биохимия атеросклероза

8 Jim W. Burgess et al.

Lipase activity in plasma also appears to exert effects on RCT. Increased hydrolysis of TG-rich lipoproteins by lipoprotein lipase (LPL) results in elevated levels of HDL in the bloodstream and may positively impact RCT [42, 43]. In agreement with these findings, low levels of LPL activity, through knockout or mutation in animal models or human LPL deficiency, are correlated with reduced levels of HDL [44, 45]. LPL may indirectly impact RCT through the generation of lipoprotein remnants that transport cholesterol to the liver. The generation of remnants produces substrates for CETPmediated transfer of CE from HDL [42] thereby providing additional carriers for the transport of cholesterol to the liver. Thus, LPL may stimulate RCT by increasing HDL levels and enhancing CE transport to the liver.

Hepatic lipase (HL) may also play a role in the movement of cholesterol to the liver. HL is expressed primarily in the liver and is found bound to the sinusoidal endothelium [46]. HL hydrolyzes HDL phospholipids and triglycerides (TGs) as well as chylomicron and VLDL lipids [47]. A portion of nascent HDL is derived from lipase-mediated hydrolysis of TG-rich lipoproteins and lipolysis of chylomicron and VLDL lipids is correlated with an increase in circulating HDL [42]. It is assumed that high-LPL/low-HL activity is related to high-HDL levels and that enhanced TG-rich hydrolysis is associated with a stimulation of cholesterol transport [42]. Studies have shown that hypertriglyceridemia is associated with low-HDL levels and high-HL activity [48]. This appears to suggest that a low LPL/high HL may be causative to high-TG and low-HDL levels. This phenotype is also commonly associated with increased risk of atherosclerosis. HL may also catalyze the actions of CETP to promote RCT. TG-enrichment of HDL by CETP followed by HL-mediated hydrolysis has been shown to enhance uptake of CE by scavenger receptor class B type I (SR-BI) [49].

Transfer of HDL-Associated Cholesterol to the Liver

Cholesterol is stored and transported in the bloodstream in HDL and the apoB-containing lipoproteins almost exclusively as CE. More than half of the apoB-associated cholesterol is internalized by hepatic LDL-receptors, which are located in clathrin-coated pits on the hepatocyte cell surface. The receptor–ligand complex is delivered to lysosomes by the endosomal pathway [50]. The LDL-receptor is efficiently returned to the cell surface by recycling endosomes and returned to coated pits for another round of binding and internalization. ApoB-associated cholesterol can also be internalized by the multifunctional LDL-receptor related protein (LRP) [51]. Holoparticle uptake by this path is complex and involves interactions between LRP and cell surface heparin sulfate proteoglycans [52]. These long unbranched highly polyanionic molecules are required for LRP-mediated lipoprotein uptake and act by forming a binding matrix with lipoproteins through associations with apoE, HL, or LPL [53]. Regardless of the receptor and pathways involved, internalized apoB-containing lipoproteins are delivered to lysosomes and completely degraded to amino acids, FC, and free fatty acids (Fig. 1.3).

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HDL cholesterol can be taken into cells without parallel apolipoprotein uptake and degradation. This process, termed selective uptake, is believed to be an important step in RCT. SR-BI has been shown to mediate this process in rodents. SR-BI drives selective uptake by a poorly understood two-step process: binding of HDL via apoA-I followed by selective transfer of cholesterol to cells. Wang et al. [54] suggested that the action of HL on apoA-I- containing lipoproteins may facilitate the SRBI-mediated uptake of HDL lipid. This was later confirmed by another group that demonstrated the bridging properties of HL and proteoglycans with SR-BI [55]. Bridging of cells and lipoproteins has also been recently suggested to induce the SR-BI- independent selective uptake of CE [56]. CD36, an SR-BI-related protein and best known for its ability to mediate uptake of oxidized LDL also mediates selective uptake, although to a lesser extent than SR-BI [57].

Three models have been proposed to describe the process of selective uptake. In the first model, SR-BI mediates the fusion between HDL and the plasma membrane, allowing the lipid transfer to the plasma membrane down a concentration gradient [58]. Rodrigueza et al. [59] have suggested that SR-BI forms a nonaqueous channel in the plasma membrane, through which cholesterol can move down a concentration gradient into the cell. Finally, a retroendocytic mechanism has been proposed in which SR-BI-associated HDL is internalized in caveolae and cholesterol is removed intracellularly followed by resecretion of cholesterol-poor HDL [60].

In rats, 60–70% of HDL-C is removed by SR-BI-mediated selective uptake [61]. The human homolog of SR-BI, termed CLA-1, exhibits similar tissue distribution [62], binding properties for a wide spectrum of plasma lipoproteins, and identical cholesterol transfer capacities as those of murine SR-BI [63]. Data from a human hepatic cell model demonstrate that CLA-1 is responsible for the selective uptake of cholesterol from HDL and LDL particles [64]. Furthermore, recent epidemiological studies have identified single-nucleotide polymorphisms in the CLA-1 gene that are associated with abnormal plasma lipid levels and lipoprotein composition [65]. These studies indicate that SR-BI/CLA-1 play a pivotal role in RCT and the metabolism of the cholesterol component of both HDL and apoB-lipoproteins in humans.

Cholesterol homeostasis in the liver is tightly controlled at the receptor and synthesis level. High-intracellular concentrations of cholesterol downregulates the LDL receptor [66] and hydroxymethylglutaryl coenzyme A (HMGCoA) reductase (the rate-limiting step in cholesterol synthesis) expression [67]. This process is regulated by SREBP [68]. The regulation of LRP expression is poorly understood although it has been reported that certain growth factors, for example insulin and nerve growth factors as well as cytokines like interleukin-β and tumor necrosis factor-α, upregulate the synthesis of LRP in HepG2 cells [69]. The expression of SR-BI gene is modulated by the activation of multiple signaling pathways, mediated by the involvement of SREBP, LXR, and PPAR-α [70].

Enterohepatic Metabolism of Cholesterol

Both the liver and the intestine are essential organs in the regulation of cholesterol metabolism. Cholesterol that is transported to the liver via lipoproteins becomes a substrate for bile acid synthesis and can be secreted into the bile in the form of bile acids and cholesterol. This cholesterol–bile acid pool is released into the large intestine where it is recycled and reabsorbed via the enterohepatic circulatory pathway. However, approximately 50% of cholesterol that is secreted into the gastrointestinal tract is not absorbed and is excreted [71]. Thus, the enterohepatic pathway (Fig. 1.3) provides the major route for cholesterol removal from the body.

Cholesterol that is taken up by the liver is made available for storage, membrane function, hormone and vitamin synthesis, and bile acid synthesis. FC that is taken into the hepatocyte can be esterified by ACAT [72], which is an intracellular enzyme that catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl coenzyme A. Cholesterol hydrolases such as neutral cholesterol ester hydrolase (nCEH), also known as hormone-sensitive lipase, catalyze the hydrolytic cleavage of CEs to form FC [73]. The process by which cholesterol is mobilized from the lipid droplet is uncertain. It is likely that transfer proteins such as caveolin [74] or the steroidogenic acute regulatory protein (StAR) [75] stimulate CE hydrolysis and mobilization to the endoplasmic reticulum for bile acid synthesis or to the mitochondria for steroidogenesis.

Bile acids are end products of cholesterol metabolism and function to emulsify exogenous and endogenous lipids. HDL has been implicated as the preferential source of cholesterol for bile acid synthesis such that most of the nonesterified cholesterol from HDL is converted to bile acids [76]. The conversion of cholesterol into bile acids is initiated by the hepatic P450 enzyme, cholesterol 7α-hydroxylase (CYP7A1) [77]. This is followed by multiple hydroxylations of the cholesterol steroid ring structure and cleavage of the side chain. Thus, the bile acids retain both lipophilic and hydrophilic properties and this amphipathic property allows for the formation of mixed micelles with phospholipids and cholesterol in the bile.

In the hepatocyte, cholesterol transport into the bile involves multiple factors, all of which influence cholesterol homeostasis. The ability to transport bile acids and cholesterol across the canalicular plasma membrane of the hepatocyte is a controlling factor in biliary lipid secretion/excretion. A specific membrane transporter belonging to the ABC-binding cassette family of proteins, termed the bile salt export pump (ABCB11), is responsible for bile acid transport across the canalicular membrane [78]. Changes in the expression of hepatic ABCG5 and ABCG8 transporters has been shown to be correlated with changes in biliary cholesterol secretion [79]. Thus, ABCG5 and ABCG8 may help to facilitate the excretion of FC into the bile. Once secreted into the bile, the bile acids form very strong molecular attractions to phospholipids and aid in solubilizing FC for transport into the intestine.

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The majority of bile acids in the intestinal tract are reabsorbed. This is confirmed by the finding that relatively low levels (approximately 5%) of bile acids are present in the feces [80]. Thus, up to 95% of bile acid is reabsorbed by the small intestine into the portal vein and returned to the liver, where it either functions to regulate bile acid synthesis or is recirculated into the bile. This enterohepatic circulation recycles approximately ten times per day and has a major influence on the level of bile acid synthesis and hence, cholesterol homeostasis. Biliary cholesterol is also regulated by the enterohepatic circulation. Approximately 50% of biliary cholesterol is reabsorbed; however, this value can range between 20 and 80% depending on differences between individuals.

The regulation of the enterohepatic metabolism of cholesterol is of key interest, as the cholesterol and bile acids that are not reabsorbed constitute the major route for cholesterol excretion from the body. The enterohepatic metabolism of cholesterol is a process that is largely regulated at the molecular level. Many nuclear hormone receptors have been identified that play significant roles in the transcriptional control of the genes involved in bile acid synthesis and cholesterol absorption. Two nuclear hormone receptors that are involved in cholesterol homeostasis are the LXR and the farnesoid X receptor (FXR) [81]. Upon ligand binding, these receptors form a heterodimer with RXR and interact with a response element within the proximal promoter regions of genes involved in cholesterol metabolism. In the liver, LXR regulates the 7α-hydroxylation of cholesterol by inducing the expression of CYP7A1, and thus enhances the catabolism/excretion of cholesterol [82]. However, as a feedback control, FXR can bind to bile acids, followed by interaction with a negative response element on the CYP7A1 gene, causing an inhibition of bile acid synthesis [83]. In addition to FXR, the hepatocyte nuclear factor-4α (HNF-4α) is also implicated in the downregulation of CYP7A1 [84]. Thus, bile acids returning to the liver through the enterohepatic circulation downregulate the transcription of CYP7A1. These receptor systems therefore work in tandem to control cholesterol homeostasis through their ability to enhance or inhibit bile acid synthesis.

The LXR receptor is also involved in the regulation of cholesterol transport proteins such as the ABC transporters at extrahepatic locations such as the intestine. Upon binding cholesterol and/or its metabolites, LXR upregulates the transcription of ABCA1, ABCG5, and ABCG8, leading to increased efflux of intracellular cholesterol [85]. ABCA1 activity is also suggested to be enhanced by LXR interacting with PPAR [86]. In the liver, PPAR-α has been shown to decrease CYP7A1 expression [87] while increasing hepatic SR-BI levels [88] leading to increased hepatic cholesterol uptake.

Nuclear receptors are highly involved in the regulation of RCT, bile acid synthesis, and cholesterol excretion. Thus, alterations in receptor-dependent mechanisms could lead to differences in the amount of mRNA that is transcribed. Based on this concept, these nuclear receptors are likely targets for therapeutic interventions for the treatment of atherosclerosis.

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raise HDL levels [101], niacin has shown considerable clinical benefits by elevating HDL cholesterol by 15–30% [102]. Among the various mechanisms characterized are inhibition of lipolysis in adipose tissue, inhibition of TG synthesis, and inhibition of apoA-I catabolism [102]. Unfortunately the adverse effects associated with this drug make compliance poor. Raising HDL can also be achieved using fibrates or certain statins such as simvastatin, however these effects are fairly modest (usually <10%). Fibrates, such as gemfibrozil and fenofibrate, are best known for their TG-lowering effects. Their mechanism of action is also complex. They belong to the class of PPAR agonists [101, 102]. PPAR agonists are a family of nuclear hormone receptors that are widespread throughout the body. Fibrates stimulate PPAR- α in the liver and other tissues, leading to the expression of multiple genes involved in lipoprotein metabolism. Fibrates stimulate apoA-I and ABCA1 synthesis and decrease the synthesis of TGs. Fibrates are also known to enhance lipase synthesis and activity, suggesting that conventional drugs therapies to treat dyslipidemia act, at least in part, by stimulating LPL, HL, and EL. Fibrates also increase SR-BI levels in human monocytes and macrophages, although an opposite effect is observed in murine liver at a posttranscriptional level [103].

Some drugs under development have been designed to directly promote RCT. Among the more novel approaches is administration of apoA-I or related peptides (artificial HDL), either as long-term oral therapy or by infusion for subacute treatment. In a recent study involving a naturally occurring apoA-I variant (apoA-I Milano) administered intravenously [104], coronary atheroma volume decreased by 1% after 5 weeks. This approach represents a paradigm shift in thinking about lipid therapy, which is generally considered to reduce risk gradually over months to years. Intravenous administration of these compounds is thought to rapidly mobilize cholesterol from arteries for disposal by the liver, thereby stabilizing vulnerable plaque.

Inhibition of CETP is another approach to raise HDL levels, although it is unclear whether it will positively affect RCT. CETP inhibitors such as torcetrapib and JTT-705 are currently in clinical trials and have shown promising elevations in apoA-I and HDL [105, 106]. A vaccine against CETP antigen is also being evaluated in clinical trials [100]. Phosphatidylinositol is being tested as an HDL-elevating therapeutic in clinical trials and early efficacy results suggest that the compound can significantly elevate both apoA-I and HDL cholesterol levels [107]. Phosphatidylinositol also stimulates multiple steps in the RCT pathway. This naturally occurring lipid was shown to increase cholesterol efflux from cholesterol-loaded macrophages through the inositol-signaling cascade and to increase cholesterol transport to the liver and feces [30]. Drugs that inhibit HDL apoA-I catabolism or the remodeling of HDL particles [108] (e.g., EL inhibitors) represent another promising approach.

The enterohepatic circulation plays an important role in the excretion of cholesterol derived from RCT and a number of strategies have been designed to pharmacologically inhibit cholesterol absorption (or reabsorption) in the

gut. The micellar solubilization of cholesterol can be disrupted with the use of agents such as orlistat (Xenical), a lipase inhibitor, which forms an oil phase in the intestinal lumen which entraps cholesterol, allowing for its fecal excretion [109]. In addition, bile acid resins have also been used to interfere with cholesterol absorption. Bile acid resins, such as colesevelam, bind to both cholesterol and bile acids in the intestinal tract, forming an insoluble matrix, which allows for their subsequent elimination in the feces [110]. A disadvantage of bile acid resins is their potential ability to additionally block fat-soluble vitamin absorption. More recently, a major focus has been directed towards ezetimibe, a cholesterol absorption inhibitor that interrupts the absorption of dietary cholesterol and biliary cholesterol without affecting the absorption of fat-soluble vitamins. Ezetimibe is rapidly absorbed and is recycled enterohepatically multiple times [111].

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