Hypo-High-Density Lipoproteinemia Is Associated With Preoperative Tear Size and With Postoperative Retear in Large to Massive Rotator Cuff Tears.

PURPOSE: To evaluate any association of specific subtypes of dyslipidemia with increments of preoperative tear size and with structural integrity after arthroscopic rotator cuff repair (ARCR). METHODS: One surgeon's consecutive patients who underwent ARCR from January 2011 to June 2018 were reviewed. The inclusion criteria were minimum 1-year follow-up ultrasonography, blood tests, physical examination, and provision of informed consent. The exclusion criteria were incomplete laboratory tests, history of acute trauma, previous shoulder surgery, isolated subscapularis tendon tear, inappropriate radiographs, no 1-year follow-up ultrasonography, and medication with lipid-lowering drugs. Associated preoperative factors for the increments of tear size and for retear after ARCR were determined using logistic regression analysis. Statistical significance was set at P < .05. RESULTS: Of the 502 ARCR patients from the study period, 195 patients (195 shoulders), with a mean age of 60.5 ± 7.5 years, met the inclusion and exclusion criteria. Age (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1-1.3), diabetes (OR, 3.6; 95% CI, 1.7-7.5), and hypo-high-density lipoproteinemia (hypo-HDLemia) (OR, 2.9; 95% CI, 1.5-5.6) were significantly associated with increments of preoperative tear size (P ≤ .01). Diabetes (OR, 3.0; 95% CI, 1.3-6.6), critical shoulder angle (OR, 2.0; 95% CI, 1.4-3.0), and tear size (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with retear after ARCR in overall study subjects (P = .01). Diabetes (OR, 3.8; 95% CI, 1.3-11.4), hypo-HDLemia (OR, 3.0; 95% CI, 1.1-8.8), and critical shoulder angle (OR, 1.5; 95% CI, 1.1-2.3) had significant associations with retear after ARCR in patients with a large to massive preoperative tear size (P ≤ .04). CONCLUSIONS: Preoperative hypo-HDLemia (high-density lipoprotein level < 40 mg/dL in male patients and < 50 mg/dL in female patients) has a significant association with the increments of preoperative tear size and with retear after ARCR in large- to massive-sized rotator cuff tears. LEVEL OF EVIDENCE: Level IV, case series.

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders.

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

Long-Term Energy Deficit in Mice Causes Long-Lasting Hypothalamic Alterations after Recovery.

Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1ß mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin.

Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of high-sensitivity C-reactive protein in apparently healthy Japanese.

The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese.

Effect of HDL composition and particle size on the resistance of HDL to the oxidation.

OBJECTIVES: To study the resistance of HDL particles to direct oxidation in respect to the distribution of HDL particles. DESIGN AND METHODS: We studied HDL composition, subclass distribution, and the kinetics of CuSO4-induced oxidation of total HDL and HDL3 in vitro in 36 low-HDL-C subjects and in 41 control subjects with normal HDL-C. RESULTS: The resistance of HDL3 to oxidation, as assessed from the propagation rate was significantly higher than that of total HDL. The propagation rate and diene formation during HDL oxidation in vitro was attenuated in HDL derived from low-HDL-C subjects. Propagation rate and maximal diene formation during total HDL oxidation correlated significantly with HDL mean particle size. The propagation rate of total HDL oxidation in vitro displayed a significant positive association with HDL2 particle mass and HDL mean particle size by multiple regression analyses. CONCLUSIONS: These observations highlight that the distribution of HDL subpopulations has important implications for the potential of HDL as an anti-oxidant source.

A Low Early High-density Lipoprotein Cholesterol Level Is an Independent Predictor of In-hospital Death in Patients with Acute Coronary Syndrome.

Objective In patients with acute coronary syndrome (ACS), low high-density lipoprotein cholesterol (HDL-C) levels in samples collected after an overnight fast are diagnostic indicators and well-established predictors of adverse outcomes. However, the relationship between the HDL-C levels in samples collected just after arrival (early HDL-C) and in-hospital mortality remains unknown. The purposes of the present ACS study were to (1) evaluate the association between the early HDL-C levels of patients and in-hospital mortality and (2) compare the early HDL-C level with other well-known determinants associated with in-hospital mortality. Methods This retrospective study surveyed 638 consecutive ACS patients and then assessed the possible determinants of in-hospital mortality. All initial blood samples, including that for early HDL-C, were drawn within one hour of arrival. Results In the present study, the overall in-hospital mortality was 5.9%. A multivariable analysis showed that a low early HDL-C [odds ratio (OR) 2.53, 95% confidence interval (CI) 1.14-5.62], elevated troponin T (OR 4.40, 95% CI 1.26-15.29) and high Killip class (OR 15.41, 95% CI 7.29-32.59) were independent predictors of in-hospital mortality. A Kaplan-Meier survival analysis indicated that there the in-hospital outcome for the low early HDL-C group was significantly worse than that for the high early HDL-C group (age- and gender-adjusted hazard ratio 2.40, 95% CI 1.15-5.00, p=0.02). Conclusion ACS patients with low early HDL-C levels had higher in-hospital mortalities than those who did not have low early HDL-C levels. In addition to the already well-known determinants, low early HDL-C should also be considered as an independent predictor of in-hospital mortality in ACS patients who present to a cardiac care unit.

Predominance of a proinflammatory phenotype in monocyte-derived macrophages from subjects with low plasma HDL-cholesterol.

OBJECTIVE: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation. METHODS AND RESULTS: Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects. CONCLUSIONS: The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.

Effects of dietary sodium on reactive oxygen species formation and endothelial dysfunction in low-density lipoprotein receptor-deficient mice on high-fat diet.

Hypertension and high serum cholesterol level are important risk factors for atherosclerosis and coronary heart disease. In the present study we tested the hypothesis whether high sodium intake, when given in combination with Western type high-fat diet, induces endothelial dysfunction and promotes atherosclerosis. Furthermore, the role and enzyme sources of increased oxidative stress were examined. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) and control C57Bl/6 mice received either high-fat, normal-sodium diet (fat 18% and cholesterol 0.5%; NaCl 0.7%; w/w) or high-fat, high-sodium diet (7% NaCl w/w) for 12 weeks. Superoxide formation was assessed by lucigenin enhanced chemiluminescence, endothelial functions were examined ex vivo, and atherosclerotic lesions from the aorta were assessed by light microscopy. High-fat, high-sodium diet increased systolic blood pressure in LDLR(-/-) mice but not in C57Bl/6 mice, whereas it induced cardiac hypertrophy in both mouse strains. Dietary combination of fat and sodium induced endothelial dysfunction in LDLR(-/-) mice. Preincubation with a superoxide scavenger Tiron normalized endothelial dysfunction, whereas the hydrogen peroxide scavenger catalase did not alter endothelial function. High sodium intake induced superoxide formation in LDLR(-/-) mice on high-fat diet. Stimulation of muscarinic receptors in the endothelial cells by acetylcholine increased superoxide generation, whereas preincubation with the nitric oxide synthase (NOS) inhibitor L-arginine methyl ester or endothelium removal reduced superoxide production. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase by apocynin decreased vascular superoxide formation whereas the xanthine oxidase inhibitor oxypurinol did not significantly affect oxidative stress in LDLR(-/-) mice. In conclusion, the detrimental effects of dietary sodium on endothelial function and progression of atherosclerosis in LDLR(-/-) mice on high-fat diet are mediated by increased ROS formation mainly through uncoupled NOS and NADPH oxidase. The present study also underscores the importance of superoxide and endothelial NOS uncoupling in the pathogenesis of endothelial dysfunction.

Low serum levels of High-Density Lipoprotein cholesterol (HDL-c) as an indicator for the development of severe postpartum depressive symptoms.

Postpartum depression (PPD) is a psychiatric complication of childbirth affecting 10-20% of new mothers and has negative impact on both mother and infant. Serum lipid levels have been related to depressive disorders, but very limited literatures are available regarding the lipid levels in women with postpartum depression. The present study is aimed to examine the association of serum lipids with the development of postpartum depressive symptoms. This is a cross sectional study conducted at a tertiary care hospital in South India. Women who came for postpartum check-up at 6th week post-delivery were screened for PPD (September 2014-October 2015). Women with depressive symptoms were assessed using EPDS (Edinburgh Postnatal Depression Scale). The study involved 186 cases and 250 controls matched for age and BMI. Serum levels of lipid parameters were estimated through spectrophotometry and the atherogenic indices were calculated in all the subjects. Low serum levels of Total Cholesterol (TC) and High Density Lipoprotein cholesterol (HDL-c) were significantly low in PPD women with severe depressive symptoms. The study recorded a significant negative correlation between HDL-c and the EPDS score in PPD women (r = -0.140, p = 0.05). Interestingly, the study also observed a significant negative correlation between Body Mass Index (BMI) and EPDS scores in case group (r = -0.146, p = 0.047), whereas a positive correlation between the same in controls (r = 0.187, p = 0.004). Our study demonstrated that low levels of serum HDL-c is correlated with the development of severe depressive symptoms in postpartum women. Study highlights the role of lipids in the development of postpartum depressive symptoms.

Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia.

Steinberg and colleagues have previously described a unique kindred with normotriglyceridemic hypobetalipoproteinemia (1979. J. Clin. Invest. 64:292-301). In a reexamination of this kindred, we found an abnormal apolipoprotein (apo) B species, apo B-37 (203,000 mol wt), in the plasma lipoproteins of multiple members of the kindred. In affected individuals apo B-37 was found in very low density lipoproteins, along with the normal apo B species, apo B-100 and apo B-48. High density lipoproteins (HDL) also contained apo B-37, but no other apo B species. The first 13 amino-terminal amino acids of apo B-37 were identical to those of normal apo B-100. We utilized a panel of 18 different apo B-specific monoclonal antibodies and polyclonal antisera specific for apo B-37 and the thrombin cleavage products of apo B-100 to map apo B-37 in relation to apo B-100, apo B-48, and the thrombin cleavage products of apo B-100. The results of those immunochemical studies indicated that apo B-37 contains only amino-terminal domains of apo B-100. In affected individuals, the majority of apo B-37 in plasma was contained in the HDL density fraction. Within that fraction apo B-37 was found on discrete lipoprotein particles, termed Lp-B37, that had properties distinct from normal HDL particles containing apo A-I. This report documents for the first time the existence of an abnormal apo B species in humans. Further study of apo B-37 and lipoprotein particles containing apo B-37 should lead to an improved understanding of apo B structure and function.

Radioimmunoassay of human arginine-rich apolipoprotein, apoprotein E. Concentration in blood plasma and lipoproteins as affected by apoprotein E-3 deficiency.

A radioimmunoassay for apolipoprotein E in human blood serum has been developed that measures equally the major polymorphic species of the protein (apolipoproteins E-1, E-2, E-3, and E-4) and the apo E in the dimer of apolipoproteins E and A-II. The assay is specific and yields values for apolipoprotein E in very low density lipoproteins that agree closely with those obtained by a quantitative electrophoretic method. Apolipoprotein E is also present in at least one species of high density lipoprotein, but the content of apolipoprotein E in the lipoprotein fractions of plasma is uncertain owing to dissociation during ultracentrifugation. The concentration of apolipoprotein E is higher in serum of normolipidemic, premenopausal women than in men of comparable age and is a direct function of the serum triglyceride level. Apolipoprotein E levels are increased out of proportion to triglyceride levels in hyperlipidemic patients with familial dysbetalipoproteinemia (homozygotes for lack of apolipoprotein E-3). Heterozygous relatives of homozygotes have significantly higher apolipoprotein E levels in serum than unaffected relatives. The concentration of partially degraded (remnant) triglyceride-rich lipoproteins also appears to be increased in heterozygotes, who comprise about 15% of the population.

Properties of the plasma very low and low density lipoproteins in Tangier disease.

The absence of normal high density lipoproteins (HDL) in Tangier disease is well established, but the properties of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in this disorder have not been well defined. The profiles obtained by analytic ultracentrifugation and the chemical composition, morphology, and electrophoretic mobility of Tangier and normal VLDL and LDL were compared. Apolipoproteins were fractionated by gel chromatography and characterized by amino acid analysis, polyacrylamide-gel electrophoresis, and immunochemical reactivity. Concentrations of low density lipoproteins of S(f) (o) 0-12 were reduced in three of six Tangier plasmas studied by analytic ultracentrifugation. Accumulation of intermediate density lipoproteins (S(f) (o) 12-20) was not observed. Two subjects with hypertriglyceridemia had normal VLDL (S(f) (o) 20-400) levels, suggesting that abnormalities of chylomicron metabolism probably account for the hypertriglyceridemia frequently observed in this disorder. Tangier VLDL migrate more slowly than normal VLDL on paper electrophoresis, yet their morphology, gross chemical composition, and qualitative apolipoprotein content are similar. Quantitative abnormalities in C-apolipoproteins, however, were observed in Tangier VLDL. When patients were consuming unrestricted diets, C apoproteins accounted for 19-49% of the protein in lipoproteins of d < 1.006 g/ml. Ingestion of low-fat, high-carbohydrate diets reduced the VLDL-C-apoprotein content in all Tangier patients (mean = 17% of VLDL protein vs. 43% in controls). These findings suggested that a major proportion of the C apoproteins in Tangier plasma is associated with chylomicrons or their remnants, perhaps because the C-apoprotein reservoir normally provided by HDL is absent. This secondary mechanism for C-apoprotein conservation is lost when dietary fat is withdrawn.LDL-2 (1.035 < d < 1.063) from Tangier and control plasma had identical electrophoretic mobilities. Tangier LDL-2 had slightly smaller median diameters (210-225 A vs. 230-240 A in controls) and a quite different composition than normal LDL-2. Triglyceride accounted for a mean of 29% of Tangier LDL-2 mass (control = 6%) and the cholesteryl ester content was reduced by about 50%. Thus, HDL may be required for the generation of chemically normal LDL. Alternatively, the fundamental defect in Tangier disease may involve all lipoprotein classes.

Comparative in vitro study of the pro-apolipoprotein A-I to apolipoprotein A-I converting activity between normal and Tangier plasma.

We examined the ability of the plasma of a 52-yr-old male Tangier patient to effect the conversion of radiolabeled pro-apolipoprotein A-I (apo A-I), isolated from hepatoma cell culture media, into mature apo A-I. The conversion was assessed by amino-terminal sequence analysis, isoform patterns with two-dimensional gel electrophoresis, and a rapid assay based on the different solubilities of intact pro-apo A-I and its hexapeptide prosegment in 10% trichloroacetic acid. We found that the converting activity of Tangier plasma was comparable to that exhibited by control normolipidemic plasma and that in both cases pro-apo A-I was correctly processed at the Gln-Asp bond. After ultracentrifugal fractionation of Tangier plasma at d = 1.21 g/ml, the pro-apo A-I-to-mature apo A-I converting activity was mainly recovered in the middle fraction of d = 1.225 g/ml and was at least 10-fold more effective than the top and bottom fractions. In contrast, in normal plasma the activity was only present in the top and bottom fractions. It has been previously established that in Tangier plasma the pro-apo A-I/apo A-I ratio is significantly higher than normal (1 vs. 0.02). Our studies suggest that this abnormal ratio is not the result of a reduced converting enzyme activity and may relate to differences in turnover rates between Tangier and normal plasma apolipoproteins.

Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo.

Previous data suggest that apolipoprotein (apo) CIII may inhibit both triglyceride hydrolysis by lipoprotein lipase (LPL) and apo E-mediated uptake of triglyceride-rich lipoproteins by the liver. We studied apo B metabolism in very low density (VLDL), intermediate density (IDL), and low density lipoproteins (LDL) in two sisters with apo CIII-apo AI deficiency. The subjects had reduced levels of VLDL triglyceride, normal LDL cholesterol, and near absence of high density lipoprotein (HDL) cholesterol. Compartmental analysis of the kinetics of apo B metabolism after injection of 125I-VLDL and 131I-LDL revealed fractional catabolic rates (FCR) for VLDL apo B that were six to seven times faster than normal. Simultaneous injection of [3H]glycerol demonstrated rapid catabolism of VLDL triglyceride. VLDL apo B was rapidly and efficiently converted to IDL and LDL. The FCR for LDL apo B was normal. In vitro experiments indicated that, although sera from the apo CIII-apo-AI deficient patients were able to normally activate purified LPL, increasing volumes of these sera did not result in the progressive inhibition of LPL activity demonstrable with normal sera. Addition of purified apo CIII to the deficient sera resulted in 20-50% reductions in maximal LPL activity compared with levels of activity attained with the same volumes of the native, deficient sera. These in vitro studies, together with the in vivo results, indicate that in normal subjects apo CIII can inhibit the catabolism of triglyceride-rich lipoproteins by lipoprotein lipase.

Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier).

Tangier disease is a rare familial disorder characterized by enlarged orange tonsils, transient peripheral neuropathy, hepatosplenomegaly, and lymphadenopathy, as well as striking reductions in plasma high density lipoproteins (HDL) and their major protein constituents, apolipoproteins (apo)A-I and A-II. In order to test the hypothesis that Tangier patients have abnormal apoA-I or apoA-II, the in vitro lipoprotein binding and in vivo metabolic characteristics of these proteins isolated from normal and Tangier plasma, were studied in normal subjects and patients with Tangier disease. After incubation with normal plasma, significantly greater percentages of radiolabeled Tangier apoA-I were associated with the 1.063-g/ml supernate (6%) and the 1.21 g/ml infranate (19%), and a lower percentage with HDL (75%), than those observed for normal apoA-I (2, 8, and 90%, respectively). In contrast, the lipoprotein binding properties of normal and Tangier apoA-II were very similar. Following the injection of radiolabeled normal and Tangier apoA-I into normal subjects (n = 4), the mean residence times of the specific activity for apoA-I(Tangier) were significantly lower, both in plasma (1.29 d) and in HDL (1.34 d), than those observed for normal apoA-I (3.80 and 4.06 d). In Tangier homozygotes the decay rates of these tracers were very rapid and were similar. No significant differences between the kinetics of normal and Tangier apoA-II were observed in normal subjects (n = 2). Tangier homozygotes (n = 3) had mean plasma HDL cholesterol, apoA-I, and apoA-II concentrations that were 4, 2, and 11% of normal (n = 24), respectively, whereas for heterozygotes (n = 3) these values were 46, 62, and 68% of normal. In homozygotes, in contrast to normals or heterozygotes, a significant fraction of both apoA-I and apoA-II were found in the 1.063-g/ml supernate instead of in HDL. Homozygotes had apoA-I(Tangier) synthesis rates and residence times that were 41 and 5% of values observed for normal apoA-I in normal subjects, and for apoA-II in homozygotes, these parameters were 63 and 18% of normal. Heterozygotes had apoA-I synthesis rates and residence times that were 92 and 66% of normal, and for apoA-II these values were 101 and 64% of normal. These data are consistent with the concept that apoA-I(Tangier) is functionally and metabolically distinct from normal apoA-I, and is the cause of the striking hypercatabolism of apoA-I and apoA-II, and the lipoprotein abnormalities observed in Tangier disease.

High density lipoproteins, but not other lipoproteins, provide a vehicle for sterol transport to bile.

Unesterified cholesterol (UC) that is taken up by the liver from lipoproteins is rapidly mixed by exchange with liver UC. Thus, it is not possible to quantitate the transport of UC from different lipoproteins into bile using radiolabeled UC. However, plant sterols do not exchange with UC and are secreted in bile with the same kinetics as UC. To compare the contribution to bile of sterols from different lipoproteins, we perfused isolated rat livers with VLDL, LDL, and HDL that were obtained from patients with hereditary phytosterolemia and were rich in plant sterols. After 30-min recirculating perfusions, hepatic concentrations of plant sterols were not different after different lipoproteins were perfused. However, biliary plant sterol secretion was markedly different: with the perfusion of either VLDL or LDL there was no increase in plant sterols in bile, but with perfusion of HDL, the secretion of plant sterols was increased two- to threefold (P = 0.0005). The increase in biliary plant sterols was detected 5-10 min after HDL was added to perfusates and was similarly large for each of three individual plant sterols that was tracked. Results show that when sterol transport from lipoproteins into bile can be determined, only HDL provides a vehicle for UC elimination in bile that is consistent with its putative function in reverse cholesterol transport.

Hypolipoproteinemia and hyperinflammatory cytokines in serum of severe and moderate traumatic brain injury (TBI) patients.

Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS

Differential diagnosis of familial high density lipoprotein deficiency syndromes.

Monogenic high density lipoprotein (HDL) deficiency, because of defects in the genes of apolipoprotein A-I (apoA-I), adenosine triphosphate binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT), can be assumed in patients with HDL cholesterol levels below the fifth percentile within a given population. As in a first step underlying diseases should be excluded. Patients with a virtual absence of HDL must undergo careful physical examination to unravel the clinical hallmarks of certain HDL deficiency syndromes. In addition, family studies should be initiated, to demonstrate the vertical transmission of the low HDL cholesterol phenotype. Definitive diagnosis requires specialized biochemical tests and the demonstration of a functionally-relevant mutation in one of the three discussed candidate genes. As yet no routinely used drug is able to increase HDL cholesterol levels in patients with familial low HDL cholesterol so that prevention of cardiovascular disease in these patients must be focused on the avoidance and treatment of additional risk factors.

HDL: the 'new' target of cardiovascular medicine.

Clinical, experimental and epidemiological research has shown the undeniable causal relationship between low HDL plasma concentrations and cardiovascular disease. Low HDL levels are present in about 10% of the general population and represent the most frequent form of dyslipidemia in patients with coronary disease. Reduced HDL concentrations seem to be unable to eliminate efficiently the cholesterol excess at vascular wall level, contributing to the onset of the inflammatory response that typically occurs in the pathogenesis of atherosclerosis right from its earliest stages. The results of numerous studies quite convincingly suggest that HDL is capable of exerting anti-inflammatory activity either directly or by modulating the expression of a number of acute phase proteins. Although the therapeutic options currently available for raising HDL levels still show modest efficacy, both in experimental and pre-clinical fields, genetic investigation and specifically aimed pharmacological treatment have produced more encouraging results, shedding some light on the concrete possibility of being able to treat this disease in the very near future.

Self-adaptive modification of red-cell membrane lipids in lecithin: cholesterol acyltransferase deficiency. Lipid analysis and spin labeling.

In a patient with lecithin: cholesterol acyltransferase deficiency, free cholesterol was markedly increased, and esterified cholesterol was diminished. In the patient's plasma, an increase in phosphatidylcholine (PC) and a decrease in sphingomyelin were observed. Concomitantly, an increase in a shorter acyl chain 16:0 was noted in PC, sphingomyelin and phosphatidylethanolamine (PE). In contrast to these results, longer chains such as 22:0 and 24:0 were decreased, especially in sphingomyelin. Unsaturated double bonds such as 18:1 was also increased in PC and PE. In the red-cell membrane lipids, the increase in free cholesterol was counteracted by an increase in PC and by a decrease in sphingomyelin and PE, reflecting changes in the patient's plasma lipids. Increased 16:0 (in PC) and decreased 18:0 and 24:0 were observed. The increased plasma free cholesterol due to metabolic defect (lecithin: cholesterol acyltransferase deficiency) led to decreased red-cell membrane fluidity. This effect appeared to be counteracted by changing phospholipid composition (increased PC and decreased sphingomyelin and PE), by increasing shorter chains (16:0), by decreasing longer chains (18:0 and 24:0) and by increasing unsaturated double bonds (18:2). These results can be interpreted as a self-adaptive modification of lecithin: cholesterol acyltransferase deficiency-induced red-cell membrane abnormalities, to maintain normal membrane fluidity. This speculation was supported by the ESR spin-label studies on the patient's membrane lipids. The normal order parameters in intact red cells and in total lipid liposomes were decreased if cholesterol-depleted membrane liposomes were prepared. Thus, the hardening effect of cholesterol appeared to be counteracted by the softening effects described above. Overall membrane fluidity in intact red cells of the lecithin: cholesterol acyltransferase-deficient patient was maintained normally, judged by order parameters in ESR spin-label studies.