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• Increased low-attenuation (soft) coronary plaques predict heart disease events. • Homozygous familial hypercholesterolemia (HoFH) patients have excess soft plaque. • Very small preβ-HDL (produced by plasma delipidation) accepts cell cholesterol. • In HoFH 7 weekly delipidated plasma treatments reduced soft coronary plaque 40%. • This therapy has promise for HoFH patients with significant soft coronary plaque. Increased cholesterol-rich, low-density, non-calcified atheromas as assessed by computer coronary tomography angiography analyses have been shown to predict myocardial infarction significantly better than coronary artery calcium score or the presence of obstructive coronary artery disease (CAD) as evaluated with standard coronary angiography. Low serum high-density lipoprotein (HDL) cholesterol values are an independent risk factor for CAD. Very small, lipid-poor preβ-1 HDL particles have been shown to be most effective in promoting cellular cholesterol efflux. HDL infusions have been documented to reduce aortic atherosclerosis in cholesterol-fed animal models. However, human studies using infusions of either the HDL mimetic containing recombinant apolipoprotein (apo) A-I Milano or Cerenis Compound-001 with native recombinant apoA-I have been mainly negative in promoting coronary atherosclerosis progression as assessed by intravascular ultrasound. In contrast, a study using 7 weekly infusions of autologous delipidated HDL in six homozygous familial hypercholesterolemic patients was effective in promoting significant regression of low-density non-calcified coronary atheroma regression as assessed by computed coronary angiography. This therapy has received Food and Drug Administration approval. Commonwealth Serum Laboratories has carried out a large clinical endpoint trial using an HDL complex (native apoA-I with phospholipid), and the results were negative. Our purpose is to review animal and human studies using various forms of HDL infusion therapy to promote regression of atherosclerosis. In our view, differences in results may be due to: 1) the HDL preparations used, 2) the subjects studied, and 3) the methods used to assess coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

• A patient with low HDL-cholesterol and corneal opacity was identified. • The patient showed no apparent atherosclerosis or CAD. • LCAT activity is relatively maintained and may be related to the patient's phenotype. • Novel frameshift mutation was identified in the APOA1 gene. • Aberrant structure of apoA-I might explain the retained LCAT activity. The proband was a 53-year-old Japanese woman. Despite having no atherosclerotic vascular lesions on a physiological examination, markedly decreased levels of high-density lipoprotein (HDL) were always noted at her annual medical checkup. She also had corneal opacities but neither xanthoma nor tonsillar hypertrophy. A biochemical examination showed decreased levels of both apolipoprotein A-I (apoA-I) (<5 mg/dL) and lecithin–cholesterol acyltransferase (LCAT) activity. Her brother and son also had low concentrations of HDL-cholesterol, suggesting the presence of a genetic abnormality. Therefore, a sequence analysis of the genes for ABCA1, LCAT and apoA-I proteins was performed in the proband. The analysis of the APOA1 gene revealed a novel homozygous two-nucleotide deletion in exon 4 (c.614_615delTC), which causes a frameshift after residue 205 of the apoA-I protein (p.Leu205fs). Since no mutation has been found in the ABCA1 or LCAT gene, functional abnormalities of the carboxyl-terminal region of the apoA-I protein in lipid binding might have caused the low HDL-cholesterol levels and decreased LCAT activity, possibly associated with corneal opacities but not premature CAD, in the patient. [ABSTRACT FROM AUTHOR]

ATP-binding cassette transporter A1 (ABCA1) is critical for the generation of nascent high-density lipoprotein (HDL) and plays important roles in cholesterol homeostasis. ABCA1 has two large extracellular domains (ECDs), which may interact directly with apolipoprotein A-I (apoA-I). However, the molecular mechanisms underlying HDL formation and the importance of ABCA1-apoA-I interactions in HDL formation remain unclear. We investigated the ABCA1-apoA-I interaction in photo-activated crosslinking experiments using sulfo-SBED-labeled apoA-I. ApoA-I bound to cells expressing ABCA1, but not to untransfected cells or cells expressing non-functional ABCA1. Binding was inhibited by sulfo-SBED-labeled apoA-I, and crosslinking of sulfo-SBED-labeled apoA-I with ABCA1 was inhibited by non-labeled apoA-I, suggesting that sulfo-SBED-labeled apoA-I specifically binds and crosslinks with functional ABCA1. Proteolytic digestion of crosslinked ABCA1 revealed that apoA-I bound the N-terminal half of ABCA1, and that the first ECD of ABCA1 is an apoA-I binding site. Abbreviations: ABC: ATP-binding cassette; apoA-I: apolipoprotein A-I; ATP: adenosine triphosphate; CHAPS: 3-(3-cholamidepropyl)dimethylammonio-1- propanesulphonate; DTT: dithiothreitol; ECD: extra cellular domain; EDTA: ethylenediaminetetraacetic acid; GFP: green fluorescent protein; HA: hemagglutinin; HDL: high density lipoprotein; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; sulfo-SBED: (sulfosuccinimidyl-2-[6-(biotinamido)-2-(p-azidobenzamido)hexanoamido] ethyl-1,3ʹ-dithiopropionate; NHS-ester, N-hydroxysuccinimide-ester [ABSTRACT FROM AUTHOR]

Background β 3 -adrenergic receptor (β 3 -AR) was shown to upregulate hepatic apolipoprotein A-I (apoA-I) expression and reverse atherosclerotic plaques in vivo experiments. However, the effect of β 3 -AR on apoA-I expression in vitro is unknown. The specific mechanism underlying β 3 -AR prevention of atherosclerosis is unclear. Objective The present study was designed to investigate the molecular mechanism of β 3 -AR–mediated regulation of hepatic apoA-I gene expression. Methods HepG2 cells were preincubated with/without a selective protein kinase A inhibitor (H-89) and then treated with a selective β 3 -AR agonist (BRL37344) or antagonist (SR59230A). The hepatic apoA-I expression was detected by reverse transcription real-time quantitative polymerase chain reaction and Western blot analysis. Enzyme-linked immunosorbent assay was used to evaluate the secretion of apoA-I. A recombinant plasmid containing the apoA-I promoter was constructed and transiently transfected into HepG2 cells, and dual-luciferase reporter assays were used to examine the activity of the apoA-I promoter. A chromatin immunoprecipitation polymerase chain reaction assay was used to evaluate binding activities of hepatocyte nuclear factor-4 (HNF-4), HNF-3, and early growth response protein-1. Results β 3 -AR activation significantly upregulated apoA-I expression, promoted apoA-I secretion, and enhanced the activities of the apoA-I promoter, HNF-4, and HNF-3 in hepatocytes, whereas early growth response protein-1 was not affected. Moreover, protein kinase A inhibition partially suppressed the activation of the apoA-I promoter, HNF-4, and HNF-3 and almost completely blocked the upregulation of apoA-I expression induced by β 3 -AR. Conclusion β 3 -AR activation increased the activities of the apoA-I promoter, HNF-4, and HNF-3, which might account for the mechanism of β 3 -AR-mediated upregulation of hepatic apoA-I expression. β 3 -AR might exert an anti-atherosclerotic effect by upregulating hepatic apoA-I expression and promoting the cholesterol reverse transport process. [ABSTRACT FROM AUTHOR]

The high density lipoprotein (HDL) fraction of human plasma consists of multiple subpopulations of spherical particles that are structurally uniform, but heterogeneous in terms of size, composition and function. Numerous epidemiological studies have established that an elevated high density lipoprotein cholesterol (HDL-C) level is associated with decreased cardiovascular risk. However, with several recent randomised clinical trials of HDL-C raising agents failing to reduce cardiovascular events, contemporary research is transitioning towards clinical development of the cardioprotective functions of HDLs and the identification of functions that can be exploited for treatment of other diseases. This review describes the origins of HDLs and the causes of their compositional and functional heterogeneity. It then summarises current knowledge of how cardioprotective and other functions of HDLs are regulated. The final section of the review summarises recent advances in the clinical development of HDL-targeted therapies. [ABSTRACT FROM AUTHOR]

Background & Aims The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process. Methods Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6–8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6–8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters. Results Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) ( P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls ( P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid ( P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV ( P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended. Conclusions The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons. [ABSTRACT FROM AUTHOR]

Abstract: A kindred affected with fish eye disease (FED) from Oklahoma is reported. Two probands with corneal opacification had mean levels of high-density lipoprotein (HDL) cholesterol (C), apolipoprotein (apo) A-I, and apoA-I in very large alpha-1 HDL particles that were 9%, 17%, and 5% of normal, whereas their parents and 1 sibling had values that were 61%, 77%, and 72% of normal. The probands had no detectable lipoprotein-X, and had mean low-density lipoprotein cholesterol (LDL-C) and triglyceride levels that were elevated. Their mean lecithin cholesterol acyltransferase (LCAT) activities, cholesterol esterification rates, and free cholesterol levels were 8%, 42%, and 258% of normal, whereas their parents and 1 sibling had values that were 55%, 49%, and 114% of normal. The defect was due to 1 common variant in the LCAT gene in exon 1: c101t causing a proline34leucine substitution and a novel mutation c1177t causing a threonine37methionine substitution, with the former variant being found in the father and 1 sibling, and the latter mutation being found in the mother, and both mutations being present in the 2 probands. FED is distinguished from familial LCAT deficiency (FLD) by the lack of anemia, splenomegaly, and renal insufficiency as well as normal or increased LDL-C. Both FLD and FED cases have marked HDL deficiency and corneal opacification, and FED cases may have premature coronary heart disease in contrast to FLD cases. Therapy, using presently available agents, in FED should be to optimize LDL-C levels, and 1 proband responded well to statin therapy. The investigational use of human recombinant LCAT as an enzyme source is ongoing. [Copyright &y& Elsevier]

Background: Because type 2 diabetes (T2D) is a coronary artery disease risk equivalent, it is important to identify difference in risk markers between cases with T2D and the metabolic syndrome (MetS) compared with those with MetS alone. We evaluated apolipoproteins as possible distinguishing markers in the Oklahoma Cherokee. Objective: To assess apolipoproteins (apo) A-I, B, and C-III in young adult Cherokee who have the metabolic syndrome (MetS), as defined by the National Cholesterol Education Program (NCEP), either with or without T2D. Methods: A cross-sectional comparison of young adult Oklahoma Cherokee, ages 18 to 40 years, was conducted to assess differences in the apolipoproteins caused by the presence or absence of T2D among those with MetS, after we adjusted for age and gender. Results: ApoA-I (P = .0222) and high-density lipoprotein cholesterol (HDL-C; P = .0364) were lower, and apoB (P = .0106) and the apoB to A-I ratio (P < .0001) were greater in participants with the MetS and T2D than in those with MetS but without T2D. However, cholesterol, triglyceride, low-density lipoprotein cholesterol, non-HDL-C, total apoC-III, non-HDL apoC-III and the bimodal lipoprotein distribution of apoC-III (apoC-III ratio) were not significantly different between the two groups. Conclusion: ApoA-I and HDL-C are lower and apoB and the apoB:A-I ratio are greater in those with MetS and T2D than in those who have the MetS but without T2D, suggesting that the presence of diabetes adversely influences plasma apoA-I and apoB levels. However, apoC-III and non-HDL apoC-III are unchanged by the addition of diabetes suggesting that the increased levels associated with MetS may precede T2D. [ABSTRACT FROM AUTHOR]

Abstract: LDL (Low Density Lipoprotein) is considered the major atherogenic lipoprotein whereas HDL (High Density Lipoprotein) is anti-atherogenic. In recent years also non-HDL cholesterol as well as TG (triglycerides) are included in guidelines defining cardiovascular (CV) risk and target values during lipid lowering treatment. In recent years apolipoproteins (apo) B, reflecting atherogenic, and apoA-I reflecting anti-atherogenic lipoproteins, have been shown to be superior to conventional lipids in predicting risk and reduction of events in lipid lowering trials using statins. These new data are reviewed. The apoB/apoA-I ratio, which reflects the cholesterol balance of the “bad” and “good” lipids, is a simple and accurate summary index of CV risk and it is better than the conventional LDL and other lipids as a risk marker and taget for therapy. [Copyright &y& Elsevier]

Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that are pertinent to its protective roles in cardiovascular, inflammatory and malignant pathologies. Despite the pleiotropy in ApoA-I functions, the regulation of intracellular ApoA-I levels remains poorly explored. HepG2 hepatoma cells and primary mouse hepatocytes were used as in vitro models to study the impact of genetic and chemical inhibitors of autophagy and the proteasome on ApoA-I by immunoblot, immunofluorescence and electron microscopy. Different growth conditions were implemented in conjunction with mTORC inhibitors to model the influence of nutrient scarcity versus sufficiency on ApoA-I regulation. Hepatic ApoA-I expression was also evaluated in high fat diet-fed mice displaying blockade in autophagy. Under nutrient-rich conditions, basal ApoA-I levels in liver cells are sustained by the balancing act of autophagy and of mTORC1-dependent de novo protein synthesis. ApoA-I proteolysis occurs through a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1 that targets ApoA-I to autophagosomes. However, upon aminoacid insufficiency, suppression of ApoA-I synthesis prevails, rendering mTORC1 inactivation dispensable for autophagy-mediated ApoA-I proteolysis. These data underscore the major contribution of post-transcriptional mechanisms to ApoA-I levels which differentially involve mTORC1-dependent signaling to protein synthesis and autophagy, depending on nutrient availability. Given the established role of ApoA-I in HDL-mediated reverse cholesterol transport, this mode of ApoA-I regulation may reflect a hepatocellular response to the organismal requirement for maintenance of cholesterol and lipid reserves under conditions of nutrient scarcity. • Autophagy and mTORC1-dependent de novo protein synthesis control ApoA-I expression under nutrient-rich conditions. • ApoA-I proteolysis involves a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1. • Upon aminoacid depletion, ApoA-I synthesis is suppressed and mTORC1 inactivation becomes dispensable for ApoA-I proteolysis. [ABSTRACT FROM AUTHOR]

Background Inflammation is a pathophysiological factor in diabetes and its cardiovascular complications. High-density lipoprotein (HDL) suppresses inflammation in healthy individuals. The relationship of HDL with diabetes and cardiovascular disease may be explained by HDL function rather than by HDL cholesterol level. In diabetes, HDL seems to become dysfunctional. Objective We performed a systematic review to answer the following research questions: Is the anti-inflammatory function of HDL diminished in individuals with diabetes and if so, what causes this? Methods We systematically searched Medline and Embase and included original research articles on the anti-inflammatory effects of HDL or HDL-based interventions in diabetes or diabetes models. We assessed the risk of bias of all included studies. Results Fourteen studies were included. These showed great heterogeneity in methodology, study populations, and diabetes models. Overall, HDL from subjects with type II diabetes displayed a reduced ability to suppress inflammatory processes and inflammation markers. However, the mechanisms and the in vivo effects remain largely unknown. No studies reported on HDL from individuals with other types of diabetes. In most studies, the risk of bias was high or could not be assessed. Conclusions HDL isolated from individuals with type II diabetes showed a decreased ability to suppress inflammation. However, the direction of causality and the underlying mechanisms are unknown and should be investigated. For development of treatments directed at restoring HDL anti-inflammatory function in diabetes, a standardized method for assessing HDL anti-inflammatory function needs to be developed and in vivo biomarkers must be identified. [ABSTRACT FROM AUTHOR]