Diet, hormones, gene transcription, and posttranslational modifications control the hepatic metabolism of FAs; metabolic dysregulation causes chronic diseases, including cardiovascular disease, and ...warrants exploration into the mechanisms directing FA and triacylglycerol (TAG) synthesis and degradation. Long-chain FA metabolism begins by formation of an acyl-CoA by a member of the acyl-CoA synthetase (ACSL) family. Subsequently, TAG synthesis begins with acyl-CoA esterification to glycerol-3-phosphate by a member of the glycerol-3-phosphate acyltransferase (GPAT) family. Our studies of the isoforms ACSL1 and GPAT1 strongly suggest that these proteins are members of larger protein assemblies (interactomes). ACSL1 targeted to the ER interacts with peroxisomal, lipid droplet, and tethering proteins, uncovering a dynamic role for ACSL1 in organelle and lipid droplet interactions. On the outer mitochondrial membrane (OMM), PPARα upregulates ACSL1, which interacts with proteins believed to tether lipid droplets to the OMM. In contrast, GPAT1 is upregulated nutritionally by carbohydrate and insulin in a coordinated sequence of enzyme reactions, from saturated FA formation via de novo lipogenesis to FA esterification by GPAT1 and entry into the TAG biosynthesis pathway. We propose that involved enzymes form a dynamic protein interactome that facilitates esterification and that other lipid-metabolizing pathways will exist in similar physiologically regulated interactomes. Display omitted
Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via ...blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity.
The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for ...antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 Å resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.
Protected areas (PAs) have long been criticized as creations of and for an elite few, where associated costs, but few benefits, are borne by marginalized rural communities. Contrary to predictions of ...this argument, we found that average human population growth rates on the borders of 306 PAs in 45 countries in Africa and Latin America were nearly double average rural growth, suggesting that PAs attract, rather than repel, human settlement. Higher population growth on PA edges is evident across ecoregions, countries, and continents and is correlated positively with international donor investment in national conservation programs and an index of park-related funding. These findings provide insight on the value of PAs for local people, but also highlight a looming threat to PA effectiveness and biodiversity conservation.
Mammalian lipid droplets (LDs), first described as early as the 1880s, were virtually ignored for more than 100 years. Between 1991 and the early 2000s, however, a series of discoveries and ...conceptual breakthroughs led to a resurgent interest in obesity as a disease, in the metabolism of intracellular triacylglycerol (TAG), and in the physical locations of LDs as cellular structures with their associated proteins. Insights included the recognition that obesity underlies major chronic diseases, that appetite is hormonally controlled, that hepatic steatosis is not a benign finding, and that diabetes might fundamentally be a disorder of lipid metabolism. In this brief review, I describe the metamorphosis of LDs from overlooked globs of stored fat to dynamic organelles that control insulin resistance, mitochondrial oxidation, and viral replication.
•Lipid droplets (LDs) have been noted in plant and animal cells since the 1880s.•Interest in LDs grew because of discoveries and conceptual changes in the 1990s.•LDs were ignored as organelles until specific associated proteins and functions were identified.•LDs are intrinsically associated with normal cellular and organismal energy metabolism.•LDs are functional linked to chronic diseases such as diabetes, cardiovascular disease, and cancer.
We present N-body simulations of planetary system formation in thermally evolving, viscous disc models. The simulations incorporate type I migration (including corotation torques and their ...saturation), gap formation, type II migration, gas accretion on to planetary cores and gas disc dispersal through photoevaporation. The aim is to examine whether or not the oligarchic growth scenario, when combined with self-consistent disc models and up-to-date prescriptions for disc-driven migration, can produce planetary systems similar to those that have been observed. The results correlate with the initial disc mass. Low-mass discs form close-packed systems of terrestrial-mass planets and super-Earths. Higher mass discs form multiple generations of planets, with masses in the range 10 ≲ m
p ≲ 45 M⊕. These planets generally type I migrate into the inner disc, because of corotation torque saturation, where they open gaps and type II migrate into the central star. Occasionally, a final generation of low- to intermediate-mass planets forms and survives due to gas disc dispersal. No surviving gas giants were formed in our simulations. Analysis shows that these planets can only survive migration if a core forms and experiences runaway gas accretion at orbital radii r ≳ 10 au prior to the onset of type II migration. We conclude that planet growth above masses m
p ≳ 10 M⊕ during the gas disc lifetime leads to corotation torque saturation and rapid inward migration, preventing the formation and survival of gas giants. This result is in contrast to the success in forming gas giant planets displayed by some population synthesis models. This discrepancy arises, in part, because the type II migration prescription adopted in the population synthesis models causes too large a reduction in the migration speed when in the planet-dominated regime.
The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons
. Major depression and anxiety ...disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action
. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines
, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder
. Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane
. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties
. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors
. Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.
Reducing rates of rehospitalization has attracted attention from policymakers as a way to improve quality of care and reduce costs. However, we have limited information on the frequency and patterns ...of rehospitalization in the United States to aid in planning the necessary changes.
We analyzed Medicare claims data from 2003-2004 to describe the patterns of rehospitalization and the relation of rehospitalization to demographic characteristics of the patients and to characteristics of the hospitals.
Almost one fifth (19.6%) of the 11,855,702 Medicare beneficiaries who had been discharged from a hospital were rehospitalized within 30 days, and 34.0% were rehospitalized within 90 days; 67.1% corrected of patients who had been discharged with medical conditions and 51.5% of those who had been discharged after surgical procedures were rehospitalized or died within the first year after discharge. In the case of 50.2% corrected of the patients who were rehospitalized within 30 days after a medical discharge to the community, there was no bill for a visit to a physician's office between the time of discharge and rehospitalization. Among patients who were rehospitalized within 30 days after a surgical discharge, 70.5% were rehospitalized for a medical condition. We estimate that about 10% of rehospitalizations were likely to have been planned. The average stay of rehospitalized patients was 0.6 day longer than that of patients in the same diagnosis-related group whose most recent hospitalization had been at least 6 months previously. We estimate that the cost to Medicare of unplanned rehospitalizations in 2004 was $17.4 billion.
Rehospitalizations among Medicare beneficiaries are prevalent and costly.
The heart's extraordinary metabolic flexibility allows it to adapt to normal changes in physiology in order to preserve its function. Alterations in the metabolic profile of the heart have also been ...attributed to pathological conditions such as ischemia and hypertrophy; however, research during the past decade has established that cardiac metabolic adaptations can precede the onset of pathologies. It is therefore critical to understand how changes in cardiac substrate availability and use trigger events that ultimately result in heart dysfunction. This review examines the mechanisms by which the heart obtains fuels from the circulation or from mobilization of intracellular stores. We next describe experimental models that exhibit either an increase in glucose use or a decrease in FA oxidation, and how these aberrant conditions affect cardiac metabolism and function. Finally, we highlight the importance of alternative, relatively under-investigated strategies for the treatment of heart failure. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•The heart adapts to normal changes in physiology by switching metabolic substrates.•Altered cardiac metabolism has also been identified under pathological conditions.•Increased glucose use may precede the onset of various pathologies.•Decreased fatty acid oxidation does not ameliorate dysfunction in multiple models.•Alternative strategies investigating transendothelial fuel transport are warranted.
Acyl-CoA metabolism and partitioning Grevengoed, Trisha J; Klett, Eric L; Coleman, Rosalind A
Annual review of nutrition,
01/2014, Letnik:
34
Journal Article
Recenzirano
Odprti dostop
Long-chain fatty acyl-coenzyme As (CoAs) are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain ...acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids such as triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs toward or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.
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