Abstract:Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is… Show more
“…6A) when expressed in ASH sensory neurons, i.e. the neurons that are required in C. elegans for a wide range of avoidance behaviorsand by stroking the nose of the worm with an eyelash (Caires et al, 2017;Liedtke et al, 2003). OSM-9 is the C. elegans orthologue of mammalian TRPV4; noteworthy, OSM-9 acts downstream of the DEG-1 channel in the ASH-mediated mechanical response (Colbert et al, 1997;Geffeney et al, 2011).We expressed Mus musculus (m)TRPC6 (no TRPC6 ortholog is encoded in the C. elegans genome) in ASH sensory neurons to determine whether TRPC6 can recover the touch response of osm-9 worms (Fig.…”
Section: Trp Channels Expressed In Heterologous Systems Are Insensitimentioning
TRP channels of the transient receptor potential ion channel superfamily are involved in a wide variety of mechanosensory processes, including touch sensation, pain, blood pressure regulation, bone loading and detection of cerebrospinal fluid flow. However, in many instances it is unclear whether TRP channels are the primary transducers of mechanical force in these processes. In this study, we tested stretch activation of eleven TRP channels from six mammalian subfamilies. We found that these TRP channels were insensitive to short membrane stretches in cellular systems. Furthermore, we purified TRPC6 and demonstrated its insensitivity to stretch in liposomes, an artificial bilayer system free from cellular components. Additionally, we demonstrated that, when expressed in C. elegans neurons, mouse TRPC6 restores the mechanoresponse of a touch insensitive mutant but requires diacylglycerol for activation. These results strongly suggest that the mammalian members of the TRP ion channel family are insensitive to tension induced by cell membrane stretching and, thus, are more likely to be activated by cytoplasmic tethers or downstream components and to act as amplifiers of cellular mechanosensory signaling cascades.
“…6A) when expressed in ASH sensory neurons, i.e. the neurons that are required in C. elegans for a wide range of avoidance behaviorsand by stroking the nose of the worm with an eyelash (Caires et al, 2017;Liedtke et al, 2003). OSM-9 is the C. elegans orthologue of mammalian TRPV4; noteworthy, OSM-9 acts downstream of the DEG-1 channel in the ASH-mediated mechanical response (Colbert et al, 1997;Geffeney et al, 2011).We expressed Mus musculus (m)TRPC6 (no TRPC6 ortholog is encoded in the C. elegans genome) in ASH sensory neurons to determine whether TRPC6 can recover the touch response of osm-9 worms (Fig.…”
Section: Trp Channels Expressed In Heterologous Systems Are Insensitimentioning
TRP channels of the transient receptor potential ion channel superfamily are involved in a wide variety of mechanosensory processes, including touch sensation, pain, blood pressure regulation, bone loading and detection of cerebrospinal fluid flow. However, in many instances it is unclear whether TRP channels are the primary transducers of mechanical force in these processes. In this study, we tested stretch activation of eleven TRP channels from six mammalian subfamilies. We found that these TRP channels were insensitive to short membrane stretches in cellular systems. Furthermore, we purified TRPC6 and demonstrated its insensitivity to stretch in liposomes, an artificial bilayer system free from cellular components. Additionally, we demonstrated that, when expressed in C. elegans neurons, mouse TRPC6 restores the mechanoresponse of a touch insensitive mutant but requires diacylglycerol for activation. These results strongly suggest that the mammalian members of the TRP ion channel family are insensitive to tension induced by cell membrane stretching and, thus, are more likely to be activated by cytoplasmic tethers or downstream components and to act as amplifiers of cellular mechanosensory signaling cascades.
“…Moreover, FAO maintains the cellular pool of acetyl-CoA and retains the identity of vascular ECs by reducing transforming growth factor β-induced endothelial-to-mesenchymal transition (EndMT) (Xiong et al, 2018 ). In addition to its role in EC proliferation, differentiation and permeability, FA metabolism also modulates the lipid composition of EC membranes, thereby regulating membrane stiffness and multiple cellular functions (Caires et al, 2017 ; Glatzel et al, 2018 ; Harayama and Riezman, 2018 ).…”
Section: Endothelial Cell Metabolism In Healthmentioning
Atherosclerosis and its sequelae, such as myocardial infarction and stroke, are the leading cause of death worldwide. Vascular endothelial cells (EC) play a critical role in vascular homeostasis and disease. Atherosclerosis as well as its independent risk factors including diabetes, obesity, and aging, are hallmarked by endothelial activation and dysfunction. Metabolic pathways have emerged as key regulators of many EC functions, including angiogenesis, inflammation, and barrier function, processes which are deregulated during atherogenesis. In this review, we highlight the role of glucose, fatty acid, and amino acid metabolism in EC functions during physiological and pathological states, specifically atherosclerosis, diabetes, obesity and aging.
“…One possibility is that a reduced level of PUFA-containing phospholipids impacts membrane fluidity and in turn reduces ion-channel activity. For example, AA and DHA can regulate channels such as K + channels and TRPV4 (Caires, Sierra-Valdez et al, 2017, Horimoto, Nabekura et al, 1997, Villarroel & Schwarz, 1996. Moreover, phospholipids with PUFAs can be degraded and produce the second messengers 2-AG, 1,2-diacylglycerol and IP3.…”
Highlights:1. Neuronal lipolysis prevents LD accumulation in neurons.2. Defective neuronal lipolysis leads to touch sensation defect.3. Blocking neuronal lipolysis alleviates neurodegeneration. 4. Neuronal lipolysis and de novo PUFA biosynthesis have a synergistic effect in neurodegeneration.
The incorporation of PUFAs into phospholipids promotes neurodegeneration.
AbstractLipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl-1 and lid-1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation-triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects, synergistically with decreased lipolysis.Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in regulating neural functions and neurodegeneration cell-autonomously.
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