HDL. In the capillaries of adipose tissue and muscle, triacylglycerols are hydrolyzed by endothelial lipoprotein lipase (LPL, activated by apoC-II) to produce free fatty acids which are then absorbed by the tissues. During the removal of fatty acids, a large percentage of the phospholipids and apoproteins are transferred to HDL, converting the lipoproteins to VLDL and chylomicron remnants (Fig. 6.2).
Hepatic Clearance of Remnants
The main organ involved in the clearance of remnant lipoprotein is the liver, where hepatocytes express LDL receptor (LDLR), LDL receptor-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) in high amounts. In concert with LPL and hepatic lipase (HL), these surface molecules facilitate the rapid hepatic clearance of remnant lipoproteins [29–32] that are extremely atherogenic [33] (Fig. 6.3). The most critical molecule in the remnant clearance is apoE, involved in the binding of lipoprotein to the LDLR family and HSPGs [31]. Multiple steps are involved in the uptake of remnants by hepatocytes. HSPGs interact with apoE present on the remnant surface and sequester them in the space of Disse [32]; moreover, HSPGs can bind LPL and HL that eventually may continue their lipolytic activity and prepare the particles for the successive internalization process [32, 34], which is mediated by LDLR, HSPGs, and the HSPGs/LRP complex.
Chylomicron remnants contain mainly cholesteryl esters, apoE, and apoB48 and return to the liver where they are taken up by hepatocytes via interaction with the LDL receptor which requires apoE [35]. Moreover, chylomicron remnants can acquire additional apoE, allowing the remnants to be taken up via the chylomicron remnant receptor, a member of the LDL receptor-related protein (LRP) family [35]. Alternatively, chylomicron remnants can remain sequestered in the space of Disse by binding of apoE to heparan sulfate proteoglycans and/or binding of apoB48 to hepatic lipase [35]. During this phase, chylomicron remnants may be further metabolized which increases apoE and lysophospholipid content, allowing for transfer to LDL receptors or LRP for hepatic uptake. VLDL remnant particles are immediately cleared by the liver or, alternatively, further modified by HL and cholesteryl ester transfer protein (CETP) to generate LDL.
The Role of Insulin in TGRLs Metabolism
The VLDL assembly process in the liver is tightly regulated by insulin [36, 37]: under fasting conditions, VLDL production in the liver is induced; on the contrary, in response to post-prandial insulin release, hepatic VLDL production is repressed [25, 38, 39]. This tight regulation allows the liver to rapidly adapt to metabolic shifts between fasting and feeding and to maintain plasma lipids within the physiological range [25, 39, 40] (Fig. 6.4).
Several observations suggest that insulin inhibits apoB secretion by inducing its degradation [41–44]; alternatively, insulin reduced free fatty acid (FFA) availability by reducing FFA mobilization from adipose tissue, resulting in apoB secretion inhibition [45]. The apoB gene is believed to be constitutively expressed as hepatic mRNA levels in vivo tend to be stable in most animal systems. However, several studies suggest that apoB mRNA abundance can be influenced by insulin in vivo [46, 47]. Hepatic apoB production is mainly regulated at the post-translational level by lipid availability, a process that is inhibited by insulin, resulting in an acute inhibitory effect of insulin on hepatic VLDL-triglyceride secretion to limit postprandial plasma lipid excursion. Hepatic apoB mRNA is stimulated by forkhead box O1 (FoxO1) and inhibited by insulin in a cell system [48]; moreover, hepatic activity of FoxO1 is increased during fasting and inhibited in response to feeding [49]. These observations suggest an additional mechanism by which the liver controls hepatic apoB production at the transcriptional level.
In the liver, insulin acts on fatty acids similarly to glucose: it promotes the storage of glucose as glycogen, and fatty acids as triglycerides during feeding. This will result in decreased hepatic VLDL secretion and decreased hepatic glucose release. Moreover, a decreased VLDL secretion during feeding limits the increase of plasma triglycerides during the prandial phase, when intestinal fats are absorbed to produce chylomicrons, which in turn deliver fatty acids to adipose tissue.
FoxO1 (forkhead box O1) is a transcription factor that plays a role in regulating hepatic glucose metabolism during fasting by inducing the expression of genes involved in gluconeogenesis [50]. In addition, FoxO1 may regulate lipid metabolism by inducing hepatic MTP expression, resulting in increased secretion of VLDL [48]. Under physiological conditions, this effect is reversed by insulin [48]. In the absence of insulin, FoxO1 is localized in the nucleus in a transcriptionally active form and induces the expression of MTP; after insulin release, FoxO1 is phosphorylated and translocated out of the nucleus, resulting in inhibition of FoxO1 transcriptional activity [51] (Fig. 6.4).
Insulin Resistance
Diabetes is characterized by hyperglycemia due to either defects in insulin secretion and/or insulin properties. Patients with insulin resistance are at high risk of developing diabetes and cardiovascular (CV) disease [52]. Insulin resistance is a condition of reduced responsiveness of tissues (liver, muscle, and adipose tissue) to normal circulating levels of insulin [53, 54], a condition present in different diseases, including type 2 diabetes [55], obesity, hypertension, and dyslipidemia [56]. As a result, insulin production increases to maintain normal levels of blood glucose. Insulin is a hormone essential for the maintenance of glucose homeostasis, secreted by the pancreatic β-cells mainly in response to increased circulating glucose levels after a meal [57].
When the concentration of blood glucose increases, the pancreas releases insulin into the circulation. In muscle and adipose tissues, insulin binds to cell surface receptors [58]. Following this binding, several biochemical signals are activated within the cells to take up glucose and convert it to energy [59]. If the pancreas fails to produce enough insulin or the insulin receptors do not function properly, the cells cannot uptake glucose and the level of glucose in the blood remains high.
Several defects can determine insulin resistance, including insulin receptor defects, insulin signaling defects [59, 60], mutations in insulin signaling molecules [61], and mitochondrial dysfunction [60]. In the early stages of insulin resistance, the pancreas compensates by producing more insulin to control the increased levels of glucose in the blood. This results in high blood glucose levels and high blood insulin levels (a condition known as hyperinsulinemia) at the same time. If this condition is not treated, the islets of Langerhans (the insulin-secreting groups of cells) in the pancreas may eventually shut down and decrease in number. When an insulin-resistant subject cannot maintain the degree of hyperinsulinemia required to bypass the defective action of insulin, type 2 diabetes develops.
The Role of Insulin Resistance in TGRLs Metabolism
In animal models of insulin resistance, hepatic MTP mRNA levels are significantly higher with simultaneous increase in VLDL levels [62–64]; finally, treatments that ameliorate insulin resistance and dyslipidemia determined reduced MTP expression and VLDL levels [49, 65, 66]. These observations suggest that in insulin-resistant subjects, MTP expression is no longer regulated by insulin, resulting in VLDL overproduction.
Insulin resistance is considered mainly a carbohydrate metabolism disorder; however, lipid and lipoprotein abnormalities are observed in individuals with insulin resistance [67]. These abnormalities include (1) increased plasma levels of VLDL triglyceride and apoB100, (2) reduced plasma levels of HDL and apoA-I, and (3) relatively normal LDL levels with increase of small dense LDL particles.
Acute insulin infusion reduces production of TG-rich VLDL in healthy non-obese humans [25, 40, 68, 69]; this effect can result from several mechanisms, including inhibition of hepatic MTP expression [70], increased apoB degradation [43], and inhibition of VLDL particle maturation [71]. This suppressive effect of insulin is, however, attenuated or even reversed [41, 72] when exposure to insulin is prolonged (such as in conditions of insulin resistance [68, 69]), where an increase in VLDL (mainly in the VLDL1 fraction) production is observed [73–75]. These observations suggest that chronic hyperinsulinemia plays a role in mediating the increased production of hepatic VLDL. In addition, insulin resistance of adipose tissue increases the levels of circulating free fatty acids that can enter into the liver, thus stimulating VLDL production [76]. Finally, loss of insulin inhibition of FoxO1 activity in insulin resistance increases the production of both glucose and VLDL-TG, contributing to the dual pathogenesis of hyperglycemia and hypertriglyceridemia in diabetes.
Hepatic TG in Insulin Resistance
Fatty acid flux to the liver is increased in insulin resistance [77, 78], due to a failure of insulin to inhibit TG lipolysis in adipose tissue [79]. Increased levels of fasting and post-prandial TG are features of insulin resistance [80]. The increase in post-prandial TG is due both to defective lipolysis of VLDL and chylomicrons, combined with increased VLDL secretion [80], and to increased production of chylomicrons [81]. In addition, insulin resistance also reduces lipoprotein lipase activity secondary to increased apoC-III (an inhibitor of LPL) secretion [82], resulting in reduced lipolysis of VLDL and chylomicron TG.
Another source of hepatic TG is de novo lipogenesis that contributes significantly to VLDL lipidation and production in insulin-resistant subjects. The main transcription factor of de novo lipogenesis is SREBP-1c (sterol response element-binding protein-1c) [83] that in turn is regulated by LXR (liver X receptor) [84]. Insulin plays a key role in the expression of hepatic SREBP-1c, in part by stimulating LXR expression [85, 86]; furthermore, insulin promotes the maturation of SREBP-1c independently of LXR [87].
Intestinal lipoprotein production is increased in insulin resistance; chylomicron overproduction is in fact a consequence of impaired insulin regulation. Under physiological conditions, chylomicron production is inhibited by insulin; this inhibitory process is lost or reduced in the presence of impaired insulin responsiveness. Increased postprandial TG was thought to be due to reduced chylomicron and VLDL lipolysis, combined with increased VLDL secretion [80, 88]. However, increased assembly and secretion of apoB48-containing chylomicrons has been observed in hyperinsulinemic conditions [81]. The elevation of free fatty acids in plasma increases not only hepatic, but also intestinal, lipoprotein production [81, 89], suggesting that the intestine responds to insulin resistance similarly to the liver [90].
Diabetes and Hepatic Uptake of Remnant Lipoproteins
Diabetes impairs hepatic uptake of remnant lipoproteins [29, 91, 92]. Under these pathological conditions, LDLR does not seem to significantly contribute to the reduced uptake of remnant lipoprotein [93, 94]. The major contribution to this effect appears to be related to HSPGs; as they are not proteins, a high number of genes involved in their assembly and disassembly must be regulated, both at translational and at posttranslational levels [95, 96]. In type 1 diabetes, hepatic HSPGs exhibit sulfation defects [97, 98], due to the suppression of a crucial enzyme in HSPG assembly [96]; moreover, the farnesoid X receptor, a known inducer of HSPG expression [99], is suppressed [100]. In type 2 diabetes and other diseases characterized by insulin resistance, proteoglycans exhibit several defects, including decreased sulfation [101, 102]. Insulin resistance also induces the hepatic overexpression of the heparan sulfate glucosamine 6-O-endosulfatase-2 (SULF2), an enzyme that degrades cell surface and matrix HSPGs, thus reducing the catabolism of remnant lipoprotein and contributing to postprandial dyslipoproteinemia in type 2 diabetes [103].
Triglyceride-Rich Lipoproteins and Vascular Dysfunction
The elevation in circulating free fatty acids impairs endothelium-dependent vasodilatation [104], and the decreased endothelial function may be dependent on enhanced oxidative stress [105]. The changes induced by TGRLs in the post-prandial phase are even more deleterious in terms of endothelial dysfunction and inflammation; indeed, several in vivo studies have demonstrated that post-prandial hypertriglyceridemia impairs endothelial function [106, 107]. Post-prandial hypertriglyceridemia is also associated with an inflammatory state and enhanced levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, soluble intercellular adhesion molecule (sICAM)-1, and soluble vascular cell adhesion molecule (sVCAM)-1 [108–110].
The molecular mechanisms underlying these effects of TGRLs have only recently been studied in detail. There are a few key issues that should be taken into account when analyzing the vascular effects of TGRLs. TGRLs derive either from an exogenous pathway (chylomicrons and chylomicron remnants containing apolipoprotein apoB48) or from a liver-derived pathway (VLDL and VLDL remnants containing apoB100). Under fasting conditions, however, chylomicrons are rapidly metabolized, thus the TGRL fraction is mainly composed of apoB100-rich particles, and the remnants derive mainly from the catabolism of VLDL (small VLDL and intermediate-density lipoprotein). In several dyslipidemic conditions, chylomicrons are metabolized at a lower rate, resulting in the accumulation of chylomicron remnants in the fasting state. In the post-prandial state, an enormous production of TGRLs containing both apoB48 and apoB100 occurs, leading to an impaired endothelial function. This dysfunction rapidly fades away in normotriglyceridemic subjects where the TGRLs are efficiently metabolized, whereas the condition persists in hypertriglyceridemic patients where TGRLs accumulate in the circulation. TGRLs undergo lipolysis mediated by lipoprotein lipase (LPL), generating different biologically active products that may affect endothelial cell function [111].
Early studies using HepG2 cells investigated the intracellular signaling pathway induced by VLDL exposure [112]. VLDL-induced protein kinase C activity results in the activation of mitogen-activated protein kinase (MAPK). Studies conducted in endothelial cells (ECs) indicate that VLDL can also activate nuclear factor (NF)-κB [113], a transcription factor that plays an important role in the phenotypic modulation of ECs in a pro-inflammatory condition. To date, plasminogen activator inhibitor-1 is the only gene that has been shown to be consistently induced in ECs to a larger extent when comparing VLDL from patients with hypertriglyceridemic type IV and type II versus VLDL from normolipidemic subjects [114]. Both in human umbilical vein ECs and human aortic ECs, TGRLs from hypertriglyceridemic subjects induce an increased mRNA expression of adhesion molecules, such as VCAM-1, platelet/endothelial cell adhesion molecule (PECAM)-1, and endothelial/leukocyte adhesion molecule (ELAM)-1, while TGRLs from normolipidemics induced VCAM-1 expression in both the cell lines and ELAM-1 selectively in the aortic ECs, but to a lesser extent [115]. Specific inhibition of p38 mitogen-activated protein kinase and NF-κB suggests a major involvement of these factors in adhesion molecule expression induced by TGRLs in both NTG and HTG patients. Furthermore, TGRLs induced monocyte chemoattractant protein (MCP)-1 expression in ECs, suggesting that activation of the endothelium by TGRLs could support both adhesion and transmigration of leukocytes. In addition, TGRLs from hypertriglyceridemic patients induced IL-6 expression. Again, these effects are mainly dependent on NF-κΒ activation.
The composition of the TGRL particles plays a key role in determining the pro-inflammatory response to TGRLs [116]. A different composition of VLDL (fatty acid, lipids, and apoproteins) may be responsible for the differences observed between normolipidemic and hypertriglyceridemic TGRLs. TGRLs isolated following a meal enriched in saturated fatty acids induced E-selectin and VCAM-1 expression to a higher extent than TGRLs isolated after a meal enriched in monounsaturated and polyunsaturated fatty acids [116]. Furthermore, lipolysis products from TGRLs increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis [111]. One could speculate that, in the presence of hypertriglyceridemia, the reduced activity of LPL may promote the presence of pro-inflammatory TGRLs.
Although hypertriglyceridemia is an independent risk factor for coronary artery disease [117], accumulating evidence suggests that post-prandial (hyper)lipidemia contributes to the development of atherosclerosis and coronary artery disease [118]. Several studies have demonstrated that postprandial hypertriglyceridemia impairs endothelial function, suggesting a role for triglycerides in the initiation and further progression of atherosclerosis [106, 107]. Post-prandial hypertriglyceridemia is associated with an inflammatory state and enhanced levels of TNF-α, IL-6, sICAM-1, and sVCAM-1 [108–110]. Although TGRLs isolated from fasting plasma samples of hypertriglyceridemic subjects induce an inflammatory response in ECs [115], ECs incubated with post-prandial TGRL demonstrated an increased mRNA expression of VCAM-1, ELAM-1, P-selectin, PECAM-1, and ICAM-1. Similarly, post-prandial TGRLs increased ICAM-1 and VCAM-1 protein expression [119]. Also fasting TGRLs increase adhesion molecule expression, however, the effect observed with post-prandial TGRL is much more pronounced. Furthermore, ICAM-1 expression was induced solely upon incubation with post-prandial TGRLs. Likewise, MCP-1 and IL-6 expression was induced upon incubation with post-prandial TGRLs; again, this effect is more pronounced than that observed with fasting TGRLs. As the induction of adhesion molecules and the increased release of cytokines and chemokines have been associated with endothelial dysfunction [120], our data suggest that endothelial activation by TGRL occurs during the post-prandial phase and may promote the endothelial dysfunction observed after a meal. Notably, a single high-fat meal led to a significant elevation of endothelial microparticles, known to be a sensitive indicator of endothelial disturbance, in healthy normolipidemic subjects [107]. This observation suggests that endothelial microparticles may be an indirect marker of endothelial dysfunction or injury induced by postprandial TGRL.
TGRLs and their remnants are present within human and experimental atherosclerotic lesions [121–123]: chylomicron remnants directly penetrate the endothelial cell layer and are entrapped within the subendothelial space, leading to focal accumulation [122] (Fig. 6.5). TGRLs may directly contribute to the atherosclerotic process by inducing endothelial dysfunction [124], by enhancing monocyte adhesion [125], and by triggering lipid accumulation within the artery wall [126]. Exposure to TGRLs, especially those isolated from patients with type 2 diabetes [127], leads to the intracellular accumulation of triglyceride and/or cholesteryl ester in human monocyte- [127] and murine-derived macrophages [126, 128]. Abnormal reverse cholesterol transport and low levels of high-density lipoprotein associated with hypertriglyceridemia [129, 130] can accelerate the lipid deposition process within arterial macrophages. The interaction of TGRLs with cholesterol-loaded human macrophages increases the cell lipid content while compromising the subsequent efflux of cholesterol to lipid-poor apoA-I [131]. These aspects may contribute significantly to the generation of macrophage foam cells in vivo and might account for the accelerated atherogenesis observed in patients with type 2 diabetes. Finally, remnant lipoproteins induce smooth muscle cell activation and proliferation [132, 133].
Most of the available evidence suggests that in normolipidemic subjects either in the fasting state or in the post-prandial phase, TGRL may affect endothelial function only when a pro-inflammatory environment is already present and may perhaps contribute to accelerating the damage induced by other lipid and non-lipid factors. However, in hypertrygliceridemic patients, TGRLs from the fasting state and postprandial phase can both induce endothelial dysfunction by promoting a pro-inflammatory activation of the endothelium. These findings are in line with the idea that these lipoproteins may play a significant role in the early stages of atherogenesis.
References
Karpe F, Bell M, Bjorkegren J, Hamsten A. Quantification of postprandial triglyceride-rich lipoproteins in healthy men by retinyl ester labeling and simultaneous measurement of apolipoproteins B-48 and B-100. Arterioscler Thromb Vasc Biol. 1995;15: 199–207.
Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003;46: 733–49.
Chen SH, Habib G, Yang CY, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987;238:363–6.
Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987;50:831–40.
Pan X, Hussain MM. Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J Biol Chem. 2007;282:24707–19.
Fisher EA, Pan M, Chen X, et al. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways. J Biol Chem. 2001;276:27855–63.
Benoist F, Grand-Perret T. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer protein. Synchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein. J Biol Chem. 1997;272:20435–42.
Dixon JL, Furukawa S, Ginsberg HN. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem. 1991;266:5080–6.
Zhou M, Fisher EA, Ginsberg HN. Regulated Co-translational ubiquitination of apolipoprotein B100. A new paradigm for proteasomal degradation of a secretory protein. J Biol Chem. 1998;273: 24649–53.
Williams KJ, Brocia RW, Fisher EA. The unstirred water layer as a site of control of apolipoprotein B secretion. J Biol Chem. 1990;265:16741–4.
Schumaker VN, Phillips ML, Chatterton JE. Apolipoprotein B and low-density lipoprotein structure: implications for biosynthesis of triglyceride-rich lipoproteins. Adv Protein Chem. 1994;45:205–48.
Gordon DA, Wetterau JR, Gregg RE. Microsomal triglyceride transfer protein: a protein complex required for the assembly of lipoprotein particles. Trends Cell Biol. 1995;5:317–21.
Rustaeus S, Stillemark P, Lindberg K, Gordon D, Olofsson SO. The microsomal triglyceride transfer protein catalyzes the post-translational assembly of apolipoprotein B-100 very low density lipoprotein in McA-RH7777 cells. J Biol Chem. 1998;273: 5196–203.
Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003;44:22–32.
Jamil H, Chu CH, Dickson Jr JK, et al. Evidence that microsomal triglyceride transfer protein is limiting in the production of apolipoprotein B-containing lipoproteins in hepatic cells. J Lipid Res. 1998;39: 1448–54.
Hui TY, Olivier LM, Kang S, Davis RA. Microsomal triglyceride transfer protein is essential for hepatic secretion of apoB-100 and apoB-48 but not triglyceride. J Lipid Res. 2002;43:785–93.
Manchekar M, Richardson PE, Forte TM, Datta G, Segrest JP, Dashti N. Apolipoprotein B-containing lipoprotein particle assembly: lipid capacity of the nascent lipoprotein particle. J Biol Chem. 2004;279: 39757–66.
Alexander CA, Hamilton RL, Havel RJ. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J Cell Biol. 1976;69:241–63.
Wu X, Shang A, Jiang H, Ginsberg HN. Low rates of apoB secretion from HepG2 cells result from reduced delivery of newly synthesized triglyceride to a “secretion-coupled” pool. J Lipid Res. 1996;37:1198–206.
Gibbons GF, Islam K, Pease RJ. Mobilisation of triacylglycerol stores. Biochim Biophys Acta. 2000;1483:37–57.
Gibbons GF, Bartlett SM, Sparks CE, Sparks JD. Extracellular fatty acids are not utilized directly for the synthesis of very-low-density lipoprotein in primary cultures of rat hepatocytes. Biochem J. 1992;287(Pt 3):749–53.
Fisher EA, Ginsberg HN. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem. 2002;277:17377–80.
Pan M, Liang Js JS, Fisher EA, Ginsberg HN. The late addition of core lipids to nascent apolipoprotein B100, resulting in the assembly and secretion of triglyceride-rich lipoproteins, is independent of both microsomal triglyceride transfer protein activity and new triglyceride synthesis. J Biol Chem. 2002;277:4413–21.
Wiggins D, Gibbons GF. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem J. 1992;284(Pt 2):457–62.
Malmstrom R, Packard CJ, Watson TD, et al. Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler Thromb Vasc Biol. 1997;17:1454–64.
Packard CJ, Munro A, Lorimer AR, Gotto AM, Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J Clin Invest. 1984;74:2178–92.
Gaw A, Packard CJ, Lindsay GM, et al. Overproduction of small very low density lipoproteins (Sf 20-60) in moderate hypercholesterolemia: relationships between apolipoprotein B kinetics and plasma lipoproteins. J Lipid Res. 1995;36:158–71.
Black DD. Development and physiological regulation of intestinal lipid absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion. Am J Physiol Gastrointest Liver Physiol. 2007;293:G519–24.
Williams KJ, Chen K. Recent insights into factors affecting remnant lipoprotein uptake. Curr Opin Lipidol. 2010;21:218–28.
Fuki IV, Kuhn KM, Lomazov IR, et al. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J Clin Invest. 1997;100:1611–22.
Mahley RW, Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing. J Clin Invest. 2007;117: 94–8.
Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16.
Mahley RW, Weisgraber KH, Innerarity TL, Rall Jr SC. Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism. JAMA. 1991;265:78–83.
Williams KJ, Fuki IV. Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism. Curr Opin Lipidol. 1997;8:253–62.
Cooper AD. Hepatic uptake of chylomicron remnants. J Lipid Res. 1997;38:2173–92.
Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 1995;95: 158–66.
den Boer MA, Voshol PJ, Kuipers F, Romijn JA, Havekes LM. Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production. Am J Physiol Endocrinol Metab. 2006;291:E1360–4.
Lewis GF, Steiner G. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state. Diabetes Care. 1996;19:390–3.
Sparks JD, Sparks CE. Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Biochim Biophys Acta. 1994;1215:9–32.
Malmstrom R, Packard CJ, Caslake M, et al. Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes. 1998;47:779–87.
Dashti N, Williams DL, Alaupovic P. Effects of oleate and insulin on the production rates and cellular mRNA concentrations of apolipoproteins in HepG2 cells. J Lipid Res. 1989;30:1365–73.
Sparks CE, Sparks JD, Bolognino M, Salhanick A, Strumph PS, Amatruda JM. Insulin effects on apolipoprotein B lipoprotein synthesis and secretion by primary cultures of rat hepatocytes. Metabolism. 1986;35:1128–36.
Sparks JD, Sparks CE. Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes. J Biol Chem. 1990;265:8854–62.
Sparks JD, Sparks CE, Miller LL. Insulin effects on apolipoprotein B production by normal, diabetic and treated-diabetic rat liver and cultured rat hepatocytes. Biochem J. 1989;261:83–8.
Stein DT, Esser V, Stevenson BE, et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest. 1996;97:2728–35.
Sparks JD, Collins HL, Chirieac DV, et al. Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase. Biochem J. 2006;395:363–71.
Sparks JD, Sparks CE, Bolognino M, Roncone AM, Jackson TK, Amatruda JM. Effects of nonketotic streptozotocin diabetes on apolipoprotein B synthesis and secretion by primary cultures of rat hepatocytes. J Clin Invest. 1988;82:37–43.
Kamagate A, Qu S, Perdomo G, et al. FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. J Clin Invest. 2008;118:2347–64.
Qu S, Su D, Altomonte J, et al. PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1. Am J Physiol Endocrinol Metab. 2007;292:E421–34.
Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 2007;6:208–16.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.
Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217:3–46.
Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119:S10–6.
Reaven GM. Why Syndrome X? From Harold Himsworth to the insulin resistance syndrome. Cell Metab. 2005;1:9–14.
American Diabetes Association (2007) Diagnosis and classification of diabetes mellitus. Diabetes Care 30(Suppl 1):S42–47
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415–28.
Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:665–79.
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.
DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270–87.
Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55 Suppl 2:S9–15.
Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674–82.
Bartels ED, Lauritsen M, Nielsen LB. Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes. 2002;51:1233–9.
Kuriyama H, Yamashita S, Shimomura I, et al. Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation. Hepatology. 1998;27:557–62.
Taghibiglou C, Carpentier A, Van Iderstine SC, et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 2000;275:8416–25.
Carpentier A, Taghibiglou C, Leung N, et al. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem. 2002;277:28795–802.
Chong T, Naples M, Federico L, et al. Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia. Atherosclerosis. 2006;185:21–31.
Chahil TJ, Ginsberg HN. Diabetic dyslipidemia. Endocrinol Metab Clin North Am. 2006;35:491–510. vii–viii.
Malmstrom R, Packard CJ, Caslake M, et al. Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM. Diabetologia. 1997;40:454–62.
Lewis GF, Uffelman KD, Szeto LW, Steiner G. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes. 1993;42:833–42.
Au WS, Kung HF, Lin MC. Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes. 2003;52:1073–80.
Brown AM, Gibbons GF. Insulin inhibits the maturation phase of VLDL assembly via a phosphoinositide 3-kinase-mediated event. Arterioscler Thromb Vasc Biol. 2001;21:1656–61.
Bartlett SM, Gibbons GF. Short- and longer-term regulation of very-low-density lipoprotein secretion by insulin, dexamethasone and lipogenic substrates in cultured hepatocytes. A biphasic effect of insulin. Biochem J. 1988;249:37–43.
Cummings MH, Watts GF, Pal C, et al. Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in obesity: a stable isotope study. Clin Sci (Lond). 1995;88:225–33.
Gill JM, Brown JC, Bedford D, et al. Hepatic production of VLDL1 but not VLDL2 is related to insulin resistance in normoglycaemic middle-aged subjects. Atherosclerosis. 2004;176:49–56.
Riches FM, Watts GF, Naoumova RP, Kelly JM, Croft KD, Thompson GR. Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity. Int J Obes Relat Metab Disord. 1998;22:414–23.
Sniderman AD, Cianflone K. Substrate delivery as a determinant of hepatic apoB secretion. Arterioscler Thromb. 1993;13:629–36.
Basu A, Basu R, Shah P, Vella A, Rizza RA, Jensen MD. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J Physiol Endocrinol Metab. 2001;280:E1000–6.
Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134:424–31.
Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol. 2010;55:2846–54.
Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res. 2005;36:232–40.
Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006;26:1357–63.
Cohn JS, Patterson BW, Uffelman KD, Davignon J, Steiner G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab. 2004;89:3949–55.
Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.
Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.
Cha JY, Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem. 2007;282:743–51.
Chen G, Liang G, Ou J, Goldstein JL, Brown MS. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci USA. 2004;101:11245–50.
Hegarty BD, Bobard A, Hainault I, Ferre P, Bossard P, Foufelle F. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. Proc Natl Acad Sci USA. 2005;102:791–6.
Brunzell JD, Hazzard WR, Porte Jr D, Bierman EL. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973;52:1578–85.
Duez H, Lamarche B, Valero R, et al. Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans. Circulation. 2008;117:2369–76.
Adeli K, Lewis GF. Intestinal lipoprotein overproduction in insulin-resistant states. Curr Opin Lipidol. 2008;19:221–8.
Dane-Stewart CA, Watts GF, Barrett PH, et al. Chylomicron remnant metabolism studied with a new breath test in postmenopausal women with and without type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2003;58:415–20.
Georgopoulos A, Phair RD. Abnormal clearance of postprandial Sf 100-400 plasma lipoproteins in insulin-dependent diabetes mellitus. J Lipid Res. 1991;32:1133–41.
Han S, Liang CP, Westerterp M, et al. Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice. J Clin Invest. 2009;119:1029–41.
Niesen M, Bedi M, Lopez D. Diabetes alters LDL receptor and PCSK9 expression in rat liver. Arch Biochem Biophys. 2008;470:111–5.
Grobe K, Esko JD. Regulated translation of heparan sulfate N-acetylglucosamine N-deacetylase/n-sulfotransferase isozymes by structured 5′-untranslated regions and internal ribosome entry sites. J Biol Chem. 2002;277:30699–706.
Williams KJ, Liu ML, Zhu Y, et al. Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II. Diabetes. 2005;54:1116–22.
Kjellen L, Bielefeld D, Hook M. Reduced sulfation of liver heparan sulfate in experimentally diabetic rats. Diabetes. 1983;32:337–42.
Ebara T, Conde K, Kako Y, et al. Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice. J Clin Invest. 2000;105:1807–18.
Anisfeld AM, Kast-Woelbern HR, Meyer ME, et al. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. J Biol Chem. 2003;278:20420–8.
Duran-Sandoval D, Mautino G, Martin G, et al. Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes. 2004;53:890–8.
Olsson U, Egnell AC, Lee MR, et al. Changes in matrix proteoglycans induced by insulin and fatty acids in hepatic cells may contribute to dyslipidemia of insulin resistance. Diabetes. 2001;50:2126–32.
Rohrbach DH, Hassell JR, Kleinman HK, Martin GR. Alterations in the basement membrane (heparan sulfate) proteoglycan in diabetic mice. Diabetes. 1982;31:185–8.
Chen K, Liu ML, Schaffer L, et al. Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins. Hepatology. 2010;52:1957–67.
Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–9.
Anderson RA, Evans ML, Ellis GR, et al. The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis. 2001;154:475–83.
Maggi FM, Raselli S, Grigore L, Redaelli L, Fantappie S, Catapano AL. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. J Clin Endocrinol Metab. 2004;89:2946–50.
Ferreira AC, Peter AA, Mendez AJ, et al. Postprandial hypertriglyceridemia increases circulating levels of endothelial cell microparticles. Circulation. 2004;110:3599–603.
Burdge GC, Calder PC. Plasma cytokine response during the postprandial period: a potential causal process in vascular disease? Br J Nutr. 2005;93:3–9.
Lundman P, Eriksson MJ, Silveira A, et al. Relation of hypertriglyceridemia to plasma concentrations of biochemical markers of inflammation and endothelial activation (C-reactive protein, interleukin-6, soluble adhesion molecules, von Willebrand factor, and endothelin-1). Am J Cardiol. 2003;91:1128–31.
Nappo F, Esposito K, Cioffi M, et al. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol. 2002;39:1145–50.
Eiselein L, Wilson DW, Lame MW, Rutledge JC. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. Am J Physiol Heart Circ Physiol. 2007;292:H2745–53.
Banfi C, Mussoni L, Rise P, et al. Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells. Circ Res. 1999;85:208–17.
Dichtl W, Nilsson L, Goncalves I, et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res. 1999;84:1085–94.
Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis. 1990;10:1067–73.
Norata GD, Grigore L, Raselli S, et al. Triglyceride-rich lipoproteins from hypertriglyceridemic subjects induce a pro-inflammatory response in the endothelium: Molecular mechanisms and gene expression studies. J Mol Cell Cardiol. 2006;40:484–94.
Williams CM, Maitin V, Jackson KG. Triacylglycerol-rich lipoprotein-gene interactions in endothelial cells. Biochem Soc Trans. 2004;32:994–8.
Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12.
Sniderman AD. Postprandial hypertriglyceridemia(s): time to enlarge our pathophysiologic perspective. Eur J Clin Invest. 2000;30:935–7.
Norata GD, Grigore L, Raselli S, et al. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis. 2007;193:321–7.
Constans J, Conri C. Circulating markers of endothelial function in cardiovascular disease. Clin Chim Acta. 2006;368:33–47.
Mamo JC, Wheeler JR. Chylomicrons or their remnants penetrate rabbit thoracic aorta as efficiently as do smaller macromolecules, including low-density lipoprotein, high-density lipoprotein, and albumin. Coron Artery Dis. 1994;5:695–705.
Proctor SD, Mamo JC. Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall–evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Invest. 1998;28:497–503.
Rapp JH, Lespine A, Hamilton RL, et al. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994;14:1767–74.
Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis. 1998;138:229–35.
Carantoni M, Abbasi F, Chu L, et al. Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM. Diabetes Care. 1997;20:1462–5.
Bates SR, Murphy PL, Feng ZC, Kanazawa T, Getz GS. Very low density lipoproteins promote triglyceride accumulation in macrophages. Arteriosclerosis. 1984;4:103–14.
Saito M, Eto M, Okada M, Iwashima Y, Makino I. Remnant-like particles (RLP) from NIDDM patients with apolipoprotein E3/3 phenotype stimulate cholesteryl ester synthesis in human monocyte-derived macrophages. Artery. 1996;22:155–63.
Fujioka Y, Cooper AD, Fong LG. Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages. J Lipid Res. 1998;39:2339–49.
Cavallero E, Brites F, Delfly B, et al. Abnormal reverse cholesterol transport in controlled type II diabetic patients. Studies on fasting and postprandial LpA-I particles. Arterioscler Thromb Vasc Biol. 1995;15:2130–5.
Syvanne M, Castro G, Dengremont C, et al. Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin-dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein. Atherosclerosis. 1996;127:245–53.
Palmer AM, Murphy N, Graham A. Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells. Atherosclerosis. 2004;173:27–38.
Kawakami A, Tanaka A, Nakano T, Saniabadi A, Numano F. Stimulation of arterial smooth muscle cell proliferation by remnant lipoprotein particles isolated by immuno-affinity chromatography with anti-apo A-I and anti-apo B-100. Horm Metab Res. 2001;33:67–72.
Kawakami A, Tanaka A, Chiba T, Nakajima K, Shimokado K, Yoshida M. Remnant lipoprotein-induced smooth muscle cell proliferation involves epidermal growth factor receptor transactivation. Circulation. 2003;108:2679–88.
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Pirillo, A., Norata, G.D., Catapano, A.L. (2014). Production and Metabolism of Triglyceride-Rich Lipoproteins in Both the Normal and Diabetic States. In: Jenkins, A., Toth, P., Lyons, T. (eds) Lipoproteins in Diabetes Mellitus. Contemporary Diabetes. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7554-5_6
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