BBA - Molecular and Cell Biology of Lipids (v.1791, #7)
Special Issue Title Page (iii).
Editorial Board (i).
Cellular lipid transport processes and their role in human disease by Jean E. Vance; Dennis R. Voelker (561-562).
The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes by Chongren Tang; John F. Oram (563-572).
ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that exports cholesterol from cells and suppresses macrophage inflammation. ABCA1 exports cholesterol by a multistep pathway that involves forming cell-surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Thus, ABCA1 behaves both as a lipid exporter and a signaling receptor. ABCA1 transcription is highly induced by sterols, and its expression and activity are regulated post-transcriptionally by diverse processes. ABCA1 mutations can reduce plasma HDL levels, accelerate cardiovascular disease, and increase the risk for type 2 diabetes. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels, inflammation, atherogenesis, and pancreatic β cell function. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages, raising the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become a promising new therapeutic target for treating cardiovascular disease and diabetes.
Keywords: ABCA1; Cell cholesterol export; HDL; Apolipoprotein A-I; Inflammation; Macrophage; Cardiovascular disease; Diabetes;
The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration by Robert S. Molday; Ming Zhong; Faraz Quazi (573-583).
ABCA4 is a member of the ABCA subfamily of ATP binding cassette (ABC) transporters that is expressed in rod and cone photoreceptors of the vertebrate retina. ABCA4, also known as the Rim protein and ABCR, is a large 2273 amino acid glycoprotein organized as two tandem halves, each containing a single membrane spanning segment followed sequentially by a large exocytoplasmic domain, a multispanning membrane domain and a nucleotide binding domain. Over 500 mutations in the gene encoding ABCA4 are associated with a spectrum of related autosomal recessive retinal degenerative diseases including Stargardt macular degeneration, cone–rod dystrophy and a subset of retinitis pigmentosa. Biochemical studies on the purified ABCA4 together with analysis of abca4 knockout mice and patients with Stargardt disease have implicated ABCA4 as a retinylidene-phosphatidylethanolamine transporter that facilitates the removal of potentially reactive retinal derivatives from photoreceptors following photoexcitation. Knowledge of the genetic and molecular basis for ABCA4 related retinal degenerative diseases is being used to develop rationale therapeutic treatments for this set of disorders.
Keywords: ABC transporter; ABCA4; Stargardt macular degeneration; Lipid transport; Photoreceptor; Visual cycle; Membrane protein; Retinal degenerative disease;
Emerging new paradigms for ABCG transporters by Paul T. Tarr; Elizabeth J. Tarling; Dragana D. Bojanic; Peter A. Edwards; Ángel Baldán (584-593).
Every cell is separated from its external environment by a lipid membrane. Survival depends on the regulated and selective transport of nutrients, waste products and regulatory molecules across these membranes, a process that is often mediated by integral membrane proteins. The largest and most diverse of these membrane transport systems is the ATP binding cassette (ABC) family of membrane transport proteins. The ABC family is a large evolutionary conserved family of transmembrane proteins (> 250 members) present in all phyla, from bacteria to Homo sapiens, which require energy in the form of ATP hydrolysis to transport substrates against concentration gradients. In prokaryotes the majority of ABC transporters are involved in the transport of nutrients and other macromolecules into the cell. In eukaryotes, with the exception of the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7), ABC transporters mobilize substrates from the cytoplasm out of the cell or into specific intracellular organelles. This review focuses on the members of the ABCG subfamily of transporters, which are conserved through evolution in multiple taxa. As discussed below, these proteins participate in multiple cellular homeostatic processes, and functional mutations in some of them have clinical relevance in humans.
Keywords: ABC transporter; ABCG; Sterol transporter; Multidrug resistance; Sitosterolemia; Atherosclerosis;
The lipopolysaccharide transport system of Gram-negative bacteria by Paola Sperandeo; Gianni Dehò; Alessandra Polissi (594-602).
The cell envelope of Gram-negative bacteria consists of two distinct membranes, the inner (IM) and the outer membrane (OM) separated by the periplasm. The OM contains in the outer leaflet the lipopolysaccharide (LPS), a complex lipid with important biological activities. In the host it elicits the innate immune response whereas in the bacterium it is responsible for the peculiar permeability barrier properties exhibited by the OM. The chemical structure of LPS and its biosynthetic pathways have been fully elucidated. By contrast only recently details of the transport and assembly of LPS into the OM have emerged. LPS is synthesized in the cytoplasm and at the inner leaflet of the IM and needs to cross two different compartments, the IM and the periplasm, to reach its final destination at the OM. This review focuses on recent studies that led to our present understanding of the protein machine implicated in LPS transport and in assembly at the cell surface.
Keywords: Bacterial envelope; Outer membrane biogenesis; Lipopolysac transport; Endotoxin;
Mechanism and significance of P4 ATPase-catalyzed lipid transport: Lessons from a Na+/K+-pump by Catheleyne F. Puts; Joost C.M. Holthuis (603-611).
Members of the P4 subfamily of P-type ATPases are believed to catalyze phospholipid transport across membrane bilayers, a process influencing a host of cellular functions. Atomic structures and functional analysis of P-type ATPases that pump small cations and metal ions revealed a transport mechanism that appears to be conserved throughout the family. A challenging problem is to understand how this mechanism is adapted in P4 ATPases to flip phospholipids. P4 ATPases form oligomeric complexes with members of the CDC50 protein family. While formation of these complexes is required for P4 ATPase export from the endoplasmic reticulum, little is known about the functional role of the CDC50 subunits. The Na+/K+-ATPase and closely-related H+/K+-ATPase are the only other P-type pumps that are oligomeric, comprising mandatory β-subunits that are strikingly reminiscent of CDC50 proteins. Besides serving a role in the functional maturation of the catalytic α-subunit, the β-subunit also contributes specifically to intrinsic transport properties of the Na+/K+ pump. As β-subunits and CDC50 proteins likely adopted similar structures to accomplish analogous tasks, current knowledge of the Na+/K+-ATPase provides a useful guide for understanding the inner workings of the P4 ATPase class of lipid pumps.
Keywords: P4 ATPase; Flippase; Oligomeric Na+/K+-ATPase; P-type pump reaction cycle; Lipid asymmetry; Vesicle biogenesis;
Linking phospholipid flippases to vesicle-mediated protein transport by Baby-Periyanayaki Muthusamy; Paramasivam Natarajan; Xiaoming Zhou; Todd R. Graham (612-619).
Type IV P-type ATPases (P4-ATPases) are a large family of putative phospholipid translocases (flippases) implicated in the generation of phospholipid asymmetry in biological membranes. P4-ATPases are typically the largest P-type ATPase subgroup found in eukaryotic cells, with five members in Saccharomyces cerevisiae, six members in Caenorhabditis elegans, 12 members in Arabidopsis thaliana and 14 members in humans. In addition, many of the P4-ATPases require interaction with a noncatalytic subunit from the CDC50 gene family for their transport out of the endoplasmic reticulum (ER). Deficiency of a P4-ATPase (Atp8b1) causes liver disease in humans, and studies in a variety of model systems indicate that P4-ATPases play diverse and essential roles in membrane biogenesis. In addition to their proposed role in establishing and maintaining plasma membrane asymmetry, P4-ATPases are linked to vesicle-mediated protein transport in the exocytic and endocytic pathways. Recent studies have also suggested a role for P4-ATPases in the nonvesicular intracellular trafficking of sterols. Here, we discuss the physiological requirements for yeast P4-ATPases in phospholipid translocase activity, transport vesicle budding and ergosterol metabolism, with an emphasis on Drs2p and its noncatalytic subunit, Cdc50p.
Keywords: P4-ATPase; Flippase; Drs2p; Cdc50p; Membrane asymmetry; Clathrin; Kes1p;
The yeast plasma membrane P4-ATPases are major transporters for lysophospholipids by Wayne R. Riekhof; Dennis R. Voelker (620-627).
The transbilayer movement of phospholipids plays an essential role in establishing and maintaining the asymmetric distribution of lipids in biological membranes. The P4-ATPase family has been implicated as the major transporters of the aminoglycerophospholipids in both surface and endomembrane systems. Historically, fluorescent lipid analogs have been used to monitor the lipid transport activity of the P4-ATPases. Recent evidence now demonstrates that lyso-phosphatidylethanolamine (lyso-PtdEtn) and lyso-phosphatidylcholine (lyso-PtdCho) are bona fide biological substrates transported by the yeast plasma membrane ATPases, Dnf1p and Dnf2p, in consort with a second protein Lem3p. Subsequent to transport, the lysophospholipids are acylated by the enzyme Ale1p to produce PtdEtn and PtdCho. The transport of the lysophospholipids occurs at rates sufficient to support all the PtdEtn and PtdCho synthesis required for rapid cell growth. The lysophospholipid transporters also utilize the anti-neoplastic and anti-parasitic ether lipid substrates related to edelfosine. The identification of biological substrates for the plasma membrane ATPases coupled with the power of yeast genetics now provides new tools to dissect the structure and function of the aminoglycerophospholipid transporters.
Keywords: Lysophospholipid; P-type ATPase; Edelfosine; Miltefosine; Membrane asymmetry; Flippase; Lipid transport; Trafficking; Membrane biogenesis; Golgi; Secretion;
P4 ATPases - Lipid flippases and their role in disease by Dineke E. Folmer; Ronald P.J. Oude Elferink; Coen C. Paulusma (628-635).
P4 ATPases (type 4 P-type ATPases) are multispan transmembrane proteins that have been implicated in phospholipid translocation from the exoplasmic to the cytoplasmic leaflet of biological membranes. Studies in Saccharomyces cerevisiae have indicated that P4 ATPases are important in vesicle biogenesis and are required for vesicular trafficking along several intracellular vesicular transport routes. Although little is known about mammalian P4 ATPases, some members of this subfamily appear to be associated with human disease or mouse pathophysiology. ATP8B1, a phosphatidylserine translocase, is the most extensively studied mammalian P4 ATPase. This protein is important for maintaining the detergent resistant properties of the apical membrane of the hepatocyte. Mutations in ATP8B1 give rise to severe liver disease. Furthermore, a role for Atp8b3 in mouse sperm cell capacitation has been suggested, whereas deficiency of Atp10a and Atp10d leads to insulin resistance and obesity in mice. Here we review the present status on the pathophysiological consequences of P4 ATPase deficiency.
Keywords: P-type ATPase; P4 ATPases; Bile formation; Cholestasis; Infertility; Obesity; Membrane asymmetry; Vesicular transport; Phospholipids; Cholesterol;
Intracellular sterol dynamics by Bruno Mesmin; Frederick R. Maxfield (636-645).
We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols within cells, including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and its engagement in various trafficking processes will determine its proper level in a specific membrane; making the cholesterol distribution uneven among the various intracellular organelles. The cholesterol content is important since cholesterol plays an essential role in membranes by controlling their physicochemical properties as well as key cellular events such as signal transduction and protein trafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved by vesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significant role in these processes, giving us new information about the relative importance of these two trafficking pathways in cholesterol transport. Although still poorly characterized in many trafficking routes, several potential sterol transport proteins have been described in detail; as a result, molecular mechanisms for sterol transport among membranes start to be appreciated.
Keywords: Cholesterol; Lipid; Membrane; Bilayer; Transport;
Cholesterol transport in steroid biosynthesis: Role of protein–protein interactions and implications in disease states by Malena B. Rone; Jinjiang Fan; Vassilios Papadopoulos (646-658).
The transfer of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in hormone-induced steroid formation. To ensure that this step is achieved efficiently, free cholesterol must accumulate in excess at the outer mitochondrial membrane and then be transferred to the inner membrane. This is accomplished through a series of steps that involve various intracellular organelles, including lysosomes and lipid droplets, and proteins such as the translocator protein (18 kDa, TSPO) and steroidogenic acute regulatory (StAR) proteins. TSPO, previously known as the peripheral-type benzodiazepine receptor, is a high-affinity drug- and cholesterol-binding mitochondrial protein. StAR is a hormone-induced mitochondria-targeted protein that has been shown to initiate cholesterol transfer into mitochondria. Through the assistance of proteins such as the cAMP-dependent protein kinase regulatory subunit Iα (PKA-RIα) and the PKA-RIα- and TSPO-associated acyl-coenzyme A binding domain containing 3 (ACBD3) protein, PAP7, cholesterol is transferred to and docked at the outer mitochondrial membrane. The TSPO-dependent import of StAR into mitochondria, and the association of TSPO with the outer/inner mitochondrial membrane contact sites, drives the intramitochondrial cholesterol transfer and subsequent steroid formation. The focus of this review is on (i) the intracellular pathways and protein–protein interactions involved in cholesterol transport and steroid biosynthesis and (ii) the roles and interactions of these proteins in endocrine pathologies and neurological diseases where steroid synthesis plays a critical role.
Keywords: Steroid biosynthesis; Translocator protein; Steroidogenic acute regulatory protein; Peripheral benzodiazepine receptor;
Mechanisms and consequences of impaired lipid trafficking in Niemann–Pick type C1-deficient mammalian cells by Barbara Karten; Kyle B. Peake; Jean E. Vance (659-670).
Niemann–Pick C disease is a fatal progressive neurodegenerative disorder caused in 95% of cases by mutations in the NPC1 gene; the remaining 5% of cases result from mutations in the NPC2 gene. The major biochemical manifestation of NPC1 deficiency is an abnormal sequestration of lipids, including cholesterol and glycosphingolipids, in late endosomes/lysosomes (LE/L) of all cells. In this review, we summarize the current knowledge of the NPC1 protein in mammalian cells with particular focus on how defects in NPC1 alter lipid trafficking and neuronal functions. NPC1 is a protein of LE/L and is predicted to contain thirteen transmembrane domains, five of which constitute a sterol-sensing domain. The precise function of NPC1, and the mechanism by which NPC1 and NPC2 (both cholesterol binding proteins) act together to promote the movement of cholesterol and other lipids out of the LE/L, have not yet been established. Recent evidence suggests that the sequestration of cholesterol in LE/L of cells of the brain (neurons and glial cells) contributes to the widespread death and dysfunction of neurons in the brain. Potential therapies include treatments that promote the removal of cholesterol and glycosphingolipids from LE/L. Currently, the most promising approach for extending life-span and improving the quality of life for NPC patients is a combination of several treatments each of which individually modestly slows disease progression.
Keywords: Cholesterol; Glycosphingolipid; Neuron; Glia; Neurodegeneration; Brain; Liver;
Niemann–Pick C2 (NPC2) and intracellular cholesterol trafficking by Judith Storch; Zhi Xu (671-678).
Cholesterol is an important precursor for numerous biologically active molecules, and it plays a major role in membrane structure and function. Cholesterol can be endogenously synthesized or exogenously taken up via the endocytic vesicle system and subsequently delivered to post-endo/lysosomal sites including the plasma membrane and the endoplasmic reticulum. Niemann–Pick C (NPC) disease results in the accumulation of exogenously-derived cholesterol, as well as other lipids, in late endosomes and lysosomes (LE/LY). Identification of the two genes that underlie NPC disease, NPC1 and NPC2, has focused attention on the mechanisms by which lipids, in particular cholesterol, are transported out of the LE/LY compartment. This review discusses the role of the NPC2 protein in cholesterol transport, and the potential for concerted action of NPC1 and NPC2 in regulating normal intracellular cholesterol homeostasis.
Keywords: Cholesterol; NPC2; NPC1; Late endosome; Lysosome; Lipid transport;
Niemann–Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter by Harry R. Davis; Scott W. Altmann (679-683).
Niemann–Pick C1 Like 1 (NPC1L1) has been identified and characterized as an essential protein in the intestinal cholesterol absorption process. NPC1L1 localizes to the brush border membrane of absorptive enterocytes in the small intestine. Intestinal expression of NPC1L1 is down regulated by diets containing high levels of cholesterol. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and absorption of cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that cholesterol absorption inhibitor ezetimibe specifically binds to an extracellular loop of NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice are resistant to diet-induced hypercholesterolemia, and when crossed with apo E null mice, are completely resistant to the development of atherosclerosis. Intestinal gene expression studies in Npc1l1 null mice indicated that no exogenous cholesterol was entering enterocytes lacking NPC1L1, which resulted in an upregulation of intestinal and hepatic LDL receptor and cholesterol biosynthetic gene expression. Polymorphisms in the human NPC1L1 gene have been found to influence cholesterol absorption and plasma low density lipoprotein levels. Therefore, NPC1L1 is a critical intestinal sterol uptake transporter which influences whole body cholesterol homeostasis.
Keywords: Niemann–Pick C1 Like 1 (NPC1L1); Cholesterol transporter; Ezetimibe;
CERT-mediated trafficking of ceramide by Kentaro Hanada; Keigo Kumagai; Nario Tomishige; Toshiyuki Yamaji (684-691).
The transport and sorting of lipids from the sites of their synthesis to their appropriate destinations are fundamental for membrane biogenesis. In the synthesis of sphingolipids in mammalian cells, ceramide is newly produced at the endoplasmic reticulum (ER), and transported from the ER to the trans Golgi regions, where it is converted to sphingomyelin. CERT mediates the ER-to-Golgi trafficking of ceramide. CERT contains several functional domains and motifs including i) a START domain capable of catalyzing inter-membrane transfer of ceramide, ii) a pleckstrin homology domain, which serves to target the Golgi apparatus, iii) a FFAT motif which interacts with the ER-resident membrane protein VAP, and iv) a serine-repeat motif, of which hyperphosphorylation down-regulates CERT activity. It has been suggested that CERT extracts ceramide from the ER and carries it to the Golgi apparatus in a non-vesicular manner and that efficient CERT-mediated trafficking of ceramide occurs at membrane contact sites between the ER and the Golgi apparatus.
Keywords: PH domain; START domain; FFAT motif; Membrane contact site;
Export and functions of sphingosine-1-phosphate by Roger H. Kim; Kazuaki Takabe; Sheldon Milstien; Sarah Spiegel (692-696).
The sphingolipid metabolite, sphingosine-1-phosphate (S1P), has emerged as a critical player in a number of fundamental biological processes and is important in cancer, angiogenesis, wound healing, cardiovascular function, atherosclerosis, immunity and asthma, among others. Activation of sphingosine kinases, enzymes that catalyze the phosphorylation of sphingosine to S1P, by a variety of agonists, including growth factors, cytokines, hormones, and antigen, increases intracellular S1P. Many of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface in an autocrine and/or paracrine manner. Therefore, understanding the mechanism by which intracellularly generated S1P is released out of cells is both interesting and important. In this review, we will discuss how S1P is formed and released. We will focus particularly on the current knowledge of how the S1P gradient between tissues and blood is maintained, and the role of ABC transporters in S1P release.
Keywords: ABC transporter; Sphingosine-1-phosphate; Sphingosine kinase; Release;