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Nature Communications Oct 2023Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain,...
Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the ALAL residues dissociates from membrane, exposing the QKR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Topics: Animals; Male; Mice; Biological Transport; Cell Membrane; Cholesterol; Intestinal Absorption; Membrane Transport Proteins
PubMed: 37833289
DOI: 10.1038/s41467-023-42179-5 -
Scientific Reports Aug 2022Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid...
Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid bilayers poses a tremendous challenge to researchers. The current stage of development of structural biology, in addition to new research tools, has largely facilitated the acquisition of knowledge about transporters and mechanisms. This Collection presents recent studies, covering bioenergetics, structure and functional characterization of various transporters, lipids-protein interactions, and novel research tool development.
Topics: ATP-Binding Cassette Transporters; Biological Transport; Cell Membrane; Membrane Transport Proteins; Protein Conformation
PubMed: 35918457
DOI: 10.1038/s41598-022-17524-1 -
Nature Medicine May 2017Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of...
Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
Topics: Adipose Tissue, Brown; Animals; Biological Transport; CD36 Antigens; Cell Membrane; Cold Temperature; Energy Metabolism; Fatty Acid Transport Proteins; Fatty Acids; Female; Fluorodeoxyglucose F18; Humans; Insulin Resistance; Male; Mice; Obesity; Oleic Acids; Overweight; Positron Emission Tomography Computed Tomography; RNA, Messenger; Radiopharmaceuticals; Thermogenesis; Triglycerides
PubMed: 28346411
DOI: 10.1038/nm.4297 -
Nature Jan 2024Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most...
Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.
Topics: Acinetobacter; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Binding Sites; Biological Transport; Cell Membrane; Lipopolysaccharides; Membrane Transport Proteins; Microbial Viability; Protein Conformation; Substrate Specificity
PubMed: 38172635
DOI: 10.1038/s41586-023-06799-7 -
Biochimica Et Biophysica Acta.... May 2021Transport proteins are essential for cells in allowing the exchange of substances between cells and their environment across the lipid bilayer forming a tight barrier.... (Review)
Review
Transport proteins are essential for cells in allowing the exchange of substances between cells and their environment across the lipid bilayer forming a tight barrier. Membrane lipids modulate the function of transmembrane proteins such as transporters in two ways: Lipids are tightly and specifically bound to transport proteins and in addition they modulate from the bulk of the lipid bilayer the function of transport proteins. This overview summarizes currently available information at the ultrastructural level on lipids tightly bound to transport proteins and the impact of altered bulk membrane lipid composition. Human diseases leading to altered lipid homeostasis will lead to altered membrane lipid composition, which in turn affect the function of transporter proteins.
Topics: Animals; Biological Transport; Humans; Lipid Bilayers; Membrane Lipids; Membrane Transport Proteins; Protein Binding
PubMed: 33476785
DOI: 10.1016/j.bbadis.2021.166079 -
Biochemical Society Transactions Aug 2020The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope... (Review)
Review
The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.
Topics: Antitubercular Agents; Bacterial Proteins; Biological Transport; Drug Development; Lipids; Membrane Transport Proteins; Mycolic Acids; Protein Conformation
PubMed: 32662825
DOI: 10.1042/BST20190950 -
Current Biology : CB Apr 2018The plasma membrane is a ∼4 nm thick phospholipid bilayer that defines the boundary of a cell, segregating internal content from the external environment. Its... (Review)
Review
The plasma membrane is a ∼4 nm thick phospholipid bilayer that defines the boundary of a cell, segregating internal content from the external environment. Its hydrophobic interior presents a barrier to the exchange of ions and polar solutes between the inside and outside of the cell, as well as to the spontaneous reorientation of lipids between the two leaflets of the bilayer. Specific transport systems, e.g. ion channels and lipid flippases, are needed to enable the passage of these molecules across the plasma membrane at physiologically relevant rates. Although the influential fluid mosaic membrane model of 1972 depicted the membrane as an archipelago of protein islands within a uniform sea of lipids, its micrometer-scale lateral heterogeneity was recognized relatively quickly, evolving into the current picture of structural granularity at the nanoscale.
Topics: Biological Transport; Cell Membrane; Hydrodynamics; Lipid Bilayers; Lipid Metabolism; Lipids; Membrane Microdomains; Membrane Proteins
PubMed: 29689220
DOI: 10.1016/j.cub.2018.01.007 -
Annual Review of Cell and Developmental... Oct 2023The life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic... (Review)
Review
The life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic along the secretory and endocytic pathways and lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few lipids at a time and were thought to mediate transport by shuttle-like mechanisms. Over the last few years, a new family of LTPs has been discovered that is defined by a repeating β-groove (RBG) rod-like structure with a hydrophobic channel running along their entire length. This structure and the localization of these proteins at membrane contact sites suggest a bridge-like mechanism of lipid transport. Mutations in some of these proteins result in neurodegenerative and developmental disorders. Here we review the known properties and well-established or putative physiological roles of these proteins, and we highlight the many questions that remain open about their functions.
Topics: Carrier Proteins; Proteins; Biological Transport; Cell Membrane; Lipids
PubMed: 37406299
DOI: 10.1146/annurev-cellbio-120420-014634 -
Amino Acids Dec 2021The retina is one of the most energy-demanding tissues in the human body. Photoreceptors in the outer retina rely on nutrient support from the neighboring retinal... (Review)
Review
The retina is one of the most energy-demanding tissues in the human body. Photoreceptors in the outer retina rely on nutrient support from the neighboring retinal pigment epithelium (RPE), a monolayer of epithelial cells that separate the retina and choroidal blood supply. RPE dysfunction or cell death can result in photoreceptor degeneration, leading to blindness in retinal degenerative diseases including some inherited retinal degenerations and age-related macular degeneration (AMD). In addition to having ready access to rich nutrients from blood, the RPE is also supplied with lactate from adjacent photoreceptors. Moreover, RPE can phagocytose lipid-rich outer segments for degradation and recycling on a daily basis. Recent studies show RPE cells prefer proline as a major metabolic substrate, and they are highly enriched for the proline transporter, SLC6A20. In contrast, dysfunctional or poorly differentiated RPE fails to utilize proline. RPE uses proline to fuel mitochondrial metabolism, synthesize amino acids, build the extracellular matrix, fight against oxidative stress, and sustain differentiation. Remarkably, the neural retina rarely imports proline directly, but it uptakes and utilizes intermediates and amino acids derived from proline catabolism in the RPE. Mutations of genes in proline metabolism are associated with retinal degenerative diseases, and proline supplementation is reported to improve RPE-initiated vision loss. This review will cover proline metabolism in RPE and highlight the importance of proline transport and utilization in maintaining retinal metabolism and health.
Topics: Animals; Biological Transport; Humans; Macular Degeneration; Membrane Transport Proteins; Proline; Retina; Retinal Pigment Epithelium
PubMed: 33871679
DOI: 10.1007/s00726-021-02981-1 -
Current Opinion in Structural Biology Oct 2022The cell envelope of Gram-negative bacteria is composed of an inner membrane, outer membane, and an intervening periplasmic space. How the outer membrane lipids are... (Review)
Review
The cell envelope of Gram-negative bacteria is composed of an inner membrane, outer membane, and an intervening periplasmic space. How the outer membrane lipids are trafficked and assembled there, and how the asymmetry of the outer membrane is maintained is an area of intense research. The Mla system has been implicated in the maintenance of lipid asymmetry in the outer membrane, and is generally thought to drive the removal of mislocalized phospholipids from the outer membrane and their retrograde transport to the inner membrane. At the heart of the Mla pathway is a structurally unique ABC transporter complex in the inner membrane, called MlaFEDB. Recently, an explosion of cryo-EM studies has begun to shed light on the structure and lipid translocation mechanism of MlaFEDB, with many parallels to other ABC transporter families, including human ABCA and ABCG, as well as bacterial lipopolysaccharide and O-antigen transporters. Here we synthesize information from all available structures, and propose a model for lipid trafficking across the cell envelope by MlaFEDB.
Topics: ATP-Binding Cassette Transporters; Bacteria; Biological Transport; Cell Membrane; Escherichia coli Proteins; Humans; Lipopolysaccharides; Membrane Lipids; O Antigens; Phospholipids
PubMed: 35981415
DOI: 10.1016/j.sbi.2022.102429