ApoA-I containing lipoproteins

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ApoAI containing lipoproteins
Changes of lipid- and lipoprotein metabolism in diabetes mellitus and the metabolic syndrome with elevated triglycerides, reduced α-HDL particles, elevated small dense LDL
and LCAT dysfunction as well as genetic defects in the HDL-regulator-gene ABCA1 and disorders of apolipoprotein E (apo E)-metabolism are closely associated with vascular
diseases, MI and the development of chronic renal disease. HDL exerts an important function in reverse cholesterol transport and plays also a major atheroprotective role in the
suppression of oxidant-, inflammatory-, adhesive and thrombotic events. Disorders of lipid and lipoprotein metabolism in association with hyperglycemia and insulin resistance are
major progression factors for the development of glomerulopathies, mesangial proliferation und tubular damage.

HDL particles are thought to protect against atherosclerosis primarily by mediating reverse cholesterol transport to the liver for excretion in bile (Schmitz and Büchler 2002; Schmitz and Drobnik 2002). Mature HDL particles are generated from lipid-free apoAI or lipid-poor preβ- HDL and cellular cholesterol taken up by preβ-HDL is subsequently esterified by the action of lecithin-cholesterol acyltransferase (LCAT), which leads to maturation and increased particle size (Stein and Stein 2005). Esterified cholesterol from mature HDL particles can be taken up by the liver directly via selective uptake mediated by SR-BI, or indirectly through exchange and transfer of triglycerides and cholesteryl esters to LDL mediated by PLTP/CETP and apoE dependent mechanisms (Sparks and Pritchard 1989). In hereditary, lecithin:cholesterol acyltransferase (LCAT) deficiency, HDL metabolism isseverely affected, and carriers of this deficiency have low levels of both HDL and LDL cholesterol with the accumulation of an aberrant lipoprotein, Lp-X (Glomset et al. 1970; Norum and Gjone 1967). However, in spite of low HDL cholesterol levels, cardiovascular disease is not common among LCAT-deficient subjects (Glomset et al. 1995; Assman et al. 1991). LCAT is critical for esterification of cholesterol, and in the absence of this enzyme HDL maturation is affected, resulting in small discoidal HDL particles which are thought to be deficient in promoting reverse cholesterol transport (Jonas 2000). On the other hand, LDL particles are also affected by the deficiency in cholesterol esterification and have higher relative amounts of phospholipids, triglyceride, and cholesterol (Glomset et al. 1978; Deeb et al. 2003). The physicochemical changes in lipoprotein properties observed in LCAT deficiency are likely to be associated with significant metabolic aberrations. Thus, the relative lack of cholesteryl esters in LDL could result in an LDL fraction with reduced atherogenicity, which might contribute to the apparent lack of CAD in these patients. The relative triglyceride enrichment of LDL under these conditions might further make LDL a better substrate for lipase activity, which could contribute to a reduction in LDL plasma circulation time. A recent study (Nishiwaki et al. 2006) suggests an upregulation of LDL receptors in LCAT-deficiency as well as a change in LDL particle properties, resulting in faster clearance of LDL from LCAT-deficient subjects compared with LDL from normals. These results differ from changes induced by hypolipidemic agents, where upregulation of LDL receptor commonly result in the initial clearance of particle with higher receptor affinity, causing accumulation of particles with a lower affinity for the receptor (Young et al. 1989; Berglund et al. 1989; Berglund et al. 1998). The changes observed in LCAT deficiency are consistent with a double effect on LDL clearance compared with normals—increased particle clearance, perhaps attributable to triglyceride enrichment, and a simultaneous increase in LDL receptor activity, likely resulting from a relatively decreased uptake of cholesteryl ester by the liver (Figure 84). Moreover, an unchanged VLDL or IDL apoB clearance but an increased VLDL apoBproduction rate in parallel with a decrease in IDL apoB production in the patients. In the LCAT-deficient subjects, more of the VLDL was cleared directly and less converted to IDL and LDL compared with normals. Whether a faster clearance of VLDL can be explained by an upregulation of LDL receptors or is attributable to other mechanisms remains to be shown. However, there was no indication of an impaired conversion of VLDL to LDL in LCAT deficiency.

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Altogether, the results by Nishiwaki et al show profound changes in the metabolism of apoBcontaining lipoproteins in LCAT deficiency, and they provide a basis for conclusions
regarding the lower net atherogenic potential of LDL in these subjects. However, whether these observations explain the apparent protection from cardiovascular disease in these
patients, or whether other mechanisms, such as alternative pathways for reverse cholesterol transport are contributory, remain to be seen (Ayyobi et al. 2004; Berard et al. 2001).
Interestingly, studies on heterozygotes for LCAT deficiency have shown the presence of atherosclerosis, which might perhaps suggest that any sizeable presence of "N-LDL" may contribute to atherogenicity under heterozygous or partial LCAT deficient conditions (Ayyobi et al. 2004; Miettinen et al. 1998). There is increasing evidence that HDL metabolism beyond reverse cholesterol transport plays also a major atheroprotective role in the suppression of oxidant-, inflamatory-, adhesive and thrombotic events (Visvikis-Siest and Marteau 2006; Dahlback and Nielsen 2006; Camici 2005) Apolipoprotein M, a recently identified lipocalin with a hydrophobic ligand pocket, located in
the MHC class III region on chr. 6p21.33, was shown to be important for the formation of preß HDL and is exclusively expressed in liver and kidney proximal tubules (Dahlback and Nielsen 2006). ApoM levels may be a useful serum marker for the identification of MODY3 patients which carry mutations in the HNF1α gene which is together with leptin required for apoM promoter upregulation and TGF-ß downregulation (Richter et al. 2003; Xu et al. 2004; Xu et al. 2004). Loss of apoM in HNF1α deficient mice results in the disappearance of preß HDL and the appearence of unusually large HDL particles in plasma and hepatic overexpression of apoM led to a reduction of atherosclerosis (Wofrum et al. 2005).ApoE polymorphisms not only influence the dominant association with HDL and apoB containing lipoproteins with the consequence of altered lipoprotein metabolism but may also determine the outcome towards a predisposition to stroke or MI (Pezzini et al. 2004, Slooter et al. 2004).
Paraoxonase (PON1), an HDL associated enzyme protects LDL against oxidation and within the PON1 gene, both the Glu92Arg and the Leu55Met polymorphism impair paraoxonase activity, but their relation with CAD risk is still inconsistent (Garin et al. 1997; Leviev and James 2000). These discrepancies could be due to an additional T(-107)C promoter variant. Three new polymorphisms of PON1 were recently described to correlate also with low PON1 activity (Jarvik et al. 2003) and smoking behavior may interact with PON1 polymorphisms (Robertson et al. 2003). Orosomucoid (ß1-acid glycoprotein AGP) is an acute phase protein with a protective role for the vascular endothelium and glomerular permselectivity (Camici 2005, Hochepied et al. 2003). Expression of the AGP gene is controlled by glucocorticoids a cytokine network including IL-1ß, TNFα, and IL-6 (Fournier et al. 2000). AGP binds steroid hormones and neutral lipophilic drugs and both, the immunomodulatory and binding activities of AGP are dependent on glycosylation status (Fournier et al. 2000). AGP and also part of the lipid binding fraction of albumin and their oxidised forms bind to HDL fractions and may evolve as useful biomarkers for the quantitative and qualitative evaluation of oxidative stress (Otagiri 2005).

Finally lymphotoxin α (LTA) has been identified as a candidate locus on Chr6p21 with susceptibility to MI with relevant SNPs in exon 1 G10A, intron 1 A252G and exon 3 Ter26Asn (Ozaki et al. 2002). 5-lipoxygenase activating protein (ALOX5AP) with an important role in stroke and MI (Kakonarson et al. 2005), Calpain 10 which cleaves ABCA1 at PEST domains (Wang et al. 2003) and retinol binding protein 4 (RBP4) which transports the important mediators RA/ATRA involved in high triglyceride low HDL syndromes and is involved in T2DM (Polonsky 2006)) and the potassium inward rectifier KCNJ9/GIRK3 for which noncoding SNPs were found associated with T2D in Pima Indians (Wolford et al. 2001; Vaughn et al. 2000), are all involved in the ABCA1/HDL pathway and recently our groupdemonstrated that ABCA1 and GIRK3 form a functional complex similarly to Kir6.2 and the SUR1 gene in the insulin secretion pathway (manuscript submitted). Insulin resistance in conjunction with elevated triglycerides, reduced HDL and the presence of small dense LDL associated with genetic alterations in the HDL-regulator-gene ABCA1, the HDL maturation enzyme LCAT and the apolipoprotein E-2 or E-4 allele as well as other abnormalities in the atheroprotective role of HDL are closely associated with the development of chronic renal disease. A progressive glomerulopathy with deposition of immune complexes was observed in ABCA1 knockout mice (Christiansen-Weber et al. 2000) as well as apo J/clusterin deficient mice (Rosenberg et al. 2002). A similar increase in
mesangial proliferation was found in ApoE-/- mice, but not in hyperlipidemic apoB overexpressing animals (Chen et al. 2001). These effects are at least in part based on the role of apolipoproteins in the metabolism of immune complexes respectively on the antiproliferative induction of matrix-heparansulfate-proteoglycans. The association of the
apoE genotype with terminal renal insufficiency in a Japanese population supports the relevance of this protein for kidney diseases (Oda et al. 1999). Experimental nephropathy in a rat model leads to changes in the local expression of scavenger receptor B1 and ABCA1 (Johnson et al. 2003), to the upregulation of HMG-CoA reductase and LDL receptors within proximal tubules (Zager et al. 2003) as well as to an altered hepatic synthesis of lipid metabolism enzymes (Liang et al. 2002). Furthermore, modulation of cellular lipid metabolism within renal tubular cells points to an important impacton kidney function. Raft association of nephrin and podocin within the glomerular diaphragma of the podocyte (Simons et al. 2001; Saleem 2002) might be responsible for modified cellular function during lipid loading (Figure 85).

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Glomerulum and proximal tubules are significantly involved in HDL metabolism and chronic kidney-failure is associated with reduced HDL-cholesterol and elevated triglycerides
(Samuelsson et al. 1997; Weinstock et al. 2001; Keane 2002). HDL apolipoproteins like Apo AI, Apo AIV, as well as preβ-HDL-precursors and Lecithin:Cholesterol Acyltransferase (LCAT) are filtered in the glomerulum and subsequently reabsorbed by the cubilin/amnionless/megalin receptor complex in the proximal tubules (Willnow et al. 1996; Birn et al. 2000; Strope et al. 2004). In contrast, patients with an impaired renal function loose apoA-I in the urine (Ritter et al. 2002). Apo AI and Apo AIV either undergo lysosomal degradation in proximal tubule cells (Dallinga-Thie et al. 2005; Haiman et al. 2005) or are secreted basolaterally through the ABCA1-pathway (Neufeld et al. 2002) and recycled into the lymph (Haiman et al. 2005). The mechanism switching Apo AI- and Apo AIV-processing from lysosomal degradation towards basolateral secretion is currently unknown. Besides the apical cubilin/amnionless/megalin receptor complex and the basolateral localised ABCA1 additional Apo AI interacting membrane proteins like the apical scavenger receptor B1 (SRB1), the cell membrane bound ATP synthase β-subunit (Martinez et al. 2003) and the modulator protein Apo AI binding protein (AI-BP) have been identified (Ritter et al. 2002). In megalin KO mice, no urinary loss of apoA-I could be observed, but the AI-BP level is elevated compared to wildtype (Faber et al. 2006).

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