Effect of desialylation of very low-density lipoproteins on their catabolism by lipoprotein lipase

Very low-density lipoproteins (VLDL) contain sialylated apolipoproteins (apo) (eg, apo CIII1-3) that inhibit apo CII activation of lipoprotein lipase (LPL) and also uptake of triglyceride (TG)-rich lipoproteins by the liver. Hypertriglyceridemic patients can have an excess of sialylated apo CIII (apo CIII1 or apo CIII2) in VLDL. These observations have prompted the notion that sialic acid in VLDL may impede LPL or receptor-mediated clearance of VLDL and thus result in hypertriglyceridemia. The aim of this study was to determine whether desialylation of VLDL altered their property as a substrate for LPL. VLDL isolated from five hypertriglyceridemic patients was desialylated with neuraminidase, labeled with a fluorescent probe, dansyl phosphatidylethanolamine and 600 micrograms of labeled VLDL TG were incubated with a constant amount of purified bovine LPL. The change in fluorescence against time was monitored on a recorder to yield curves representing continuous lipolysis of VLDL by LPL. Mean initial velocity of reaction (Vi) and extent of lipolysis measured as total increase in fluorescence over baseline at 30 minutes (F30/FO) were similar (Vi = 10.2 +/- 0.37 control v 10.2 +/- 0.42 u/min desialylated VLDL; F30/FO = 4.1 +/- 0.15, control v 4.1 +/- 0.07 desialylated VLDL; n = 5). Thus, sialic acid does not influence VLDL catabolism by LPL. Our study does not exclude a possible role of the sialic acid in receptor mediated uptake of remnants produced by initial catabolism of VLDL by LPL.     

Catabolism of low density lipoproteins by perfused rabbit livers: Cholestyramine promotes receptor-dependent hepatic catabolism of low density lipoproteins

Rabbits fed a wheat starch/casein diet develop a marked hypercholesterolemia accompanied by a decrease in the number of EDTA-sensitive binding sites on plasma membrane fractions of the liver for low density lipoproteins (LDL) and β-migrating very low density lipoproteins [Chao, Y.-S., Yamin, T.-T. & Alberts, A. W. (1982) J. Biol. Chem., in press]. Inclusion of 1% cholestyramine resin in this diet prevents the increase in plasma cholesterol, increases the removal of LDL from plasma, and increases the number of hepatic plasma membrane LDL-binding sites. To determine the functional role of hepatic LDL-binding sites in the catabolism of LDL, we studied the catabolism of ¹²⁵I-labeled LDL (¹²⁵I-LDL) by in situ perfused rabbit livers in a recirculating system. The rate of catabolism was measured from the increment of nonprotein-bound radioiodine in the perfusate. The receptor-dependent catabolism of LDL by the liver was calculated from the difference of hepatic catabolism of ¹²⁵I-LDL and catabolism of ¹²⁵I-labeled cyclohexanedione-modified LDL, which does not bind to LDL receptors. The data show that about 74% of LDL catabolized by perfused livers from chow-fed rabbits is through the receptor-dependent pathway and 26% is through the receptor-independent pathway. In rabbits fed a cholesterol diet, the hepatic catabolism of ¹²⁵I-LDL is reduced, and the receptor-dependent catabolism of ¹²⁵I-LDL is abolished. In rabbits fed the wheat starch/casein diet, the receptor-dependent catabolism of ¹²⁵I-LDL is reduced by 40% when compared with hepatic catabolism in chow-fed rabbits. Perfused livers from rabbits fed the wheat starch/casein diet supplemented with 1% cholestyramine show a 5,4-fold increase of receptor-dependent catabolism of ¹²⁵I-LDL when compared with that of livers from rabbits fed the wheat starch/casein diet alone. Thus, these studies demonstrate that the change in the number of rabbit hepatic membrane LDL receptors induced by dietary manipulation and drugs is correlated to the functional rate of removal of LDL by the liver.     

A quantitative trait locus influences coordinated variation in measures of ApoB-containing lipoproteins

Lipoprotein phenotypes are known to be strongly intercorrelated. These intercorrelations are due to genetic and environmental effects on common metabolic pathways. The purpose of this study was to determine if we could localize genes that exert pleiotropic effects on multiple related lipoprotein traits in humans. Using data from the San Antonio Family Heart Study, we extracted principal components from a set of 12 intercorrelated lipoprotein traits that included phenotypes reflecting lipid and protein concentrations and size distributions for LDLs and HDLs. Five principal components were extracted from the data and all were significantly heritable (h(2) = 0.41-0.57). When subjected to linkage analyses, only one, Component 5, returned a LOD score > or = 3 (LOD score was 3.0 at 38cM on chromosome 15; genome-wide P-value = 0.039). LDL median diameter (-0.529), non-HDLC (-0.422), and ApoB (-0.403) concentrations were the only traits with loadings (absolute value) >0.4, suggesting Component 5 is related to LDL size or perhaps more generally to beta-lipoprotein metabolism. Surprisingly, none of the 12 original lipoprotein traits had a LOD >1 in this region of chromosome 15. These data provide evidence for a novel gene, influencing beta-lipoprotein phenotypes, whose effect(s) is detected only when several lipoprotein traits are considered together.     

ApoB-containing lipoproteins promote infectivity of chlamydial species in human hepatoma cell line

AIM: To evaluate the direct binding of two main chlamydial biovars (C. trachomatis and C. pneumoniae) to plasma lipoproteins and its effect on chlamydial infection rate in human hepatoma cell line (HepG2 cells).METHODS: Murine plasma lipoproteins were fractionated and isolated using fast-performance liquid chromatography (FPLC), spotted on nitrocellulose membrane and incubated with chlamydial suspensions. Direct binding of chlamydial particles to lipoprotein fractions has been studied using lipopolysaccharide-specific antibodies in immuno-dot blot binding assay and immunoprecipitation analysis. Immunostaining protocol as well as flow cytometry analysis have been employed to study the infectivity rate of chlamydial species in HepG2 cells.RESULTS: Elementary bodies of both C. trachomatis and C. pneumoniae bind ApoB-containing fractions of plasma lipoproteins. That binding becomes stronger when heat-denatured FPLC fractions are used, suggesting a primary role of apolipoproteins in interaction between chlamydial particle and lipoprotein. Both chlamydial biovars efficiently propagate in human hepatoma cell line - HepG2 cells even in serum free conditions forming late-stage inclusion bodies and releasing extracellular elementary bodies. Preincubation of C. trachomatis and C. pneumoniae with native ApoB-containing lipoproteins enhances the rate of chlamydial infection in HepG2 cells.CONCLUSION: A productive infection caused by C. trachomatis and C. pneumoniae may take place in human-derived hepatocytes revealing hepatic cells as possible target in chlamydial infection. Obtained results may suggest the participation of lipoprotein receptors in the mechanism of attachment and/or entry of chlamydial particles into target cells.     

Endothelial lipase is increased by inflammation and promotes LDL uptake in macrophages

AIM: Endothelial lipase (EL) is a member of the lipoprotein lipase family that regulates HDL metabolism. EL is known to act as a bridging molecule for monocytes or lipoproteins in vascular endothelial cells. We investigated the role and regulatory mechanisms of EL expression in macrophages. METHODS: Macrophages originating from wild-type (EL+/+) and EL-deficient (EL-/-) mice were stimulated with lipopolysaccharide (LPS). The expression of EL mRNA was evaluated by northern blotting. DiI-LDL was used to measure the uptake of native low-density lipoprotein (nLDL). RESULTS: LPS increased EL mRNA levels by increasing intracellular oxidative stress in the macrophages. LPS did not affect EL expression in macrophages derived from Toll-like receptor 4 (TLR4) gene mutant mice, C3H/HeJ. The uptake of nLDL after LPS-treatment was significantly lower in macrophages from EL-/- mice than those from EL+/+ mice. Simvastatin suppressed the LPS-induced upregulation of EL expression and uptake of nLDL. CONCLUSIONS: EL expression is upregulated by LPS via TLR4 and promotes the uptake of nLDL by macrophages. Simvastatin inhibits the LPS-induced up-regulation and uptake in macrophages. Thus, our findings provide a novel role for EL in lipoprotein metabolism and would expand the range of anti-atherogenic effects of statins.     

Endothelial lipase and cholesterol metabolism

Endothelial lipase (EL), a new member of the lipase gene family, was recently cloned and has a significant role in plasma high-density lipoprotein levels (HDL). EL has a highly similar molecular homology to lipoprotein lipase and hepatic lipase. It is synthesized by endothelial cells and functions at the cell surface. EL primarily has phospholipase AI activity. Animals that overexpress EL showed decreased HDL cholesterol levels and those that lack EL show elevated levels of HDL cholesterol. The expression is highly regulated by cytokines and physical forces. These data suggest that EL may play a significant role in atherosclerosis.     

Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.

Branched esters of palmitic acid and hydroxy stearic acid (PAHSAs) are antiinflammatory and antidiabetic lipokines (1–3). PAHSA serum and adipose tissue levels correlate with insulin sensitivity and are decreased in insulin-resistant humans (2, 4). PAHSAs increase glucose-stimulated insulin secretion by enhancing the production of the gut-derived incretin glucagon-like peptide-1 (5, 6). The antiinflammatory effects of PAHSA isomers (2, 7, 8) are mediated via free fatty acid receptor 4 (FFAR4, GPR120) and modulate both innate and adaptive immune responses in a mouse colitis model (1) and type-1 diabetes (6). Therefore, PAHSAs have beneficial effects on both metabolism and the immune system (9).PAHSAs belong to the family of fatty acid (FA) esters of hydroxy FAs (HFAs) called FAHFAs, which are part of a much larger family of mono- or oligomeric FAHFA esters named estolides. Since FAHFAs contain only a single ester bond of one FA with one HFA (the estolide bond), they represent monoestolides (10). The position of the branching carbon atom defines the regioisomer (e.g., 5-PAHSA or 9-PAHSA). PAHSAs and other less-well-studied FAHFAs such as the oleic acid esters of hydroxy palmitic acid (OAHPAs) or the docosahexaenoic acid ester of 13-hydroxy linoleic acid (13-DHAHLA) derive from either dietary sources or de novo synthesis in adipose tissue and other organs (2, 11, 12). Nonesterified, free FAHFAs (free mono-estolides) can be esterified to glycerol to form FAHFA acylglycerols, which in combination with other FAs result in the formation of triacylglycerol (TAG) estolides, diacylglycerol (DAG) estolides, or monoacylglycerol (MAG) estolides. TAG estolides represent a major storage form of bioactive free FAHFAs and are present in plant oils (e.g., castor oil) (13, 14) and adipose tissue of mice (3, 15) and humans (16).Both the synthetic and catabolic pathways of FAHFAs and TAG estolides are insufficiently understood. The hydrolytic catabolism of FAHFAs and TAG estolides results in the generation of highly bioactive and physiologically relevant FAHFAs, HFAs, FAs, and DAGs. Given the structural and metabolic similarity between TAGs and TAG estolides, it seemed reasonable to suspect that canonical TAG lipases will be involved in FAHFA and TAG estolide degradation. Generally, the catabolism of TAGs in cells occurs in the cytosol (neutral lipolysis) or in lysosomes (acidic lipolysis). Neutral lipolysis represents the predominant pathway for the hydrolysis of lipid droplet-associated TAGs in adipocytes involving three major enzymes, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL). ATGL catalyzes the initial step of TAG hydrolysis, generating DAG and one FA (3, 17, 18). The enzyme belongs to the patatin-like phospholipase domain-containing (PNPLA) family of proteins comprising a number of lipid hydrolases (3, 15). ATGL is the most potent TAG hydrolase within this family but also exhibits some phospholipase, retinylesterase, and transacylase activities of undefined physiological relevance (17, 19, 20). For full TAG hydrolase activity, ATGL requires a coactivator named comparative gene identification-58 (CGI-58; also called α/β-hydrolase domain containing 5, ABHD5) (21–23). CGI-58 features α/β-hydrolase folds and also exerts some acyltransferase and protease activities (23–25). Yet, the physiological role of these activities remains elusive. ATGL exhibits unique regioselectivity for TAG substrates and preferentially hydrolyzes the sn-2 position of the glycerol chain of TAGs (26). Upon stimulation of ATGL by CGI-58 this regioselectivity broadens to the sn-1 but not the sn-3 position (26).HSL is rate-limiting for the second step of TAG lipolysis converting DAG to one FA and MAG (27). The enzyme preferentially catalyzes DAGs at the sn-3 position and cholesteryl esters (28, 29) but also cleaves TAGs (sn-1 and sn-3 position), retinylesters (30), or medium- and short-chain carboxylic acid glycerol esters (29). The enzyme is structurally unrelated to ATGL and does not require enzyme coactivators. Hormonal stimulation of neutral lipolysis by β-adrenoreceptor agonists such as catecholamines activates both ATGL and HSL by promoting the molecular interaction of ATGL with CGI-58 on the surface of TAG-containing lipid droplets (21, 31) and the translocation of HSL from the cytoplasm to lipid droplets. These processes involve the protein kinase A-dependent phosphorylation of perilipin-1, CGI-58, and HSL (31–33).Previous studies by Tan et al. (15) and our laboratory (3) demonstrated that ATGL and HSL are both able to hydrolyze FAHFA–glycerol ester bonds of TAG estolides. However, enzyme preferences for this reaction, the substrate requirements, or the contribution of these enzymes to hydrolyze the FA–HFA ester bond (estolide bond) in TAG estolides as well as in free FAHFAs remained unaddressed. Using a newly generated library of TAG estolides, we now show that ATGL and HSL play distinct roles in the formation of TAG estolides by transesterification reactions and the degradation of (TAG) estolides by hydrolysis reactions.     

Serum and urinary lipoproteins in the human nephrotic syndrome: evidence for renal catabolism of lipoproteins

The urinary excretion of lipoproteins and the possibility of catabolic alterations on glomerular filtration were investigated in four nephrotic subjects differing in etiology, serum lipoprotein profile, and 24 hr urinary output of protein and lipids. The apolipoproteins and lipoproteins of urine were compared with those of serum with respect to distribution profile, physical properties, and composition. Lipoprotein particles resembling the serum very low, intermediate, low, and high density lipoproteins (VLDL, IDL, LDL, and HDL, respectively) in density, particle size, and morphology were isolated from the urine. As expected from molecular sieving effects during glomerular filtration, the urinary HDL were more abundant than the lower density lipoproteins even when the plasma LDL was elevated markedly. However, little sieving effect was seen within the urinary HDL, which comprised a broad spectrum of particle sizes including the larger HDL₂, whose average diameter was similar to that of the plasma HDL. A sieving effect was not seen in the urinary LDL, except for a greatly increased proportion, about 20% of total particles, of HDL-like species. Intact apolipoproteins were not found in the concentrated urinary fraction isolated by ultrafiltration between the limits of 10⁴ and 5 × 10⁴ daltons. On the basis of immunoreactivity, gel electrophoresis, and amino acid composition, apolipoproteins B and AI are the major and minor proteins, respectively, of urinary LDL, and apo B is the major protein of the urinary IDL and VLDL. Apolipoproteins AI, AII, CI, CIII, and possibly AIV were isolated from the urinary HDL. As much as 20% of the protein moiety of the urinary HDL appeared to be large apolipoprotein fragments with molecular weights and isoelectric points similar to those of apo CII and apo CIII. The fragments were derived in part from apo AI, the least acidic form of which was lost preferentially. The lower density classes of urinary lipoproteins also appeared to have lost apo E and apo C's and to have undergone partial proteolysis. Apparently, the surface-exposed, readily exchangeable apolipoproteins are subject to proteolytic degradation upon glomerular filtration.     

The effects of tolbutamide on lipoproteins, lipoprotein lipase and hormone-sensitive lipase

Type 2 diabetic patients are at increased risk to develop atherosclerotic vascular disease. These patients are often treated with sulphonylurea derivatives, and it has been suggested that this treatment might contribute to the increased atherosclerotic process. The aim of the present study was therefore to investigate whether tolbutamide influences lipid metabolism in such a way that the atherosclerotic process may be promoted. Addition of tolbutamide (5-500 mg/l) to isolated rat fat adipocytes inhibited the lipoprotein lipase (LPL) activity in a dose-dependent manner to levels about 50% of those registered in the absence of tolbutamide. This effect was due to inhibition of the activation of the enzyme in the tissue and not to interference with the interaction of enzyme with its substrate. Addition of tolbutamide (500 mg/l) also inhibited noradrenaline (100 nM) and isoprenaline (40 nM)-induced lipolysis by 48.1 +/- 7.4% (mean +/- S.E.M.) and 47.3 +/- 5.5%, respectively. The decreased lipolysis in tolbutamide preincubated adipocytes was shown to be the result of an inhibition of the phosphorylation of hormone sensitive lipase (HSL). Three months of tolbutamide treatment (0.5 g t.i.d.) in diet treated type 2 diabetic patients did not influence the plasma concentrations of cholesterol, triglycerides, LDL cholesterol, HDL cholesterol as well as HDL triglycerides and HDL phospholipids, and there were no differences compared to placebo treated patients. There was a tendency towards a decrement in the elimination rate of exogenous triglycerides in the tolbutamide group (P = 0.0801). No differences between the groups and no treatment effects were seen on LPL and hepatic lipase activities. In conclusion, our in vitro data show that tolbutamide has dual effects on lipid transport, with impairment of the LPL system, which would tend to decrease plasma lipoproteins by reducing hepatic production of lipoproteins. In vivo, these two effects seem to balance each other and plasma lipoprotein levels remain unaffected.     

二甲双胍促进2型糖尿病小鼠支链氨基酸分解代谢

目的 通过观察二甲双胍（Met）对高脂联合链脲佐菌素（STZ）诱导的2型糖尿病（T2DM）小鼠支链氨基酸（BCAAs）分解代谢作用并探讨其作用机制。 方法 通过高脂饮食+注射小剂量链脲佐菌素（STZ）途径构建T2DM小鼠模型。经随机分组,将20只C57BL / 6J雄性小鼠归入下述四组:正常对照组,2型糖尿病（T2DM）组,T2DM+安慰剂（T2DM+Vehicle）组,T2DM+二甲双胍治疗（T2DM+MET）组。高效液相色谱-串联质谱法检测小鼠血浆中的BCAA水平。实时荧光定量PCR检测小鼠心脏、肝脏和骨骼肌中BCAA分解代谢相关分子mRNA水平。Western Blot方法检测限速酶支链α-酮酸脱氢酶（BCKDH）活性,即P-BCKD / BCKD的水平。 结果 与正常对照组相比,T2DM小鼠的血浆BCAA水平明显升高（P<0.05）;BCKDH酶活性显著降低（P<0.05）;BCAA分解代谢相关分子mRNA水平显著降低（P<0.05）。二甲双胍治疗的T2DM小鼠血浆BCAA含量显著降低（P<0.05）,促进BCAA分解代谢的相关分子的mRNA水平显著提高（P<0.05）,BCKDH活性显著提高（P<0.05）。 结论 二甲双胍治疗可纠正T2DM小鼠血浆BCAA水平,为临床治疗BCAA代谢异常相关疾病提供了新思路。     

Effect of lipoprotein lipase and hepatic triglyceride lipase activity on the distribution of apolipoprotein E among the plasma lipoproteins

The independent roles of human lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in determining the distribution of apolipoprotein E (apo E) among the plasma lipoproteins has been studied in vitro. In one series of three studies, postheparin plasma (10%) was incubated for 2 h with autologous plasma and the changes in the lipoprotein association of apo E after lipase exposure were determined after lipoprotein fractionation on 4% agarose columns. Specificity for LPL or HTGL was achieved by inhibition with goat anti-human HTGL or with 1 M NaCl, respectively. In another study, LPL and HTGL were partially purified from human postheparin plasma. The independent effects of these enzymes on the lipoprotein association of apo E were then examined after incubation of plasma in the absence or presence of one or both lipases. Data from both types of in vitro study showed that LPL-mediated triglyceride hydrolysis in the absence of HTGL activity was accompanied by a loss of apo E from triglyceride-rich lipoproteins, a gain or no change in the apo E-containing lipoproteins the size of intermediate density lipoproteins (IDL) and inconsistent changes in the apo E mass associated with high density lipoproteins (HDL). HTGL activity, on the other hand, in the absence of LPL, resulted in a redistribution of apo E from lipoproteins the size of IDL and a gain by those of HDL size. These studies thus support previous in vivo studies which pointed toward a specific role for HTGL in the processing of apo E containing IDL.     

Inflammation associated with the postprandial lipolysis of triglyceriderich lipoproteins by lipoprotein lipase

Although hypertriglyceridemia has repeatedly been implicated as an atherogenic condition, there are conflicting reports concerning the atherogenicity of products released from triglyceride-rich lipoproteins by lipoprotein lipase. The hydrolysis of triglyceride is a normal process by which chylomicrons and very low-density lipoproteins are metabolized and cleared from the circulation, which would suggest a beneficial role for lipoprotein lipase in reducing circulating levels of triglyceride and, therefore, reducing atherosclerotic burden. However, many in vitro studies have shown that lipolysis products such as fatty acids induce vascular cell inflammation, which can initiate or exacerbate atherosclerosis. This review summarizes the results and implications of recent studies on the effects of lipoprotein lipase on vascular inflammation, expanding upon existing controversy among human postprandial studies, animal models, and in vitro experimental models.     

All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified. Modulation of lipoprotein bioactivity by platelet-activating factor acetylhydrolase.

Mildly oxidized LDL has many proinflammatory properties, including the stimulation of monocyte chemotaxis and adhesion, that are important in the development of atherosclerosis. Although ApoB-containing lipoproteins other than LDL may enter the artery wall and undergo oxidation, very little is known regarding their proinflammatory potential. LDL, IDL, VLDL, postprandial remnant particles, and chylomicrons were mildly oxidized by fibroblasts overexpressing 15-lipoxygenase (15-LO) and tested for their ability to stimulate monocyte chemotaxis and adhesion to endothelial cells. When conditioned on 15-LO cells, LDL, IDL, but not VLDL increased monocyte chemotaxis and adhesion approximately 4-fold. Chylomicrons and postprandial remnant particles were also bioactive. Although chylomicrons had a high 18:1/18:2 ratio, similar to that of VLDL, and should presumably be less susceptible to oxidation, they contained (in contrast to VLDL) essentially no platelet-activating factor acetylhydrolase (PAF-AH) activity. Because PAF-AH activity of lipoproteins may be reduced in vivo by oxidation or glycation, LDL, IDL, and VLDL were treated in vitro to reduce PAF-AH activity and then conditioned on 15-lipoxygenase cells. All 3 PAF-AH-depleted lipoproteins, including VLDL, exhibited increased stimulation of monocyte chemotaxis and adhesion. In a similar manner, lipoproteins from Japanese subjects with a deficiency of plasma PAF-AH activity were also markedly more bioactive, and stimulated monocyte adhesion nearly 2-fold compared with lipoproteins from Japanese control subjects with normal plasma PAF-AH. For each lipoprotein, bioactivity resided in the lipid fraction and monocyte adhesion could be blocked by PAF-receptor antagonists. These data suggest that the susceptibility of plasma lipoproteins to develop proinflammatory activity is in part related to their 18:1/18:2 ratio and PAF-AH activity, and that bioactive phospholipids similar to PAF are generated during oxidation of each lipoprotein. Moreover, LDL, IDL, postprandial remnant particles, and chylomicrons and PAF-AH-depleted VLDL all give rise to proinflammatory lipids when mildly oxidized.     

Plasma metabolism of apoB-containing lipoproteins in patients with hepatic lipase deficiency

The metabolism of apoB-containing lipoproteins was investigated in the fasted state in three complete and three partial hepatic lipase (HL)-deficient subjects as well as in seven normotriglyceridemic (NTG) and two hypertriglyceridemic (HTG) controls using a 12 h primed-constant infusion of l-[5,5,5-d₃]-leucine. Two males with complete HL deficiency had increased plasma pool sizes of VLDL and IDL apoB-100 due to substantial reductions in fractional catabolic rate (FCR) of VLDL and IDL apoB-100 compared with both NTG and HTG controls. Reductions in LDL apoB-100 production rate (PR) were also observed in these two patients compared with NTG and HTG controls. Complete HL deficiency in the female proband was associated with normal VLDL apoB-100 kinetics, while plasma IDL apoB-100 pool size was increased by 124% due to an 82% decrease in the FCR of IDL apoB-100. The FCR and PR of LDL apoB-100 were reduced by 64 and 51%, respectively, in the proband compared with sex-matched controls. Partial HL-deficient patients were characterized by apoB-containing lipoprotein metabolism similar to that of controls. These results indicate that complete HL deficiency is associated with a potentially atherogenic apoB-containing lipoprotein metabolism that can be modulated considerably by secondary factors such as gender and abdominal obesity.