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We demonstrate that hydroxycholesterol, a broadly anti-viral oxysterol produced as part of the innate anti-viral response, activates miR expression in the liver to deplete virus infected cells of lipids. HCV appears to actively counteract this anti-viral response by suppressing miR expression. Collectively, our results highlight the role of microRNAs in hepatic lipid metabolism and the immunometabolic response to viral infection.

Full Record Statistics. Singaravelu, Ragunath.

Lipid Metabolism – Anatomy and Physiology

Hepatitis C virus HCV infection is a leading cause of liver transplantation and hepatocellular carcinoma worldwide. While the biological properties of phosphatidylinositol 5-phosphate have taken longer to unravel, because of the difficulties of separation of this isomer, it is now apparent that it is involved in osmoregulation both in plants and animals.

Introduction

It also has signalling functions, and although it is the least abundant phosphatidylinositol monophosphate, it is involved in signalling at the nucleus and in the cytoplasm, modulating cellular responses to various stresses, hormones and growth factors. In the endosomes, it is a regulator of protein sorting. Phosphatidylinositol 4,5-bisphosphate PI 4,5 P 2 is an essential lipid messenger with vital signalling functions as well as serving as a precursor of key metabolites, especially diacylglycerols, although there is a recent suggestion that phosphatidylinositol 4-phosphate is a more important source see below.

It is most abundant in the cytoplasmic leaflet of the plasma membrane, The oxysterol binding protein OSBP -related protein 2 ORP2 is a key regulator of both cholesterol and PI 4,5 P 2 concentrations in this membrane, as discussed in our web page on cholesterol. PI 4,5 P 2 complexes with and regulates many cytoplasmic and membrane proteins, and especially those concerned with ion channels for potassium, calcium, sodium and other ions. In most instances with the latter, it appears to be an obligatory factor; it increases the activity of ion channels by activating key proteins, while its hydrolysis by phospholipase C reduces such activity.

PI 4,5 P 2 appears to interact with cationic residues of a large array of proteins in concert with cholesterol to form localized membrane domains that are distinct from the sphingolipid-enriched rafts. Indeed, it has a much higher concentration than other phosphoinositide species in cells, although most of this is in effect sequestered by binding proteins. Also, phosphatidylinositol 4,5-bisphosphate and its diacylglycerol metabolites are important for vesicle formation in membranes. For example, a major pathway in cells for internalization of cell surface proteins such as transferrin is the clathrin-coated vesicle pathway.

PI 4,5 P 2 is essential to this process in that it binds to the machinery involved in the membrane, increasing the number of clathrin-coated pits and permitting internalization of proteins. It also has a function in caveolae , where it is concentrated at the rim. Phosphatidylinositol 4,5-bisphosphate is intimately involved in the development of the actin cytoskeleton and its attachment to the plasma membrane, thereby controlling cell shape, motility, and many other processes.

In particular it binds with high specificity to vinculin, a membrane-cytoskeletal protein that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Dysregulation of this function has been implicated in the migration and metastasis of tumour cells. In yeasts, it appears that the presence of stearic acid in position sn -1 is essential for this function.

In the cell nucleus, this lipid is believed to be involved in maintaining chromatin, the complex combination of DNA, RNA, and protein that makes up chromosomes in a transcriptionally active conformation, as well as being a precursor for further signalling molecules. It has a role in gene transcription, and RNA processing, especially in the modulation of RNA polymerase activity, and in other nuclear processes. Via its binding to specific proteins, the lipid is an essential component of the immune response of animal tissues to toxic bacterial lipopolysaccharides.

It is also involved in the pathophysiology of the HIV virus via an interaction with the Tat protein secreted by infected cells. PI 4,5 P 2 is the primary precursor of the endocannabinoid 2-arachidonoylglycerol in neurons, and it is also an essential cofactor for phospholipase D and so affects the cellular production of phosphatidic acid with its specific signalling functions. By binding specifically to ceramide kinase, the enzyme responsible for the synthesis of ceramidephosphate , it has an influence on sphingolipid metabolism.

One molecule of phosphatidylinositol 4,5-bisphosphate is bound to each subunit of the protein in the X-ray crystal structures of mammalian GIRK2 potassium channel, where it enables a conformational change that assists the transport function of the protein. Perhaps, the best characterized of the phosphoinositide signalling functions results from the hydrolysis of phosphatidylinositol phosphates by phospholipase C isoforms, in this instance to produce sn -1,2-diacylglycerols and inositol 3,4,5-trisphosphate see below , which act as second messengers.

Phosphatidylinositol 3,4-bisphosphate can be produced by two routes and regulates a variety of cellular processes with relevance to health and disease that include B cell activation and autoantibody production, insulin sensitivity, neuronal dynamics, endocytosis and cell migration. It is known to bind selectively to a number of proteins, and it acts as a secondary messenger by recruiting the protein kinases Akt protein kinase B and so may influence the cell cycle, cell survival, angiogenesis and glucose metabolism.

Review ARTICLE

During endocytosis in the endolysosomal system, it is produced from PI 4,5 P 2 and controls the maturation of endocytic coated pits. In epithelial cells, it is located on the apical membrane, i. Phosphatidylinositol 3,5-bisphosphate is present at low levels only in cells 0. It is also involved in the mediation of signalling in response to stress and hormonal cues and in the control of ion transport in membranes, while genetic studies confirm that it is essential for healthy embryonic development, especially in the nervous system. Phosphatidylinositol 3,4,5-trisphosphate is almost undetectable in quiescent cells, but its intracellular level rises very rapidly in response to an agonist.

It has been implicated in a variety of cellular functions, such as growth, cell survival, proliferation, cytoskeletal rearrangement, intracellular vesicle trafficking, and cell metabolism. In particular, it is an important component of a signalling pathway in the cell nucleus. In contrast to phosphatidylinositol 3-phosphate, it opposes autophagy. During feeding, various physiological responses lead to the secretion of insulin, which stimulates the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate and triggers a signalling cascade that leads to the suppression of autophagy.

When this pathway is impaired it has deleterious effects upon the insulin resistance associated with various metabolic diseases including obesity and diabetes. It has also been implicated in tumor cell migration and metastasis. The human immune system utilizes neutrophils, which are highly mobile cells, to eliminate pathogens from infected tissue. The first step is to track and then pursue molecular signals, such as cytokines, emitted by pathogens.

It has been established that two phospholipids operate in sequence to point the neutrophils in the correct direction. The first of these is phosphatidylinositol 3,4,5-trisphosphate, which binds to a specific protein DOCK2 and enables it to translocate to the plasma membrane. Then phosphatidic acid, generated by the action of phospholipase D on phosphatidylcholine, takes over and directs the DOCK2 to the leading edge of the plasma membrane. This causes polymerization of actin within the cell and in effect reshapes the neutrophil and points it in the direction from which the pathogens signals are coming.

On the other hand, Mycobacterium tuberculosis is able to subvert phosphoinositide signalling to arrest phagosome maturation by dephosphorylation of phosphatidylinositol 3-phosphate. As mentioned briefly above, hydrolysis of phosphatidylinositol phosphates by calcium-dependent phospholipase C or 'phosphoinositidase C' leads to generation of sn -1,2-diacylglycerols , which act as second messengers in animal cells and are of enormous metabolic importance.

There are many different enzymes of this type, but the activity of the phosphoinositide-specific phospholipase C constitutes an essential step in the inositide signalling pathways. The enzyme exists in six families consisting of at least 13 isoenzymes, each of which has a distinctive role and can have a characteristic cell distribution that is linked to a specific function. Activity of these enzymes is stimulated by signalling molecules such as G-protein coupled receptors, receptor tyrosine kinases, Ras-like GTPases and calcium ions, thus linking the hydrolysis of phosphatidylinositol phosphates to a wide range of other cellular signals.

Phosphatidylinositol and Related Phosphoinositides

As phospholipase C is a soluble protein located mainly in the cytosol, translocation to the plasma membrane is a crucial step in signal transduction. Regulation of these isoenzymes is vital for health as they are associated with the activation or inhibition of important pathophysiological processes. The other products of this reaction that are of special relevance because of their many essential functions are water-soluble inositol phosphates.

Up to 60 different compounds of this type are possible, and at least 37 of these have been found in nature at the last count, all of which are also extremely important biologically. However, polyphosphoinositides with a phosphate in position 3 are not substrates for phospholipase C.

For example, under the action of various physiological stimuli in animals, including sphingosinephosphate, and acting via various G-protein-coupled receptors, phosphatidylinositol 4,5-bisphosphate in the plasma membrane is hydrolysed to release inositol 1,4,5-trisphosphate, an important cellular messenger that diffuses into the cytosol and stimulates calcium release from an ATP-loaded store in the endoplasmic reticulum via ligand-gated calcium channels the diacylglycerols remain in the membrane to recruit and activate members of the protein kinase C family.

The increase in calcium concentration, together with the altered phosphorylation status, activates or de-activates many different protein targets, enabling cells to respond in an appropriate manner to the extracellular stimulus. To enable rapid replenishment of the phosphatidylinositol 4,5-bisphosphate used in this way, a cycle of reactions - the phosphatidylinositol cycle - must occur see below. On the other hand, a recent publication suggests that phosphatidylinositol 4-phosphate in the plasma membrane may be a more important source of diacylglycerols following stimulation of G protein—coupled receptors.

All of the various inositol phosphates appear to be involved in the control of cellular events in very specific ways, but especially in the organization of key signalling pathways, the rearrangement of the actin cytoskeleton or intracellular vesicle trafficking. They have also been implicated in gene transcription, RNA editing, nuclear export and protein phosphorylation.

As these remarkable compounds can be rapidly synthesised and degraded in discrete membrane domains or even sub-nuclear structures, they are considered to be ideal regulators of dynamic cellular mechanisms. From structural studies of inositol polyphosphate-binding proteins, it is believed that the inositides may act in part at least by modifying protein function by acting as structural cofactors, ensuring that proteins adopt their optimum conformations. In addition, phosphoinositides and the inositol polyphosphates are key components of the nucleus of the cell, where they have many essential functions, including DNA repair, transcription regulation and RNA dynamics.

It is believed that they may be activity switches for the nuclear complexes responsible for such processes, with the phosphorylation state of the inositol ring being of primary importance. As different isomers appear to have specific functions at each level of gene expression, extracellular events must coordinate the production of these compounds in a highly synchronous manner. In organisms from plants to mammals, an extra tier of regulatory mechanisms is produced by kinases that generate energetic diphosphate pyrophosphate -containing molecules from inositol phosphates.

Conversely, these can by dephosphorylated by polyphosphate phosphohydrolase enzymes to regenerate the original inositol phosphates. These inositol pyrophosphates and the enzymes involved in their metabolism are also involved in the regulation of cellular processes by modulating the activity of proteins by a variety of mechanisms. The extraordinary range of activities of phosphoinositides is relevant to major human diseases, including cancer and diabetes, making them important targets for pharmacological research and intervention.

It should also be noted that the phospholipase C isoenzymes regulate the concentration of phosphatidylinositol 4,5-bisphosphate and related lipids and thence their activities in addition to the generation of new biologically active metabolites. In plants as in animals, phosphatidylinositol and polyphosphoinositides have essential biological functions, exerting their regulatory effects by acting as ligands that bind to protein targets via specific lipid-binding domains and so alter the location of proteins and their enzymatic activities.

However, it appears that polyphosphoinositide metabolism developed in different ways after the divergence of the animal and plant kingdoms so the details of the processes in each are very different, not least because the subcellular locations of phosphoinositides are very different in plants and animals.

Phosphatidylinositol per se is of course the precursor of the phosphorylated forms and determines their fatty acid compositions. It also has a role in inhibiting programmed cell death by acting as the biosynthetic precursor of the sphingolipid ceramide phosphoinositol and so reducing the levels of ceramide. As in animals, the various phosphoinositides are produced by a series of kinases and phosphatases in many isoforms in different cellular membranes.


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For example, phosphatidylinositol is generated mainly in the endoplasmic reticulum, while PI 4-kinases and their product are located in the trans-Golgi network and nucleus, and PI4P 5-kinases and product are present in the plasma membrane. During the biosynthesis of polyphosphoinositides, the first phosphorylation occurs at the hydroxyl group at positions 3 or 4 of the inositol ring, catalysed by the appropriate kinases, while the second phosphorylation then takes place at position 5; PI 5-phosphate is produced by the action of a phosphatase on PI 3,5-bisphosphate.

How the various metabolites are transported between membranes has yet to be determined. Although what might be considered normal levels of phosphatidylinositol 4-phosphate are present, levels of phosphatidylinositol 4,5-bisphosphate and other phosphoinositides are extremely low in plants 10 to fold lower than in mammalian cells. Most other metabolites are produced via phosphatidylinositol 3-phosphate, and reports that some phosphatidylinositol 3,4,5-trisphosphate may be produced from phosphatidylinositol 4,5-bisphosphate require confirmation. In contrast to mammalian phosphatidylinositol 3-kinases, which accept both phosphatidylinositol and its monophosphates as substrates, the plant enzyme acts only on the former.