The value of HDL genetics

PURPOSE OF REVIEW: To review studies on hereditary disorders of high-density lipoprotein (HDL) metabolism and studies on HDL genetics in mice, which have both provided valuable insight into the pathways of this intriguing lipoprotein and moreover revealed targets to raise HDLc to reduce atherosclerosis. RECENT FINDINGS: To date, as many as 11 genes are considered key players in the synthesis, maturation, conversion and/or catabolism of HDL. Five of these genes have been identified in humans, APOA1, LCAT, ABCA1, LIPC, and CETP, whereas the other six genes have been identified in mice, SCARB1, ABCG1, ATPB5, PLTP, LIPG and APOM. Genetic association studies are as yet the best line of evidence of the roles of the 'murine genes' in human HDL pathways. In addition to recent genetic association studies, a third section describes exciting news on six newly proposed HDL genes VNN1, GALNT2, MMAB/MVK, CTalpha, BMP-1 and SIRT1. SUMMARY: This review provides a summary of the current literature on the genetics of HDL. New information from this research area may assist us in obtaining a better understanding of HDL biology and identifying novel pharmacological targets.     

The HDL Proteome Watch: Compilation of studies leads to new insights on HDL function

Purpose of reviewHigh density lipoproteins (HDL) are a heterogeneous family of particles that contain distinct complements of proteins that define their function. Thus, it is important to accurately and sensitively identify proteins associated with HDL. Here we highlight the HDL Proteome Watch Database which tracks proteomics studies from different laboratories across the world.Recent findingsIn 45 published reports, almost 1000 individual proteins have been detected in preparations of HDL. Of these, 251 have been identified in at least three different laboratories. The known functions of these consensus HDL proteins go well beyond traditionally recognized roles in lipid transport with many proteins pointing to HDL functions in innate immunity, inflammation, cell adhesion, hemostasis and protease regulation, and even vitamin and metal binding.SummaryThe HDL proteome derived across multiple studies using various methodologies provides confidence in protein identifications that can offer interesting new insights into HDL function. We also point out significant issues that will require additional study going forward.     

The complexity of mucins

Mucins represent the main components of gel-like secretions, or mucus, secreted by mucosae or some exocrine glands. These high-molecular-weight glycoproteins are characterized by the large number of carbohydrate chains O-glycosidically linked to the peptide. The determination of mucin molecular weight and conformation has been controversial for several reasons: 1) the methods used to solubilize mucus and to purify mucins are different and 2) the molecules have a strong tendency to aggregate or to bind to other molecules (peptides or lipids). Recently, electron microscopy has shown the filamentous shape of most mucins and their polydisperse character which, in some secretions, might correspond to a polymorphism of the peptide part of these molecules. The recent development of high pressure liquid chromatography and high-resolution proton NMR spectroscopy has allowed major progress in the structural study of mucin carbohydrate chains. These chains may have from 1 to about 20 sugars and bear different antigenic determinants, such as A, B, H, I, i, X, Y or Cad antigens. In some mucins, such as human respiratory mucins, the carbohydrate chain diversity is remarkable, which raises many questions. Mucins are molecules located at the interface between mucosae and the external environment. The carbohydrate chain diversity might allow many interactions between mucins and microorganisms and play a major role in the colonization or the defense of mucosae.     

The complexity of simplicity

What is the minimum number of genes or functions necessary to support cellular life? The concept of a 'minimal genome' has become popular, but is it a useful concept, and if so, what might a minimal genome encode? We argue that the concept may be useful, even though the goal of defining a general minimal genome may never be attained.     

The complexity of tetraspanins

Tetraspanins compose a family of structurally related molecules with four transmembrane domains. A total of 33 tetraspanins are present in the human genome, and tetraspanins are also found in plants and certain fungi. A well-known property of tetraspanins is their ability to interact with one another and many other surface proteins, which led to the suggestion that they organize a network of molecular interaction referred to as the 'tetraspanin web', and that they play a role in membrane compartmentalization. Recent studies of the dynamics of these molecules provided important new information that helped refining the models of this 'web'. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of the tetraspanins, in particular in immune response, sperm-egg fusion, photoreceptor function and the normal function of certain epitheliums or vascular development. However, in several examples, the phenotypes of tetraspanin-knockout mice are relatively mild or restricted to a particular organ, despite a wide tissue distribution.     

The interaction of lipolysis products of very low density lipoprotein with plasma high density lipoprotein (HDL): perfusate HDL with plasma HDL subfractions

The nature of the interaction of high density lipoproteins (HDL), formed during lipolysis of human very low density lipoprotein (VLDL) by perfused rat heart, with subfractions of human plasma HDL was investigated. Perfusate HDL, containing apoliproproteins (apo) E, C-II, and C-III but no apo A-I or A-II, was incubated with a subfraction of HDL (HDL-A) containing apo A-I and A-II, but devoid of apo C-II, C-III, and E. The products of the incubation were resolved by heparin-Sepharose or hydroxylapatite chromatography under conditions which allowed the resolution of the initial HDL-A and perfusate HDL. The fractions were analyzed for apolipoprotein content and lipid composition and assessed for particle size by electron microscopy. Following the incubation, the apo-E-containing lipoproteins were distinct from perfusate HDL since they contained apo A-I as a major component and apo C-II and C-III in reduced proportions. However, the HDL-A fraction contained apo C-II and C-III as major constituents. Associated with these changes in apolipoprotein composition, the apo-E-rich lipoproteins acquired cholesteryl ester from the HDL-A fraction and lost phospholipid to the HDL-A fraction. The HDL-A fraction maintained a low unesterified cholesterol/phospholipid molar ratio (0.23), while the apo-E-containing lipoproteins possessed a high ratio (0.75) characteristic of the perfusate HDL.(ABSTRACT TRUNCATED AT 250 WORDS)     

The structural complexity of DNA templates—Implications on cellular complexity

A previously formulated procedure for the quantitative evaluation of the complexities of molecules and biostructures is applied to assess the complexities of selected genomic DNA sequences. These include: (1) Several E. coli genes, including lacI, as examples of DNA sequences which are nearly as complex as possible (relative complexity=∼1). This is verified by the Lempel-Ziv (LZ) complexity analysis. (2) The telomere of a yeast chromosome, which has a considerable number of regular features that reduce complexity; the telomere shows indeed a lower structural complexity value. (3) A segment of human DNA, gene p53, which has a certain number of regular features such as 29 interspersed alu elements; these features cause a certain reduction in the complexity of the p53 gene, but do not invalidate the (previous) overall conclusion that template complexity is very high. The close to maximal complexity of the transcribed regions of p53 is validated by the LZ compression analysis. The general conclusion is that DNA base sequence composition is the dominant factor determining cellular complexity. The high complexity of DNA arrived at is a direct consequence of the template character of DNA and reflects the role of genomic DNA as a principal regulating element of a cell. It will be a challenge to find systems of lower complexity with the ability to respond to challenges from the environment to the extent that DNA templated systems do. Cellular complexity and template directed activity are thus highly intertwined properties, at the heart of many developmental, behavioral and evolutionary processes.     

The complexity of miRNA-mediated repression

Since their discovery 20 years ago, miRNAs have attracted much attention from all areas of biology. These short (∼22 nt) non-coding RNA molecules are highly conserved in evolution and are present in nearly all eukaryotes. They have critical roles in virtually every cellular process, particularly determination of cell fate in development and regulation of the cell cycle. Although it has long been known that miRNAs bind to mRNAs to trigger translational repression and degradation, there had been much debate regarding their precise mode of action. It is now believed that translational control is the primary event, only later followed by mRNA destabilisation. This review will discuss the most recent advances in our understanding of the molecular underpinnings of miRNA-mediated repression. Moreover, we highlight the multitude of regulatory mechanisms that modulate miRNA function.     

The complexity of anti-estrogen responses

The actions and biological responses of anti-estrogens are a function of: the experimental conditions, the parameters, the organ and the animal species considered. Target tissues for estrogens in the guinea-pig during the perinatal period are interesting models to explore the action of anti-estrogens. The summary of the data indicates: (1) In the fetal uterus of guinea-pig in in vivo experiments (after injection to the maternal compartment) tamoxifen acts as a real agonist concerning growth, as a partial agonist concerning the stimulation of the progesterone receptor. (2) In in vitro experiments (in organ culture of fetal uterus or in isolated cells) anti-estrogens (tamoxifen or 4-hydroxy-tamoxifen) act as antagonists and also inhibit the effects provoked by estrogens. (3) In the uterus and vagina of newborn guinea-pigs, tamoxifen and its derivatives: 4-hydroxytamoxifen and N-desmethyltamoxifen act as real agonists concerning the uterotrophic and vaginotrophic effects, and also stimulate the amount of DNA per organ, but concerning the progesterone receptor in the uterus, in the short treatment anti-estrogens act as partial agonists but they have no effect in the long treatment. In the vagina in the short treatment anti-estrogens provoke no significant effects, but in the long treatment they are full agonists. In neither of the two biological responses studied (growth and progesterone receptor) does tamoxifen and its derivatives block the action of estradiol. (4) The use of a monoclonal antibody to the estrogen receptor revealed quantitative differences in the activation of the estrogen receptor when bound to estradiol or tamoxifen. This observation was in agreement with the lesser extent of binding to DNA-cellulose of the tamoxifen-estrogen receptor complex as compared with the estradiol-estrogen receptor complex. This fact suggests an impaired activation of the estrogen receptor induced by tamoxifen which might be related to the different biological responses provoked by estrogens and anti-estrogens.     

The complexity of anatomical systems

Background  

The conception of anatomical entities as a hierarchy of infinitely graduated forms and the increase in the number of observed anatomical sub-entities and structural variables has generated a growing complexity, thus highlighting new properties of organised biological matter.     

HDL2 and HDL3 cholesterol in hepatic cirrhosis

In order to further investigate plasma lipoproteins abnormalities secondary to serious liver damage, we studied plasma lipids and lipoproteins, and in particular HDL subfractions (HDL2, HDL3), in 12 patients with cirrhosis of the liver and in 12 sex, age and weight matched healthy volunteers. Enzymatic methods were used to determine total cholesterol and triglycerides, while the extractive method of Abell et al. was used for the determination of HDL-cholesterol levels after LDL and VLDL precipitation with polyanions (MnCl2 and Na-heparin) and of HDL3-cholesterol values after HDL2 precipitation with dextran-sulphate 15,000 m.w. Total cholesterol and HDL-cholesterol levels were significantly lower in cirrhotic patients compared to normal subjects. We must emphasize that only HDL3-cholesterol was decreased in cirrhotics, whereas HDL2-cholesterol values were normal or high. We suggest that a diminished activity of hepatic triglyceride lipase might account for the decrease in HDL3-cholesterol in liver cirrhosis.     

Proliferative effect of high density lipoprotein (HDL) and HDL fractions (HDL1,2, HDL3) on virus transformed lymphoblastoid cells

The growth-promoting activities of plasma lipoproteins (LDL, HDL, HDL1,2, HDL3) and total HDL apolipoproteins on a virus transformed lymphoblastoid cell line in vitro, has been compared. When maintained in lipoprotein-deficient serum-supplemented medium, these cells do not proliferate optimally. The addition of either HDL, HDL1,2 or HDL3 induced optimal cell proliferation as compared to the result observed in fetal calf serum-supplemented medium. The HDL1,2 subfraction was found to be more potent than the HDL3 subfraction in supporting cell growth. Total HDL apolipoproteins were able to support significant cell proliferation. In contrast, LDL did not promote cell growth. In serum-free conditions and in the presence of transferrin, only HDL and HDL subfractions induced cell proliferation. These results suggest that HDL and HDL subfractions could initiate B lymphoblastoid cell growth and that total HDL apolipoproteins could support a part of cell proliferation.