Diacylglycerol kinases in nuclear lipid-dependent signal transduction pathways

Several independent groups have shown that lipid-dependent signal transduction systems operate in the nucleus and that they are regulated independently from their membrane and cytosolic counterparts. A sizable body of evidence suggests that nuclear lipid signaling controls critical biological functions such as cell proliferation and differentiation. Diacylglycerol is a fundamental lipid second messenger which is produced in the nucleus. The levels of nuclear diacylglycerol fluctuate during the cell cycle progression, suggesting that such a molecule has important regulatory roles. Most likely, nuclear diacylglycerol serves as a chemoattractant for some isoforms of protein kinase C that migrate to the nucleus in response to a variety of agonists. The nucleus also contains diacylglycerol kinases, i.e. the enzymes that, by converting diacylglycerol into phosphatidic acid, terminate diacylglycerol-dependent events. A number of diacylglycerol kinases encoded by separate genes are present in the mammalian genome. This review aims at highlighting the different isotypes of diacylglycerol kinases identified at the nuclear level as well as at discussing their potential function and regulation. Received 4 December 2001; received after revision 28 January 2002; accepted 31 January 2002     

Physiological importance of omega-3/omega-6 polyunsaturated fatty acids in man. An overview of still unresolved and controversial questions

The 'essentiality' of (omega-6) and (omega-3) fatty acids in mammals is well known. Nevertheless, some important points remain unclear concerning their implication in physiology. After a short discussion about the definition of essential fatty acids deficiency, this brief overview deals with some of these points, pointing out some of the unresolved questions. Different subjects are approached concerning the (omega-6) and (omega-3) fatty acids metabolism: desaturases, eicosanoids, production, as well as some of their metabolic effects on cell membranes, intestinal function, glucose and lipid metabolism, haemorheology.     

Regulation of SNARE fusion machinery by fatty acids

Vesicle fusion is a ubiquitous biological process involved in membrane trafficking and a variety of specialised events such as exocytosis and neurite outgrowth. The energy to drive biological membrane fusion is provided by fusion proteins called SNAREs. Indeed, SNARE proteins play critical roles in neuronal development as well as neurotransmitter and hormone release. SNARE proteins form a very tight alpha-helical bundle that can pull two membranes together, thereby initiating fusion. Whereas a great deal of attention has been paid to partner proteins that can affect SNARE function, recent genetic and biochemical evidence suggests that local lipid environment may be as important in SNARE regulation. Direct lipid modification of SNARE fusion proteins and their regulation by fatty acids following phospholipase action will be discussed here in detail. Our analysis highlights the fact that lipids are not a passive platform in vesicle fusion but intimately regulate SNARE function. Received 20 December 2006; received after revision 6 February 2007; accepted 15 March 2007     

Sticky-finger interaction sites on cytosolic lipid-binding proteins?

The cytosolic lipid-binding proteins (cLBPs) comprise a large family of small (14-15 kDa) intracellular proteins involved in the transport of small lipids, including fatty acids and retinoids within cells. Their presumed function is to solubilise, protect from chemical damage and deliver to the correct destination lipids for purposes ranging from energy metabolism (e.g. fatty acids) to signalling, gene activation and cellular differentiation (e.g. retinoids and eicosanoids). It is therefore probable that cLBPs interact directly with cellular components (membranes and/or proteins) to collect and deposit their ligands, and some external features of the different cLBPs may be involved in such interactions and determine which cellular component (integral membrane or cytosolic proteins, or membranes of different lipid compositions or domain structures) with which a given cLBP will interact. Here we have focussed on a previously unrecognised feature of cLBPs which descriminates between those for which there is empiral evidence for direct interaction with membranes, and those which do not. This is a group of bulky hydrophobic amino acid side chains (e.g. tryptophans, phenylalanines, leucines) which project directly into solvent adjacent to the portal of entry and exit of the lipid ligands. Such side chains are usually found internal to proteins, but are common at sites of protein:protein or protein:membrane interactions. These 'sticky fingers' could therefore be critical to the nature and specificity of the interactions cLBPs undergo in the web of cross-traffic in lipid movements within cells.     

Sphingolipid metabolism and its role in the skeletal tissues

The regulators affecting skeletal tissue formation and its maintenance include a wide array of molecules with very diverse functions. More recently, sphingolipids have been added to this growing list of regulatory molecules in the skeletal tissues. Sphingolipids are integral parts of various lipid membranes present in the cells and organelles. For a long time, these macromolecules were considered as inert structural elements. This view, however, has radically changed in recent years as sphingolipids are now recognized as important second messengers for signal-transduction pathways that affect cell growth, differentiation, stress responses and programmed death. In the current review, we discuss the available data showing the roles of various sphingolipids in three different skeletal cell types—chondrocytes in cartilage and osteoblasts and osteoclasts in bone. We provide an overview of the biology of sphingomyelin phosphodiesterase 3 (SMPD3), an important regulator of sphingolipid metabolism in the skeleton. SMPD3 is localized in the plasma membrane and has been shown to cleave sphingomyelin to generate ceramide, a bioactive lipid second messenger, and phosphocholine, an essential nutrient. SMPD3 deficiency in mice impairs the mineralization in both cartilage and bone extracellular matrices leading to severe skeletal deformities. A detailed understanding of SMPD3 function may provide a novel insight on the role of sphingolipids in the skeletal tissues.     

Sphingosine 1-phosphate signal survival and mitogenesis are mediated by lipid-stereospecific binding of triacylglycerol-rich lipoproteins

Proof for the role of triacylglycerol-rich lipoproteins (TRLs) in the development of cardiovascular events is accumulating. We recently reported that postprandial TRLs bind to and internalize into human aortic vascular smooth muscle cells (HA-VSMCs) by a lipid-dependent mechanism. We now show that postprandial TRLs triggered hydrolysis of sphingomyelin and stimulation of the sphingosine kinase producing sphingosine 1-phosphate (S1P). In addition, postprandial TRLs exhibited survival and mitogenic effects. Interestingly, the signals were modulated by the nature of the fatty acids located at the sn-2 position in the triacylglycerol molecules of TRL. This lipid-stereospecific regulation of S1P cellular levels in HA-VSMCs provides a novel insight into the intrinsic role of dietary fatty acids and the mechanism mediated by triacylglycerol-containing postprandial lipoproteins in the pathogenesis of atherosclerosis.Received 14 August 2003; received after revision 8 October 2003; accepted 15 October 2003     

Physiological importance of ω-3/ω-6 polyunsaturated fatty acids in man. An overview of still unresolved and controversial questions

Summary The essentiality of (-6) and (-3) fatty acids in mammals is well known. Nevertheless, some important points remain unclear concerning their implication in physiology. After a short discussion about the definition of essential fatty acids deficiency, this brief overview deals with some of these points, pointing out some of the unresolved questions. Different subjects are approached concerning the (-6) and (-3) fatty acids metabolism: desaturases, eicosanoids, production, as well as some of their metabolic effects on cell membranes, intestinal function, glucose and lipid metabolism, haemorheology.     

The egg-lipid composition of the ‘living fossil’ reptile tuatara (Sphenodon punctatus)

Summary The lipid composition of two tuatara eggs was examined. The eggs contained triacylglycerol (80%) and phospholipid (12%) as their major lipid fractions. Fatty acid analyses of the individual lipid classes indicated the presence of essential fatty acids, linoleic and arachidonic acids. The quantity of such acids in the egg yolk lipids would suggest they are factors for survival as illustrated in other species.     

Identification of a restriction point at the M/G1 transition in CHO cells

The regulation of cell cycle progression in normal mammalian cells is dependent on the presence of growth factors. In their absence, non-transformed cells will stop dividing and enter the quiescent state (G0). We show here that in Chinese hamster ovary cells, at least two serum-dependent points exist during G1 that lead to different cellular responses. The first point is located immediately after mitosis and is suggested to link with apoptosis. The second point is located late in G1, and probably corresponds with the classic restriction point R. Cells depleted of serum after the first restriction point will not stop randomly in G1 but continue G1 progression until they reach the late restriction point, as marked by translocation of p42^MAPkinase (ERK2) to the nucleus.Received 18 September 2003; received after revision 11 December 2003; accepted 19 December 2003     

Hyperinsulinemia,hyperproinsulinemia and insulin resistance in the metabolic syndrome

For better comprehension of the metabolic syndrome, it is necessary to differentiate the effect of insulin on glucose metabolism on the one hand, and on other metabolic activities on the other hand. Whereas glucose utilization is affected by insulin resistance, the effect of insulin on lipid metabolism, ion and aminoacid transport does not seem to be diminished. Lipid metabolism, however, seems to play a crucial role in the induction of the vicious cycle. Increased energy and fat ingestion may be due to an increased number of galanin secreting cells in the hypothalamus. The excessive fat intake results in an increased rate of release of insulin and increased influx of triglycerides into the blood. From these triglycerides an excess of free fatty acids is released by the action of lipoprotein lipase. The increased plasma free fatty acid level then results in insulin resistance affecting glucose metabolism. Also, these free fatty acids may impair the secretion of insulin. Induction of insulin resistance results in higher glucose levels, which may cause hyperinsulinemia. Hyperinsulinemia maintains the elevation of triglycerides. When diabetes becomes overt and elevated glucose levels prevail, the hyperinsulinism acts on the metabolic pathways which are still sensitive to insulin, namely lipid metabolism, aminoacid transport and ion transport.     

Lipid sensing and lipid sensors

Translation of nutrient stimuli through intracellular signaling is important for adaptation and regulation of metabolic processes, while deregulation by either genetic or environmental factors predisposes towards the development of metabolic disorders. Besides providing energy, fatty acids act as prominent signaling molecules by altering cell membrane structures, affecting the lipid modification status of proteins, and by modulating ligand-activated nuclear receptor activity. Given their highly hydrophobic nature, fatty acids in the aqueous intracellular compartment are bound to small intracellular lipid binding proteins which function as intracellular carriers of these hydrophobic components. This review describes recent advances in identifying intracellular pathways for cytosolic fatty acid signaling through ligand activated receptors by means of small intracellular lipid binding proteins. The mechanism behind intracellular fatty acid transport and subsequent nuclear receptor activation is an emerging concept, and advances in understanding this process provide new potential therapeutic targets towards the treatment of metabolic disorders.     

Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.     

核受体LXRa靶基因研究进展

核受体的研究近几年已有飞速的发展。LXRa(Liver X Receptor a)是一种与脂类代谢有关的核受体。研究发现LXRa的靶基因具有调节脂类的吸收、运输、转化和生物合成的功能,此外,LXRa在糖类的代谢等方面也有重要的调控作用。研究结果表明LXRa与动脉粥样硬化的发生有非常密切的关系。目前利用LXRa为靶标进行抗动脉粥样硬化药物筛选已经成为一个重要的研究方法。     

Regulation of mitochondrial oxidative phosphorylation by second messenger-mediated signal transduction mechanisms

The mitochondrial oxidative phosphorylation system is responsible for providing the bulk of cellular ATP molecules. There is a growing body of information regarding the regulation of this process by a number of second messenger-mediated signal transduction mechanisms, although direct studies aimed at elucidating this regulation are limited. The main second messengers affecting mitochondrial signal transduction are cAMP and calcium. Other second messengers include ceramide and reactive oxygen species as well as nitric oxide and reactive nitrogen species. This review focuses on available data on the regulation of the mitochondrial oxidative phosphorylation system by signal transduction mechanisms and is organised according to the second messengers involved, because of their pivotal role in mitochondrial function. Future perspectives for further investigations regarding these mechanisms in the regulation of the oxidative phosphorylation system are formulated. Received 11 December 2005; received after revision 14 January 2006; accepted 6 February 2006     

Lipid-lowering drugs

Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipidlowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs. Received 5 September 2005; received after revision 29 December 2005; accepted 26 January 2006     

Nibbling within the nucleus: turnover of nuclear contents

As the site of gene expression and regulation, the nucleus is the control center of the cell. It might be thought that degradation of nuclear contents is strictly ‘off-limits,’ given the importance of the genetic information contained within the nucleus, but it has recently been reported that partial degradation of the nucleus may occur in yeast. Here we summarize the evidence for the degradation and quality control of proteins found with the nucleus and its compartments, and of nucleic acids that may occur under certain specific conditions. Only under certain special conditions such as differentiation of the lens are the entire nuclear contents degraded. Received 6 September 2006; received after revision 25 October 2006; accepted 13 December 2006     

Lipid accumulation by a cellulolytic strain of Aspergillus niger.

Lipid accumulation by a cellulolytic mold, Aspergillus niger, was studied. The amount of lipid accumulated ranged from 13.6-16.6% on various carbon sources, namely glucose, xylose, avicel (microcrystalline cellulose) and bagasse (a natural lignocellulosic substrate). Neutral lipids, phospholipids and glycolipids of the mycelia varied from 41.0-46.2%, 34.9-38.4% and 18.7-22.6% of total lipids, respectively. Unsaturated fatty acids comprised around 80% of total fatty materials with linoleic and oleic acid predominating. Of the four nitrogen sources tested, NH4Cl was the best source for lipid synthesis from cellulose (bagasse). Optimum temperature range for growth and lipid synthesis was 25-30 degrees C.