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Journal ArticleDOI

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

01 May 2021-Cells (Multidisciplinary Digital Publishing Institute)-Vol. 10, Iss: 5, pp 1078
TL;DR: In this article, the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and spinal cord repair is discussed, and molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.
Abstract: Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease.
Citations
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Journal ArticleDOI
TL;DR: In this article , the authors review recent work regarding neuronal endoplasmic reticulum function and its relationship to neurotransmission and plasticity, and present a review of the connections between synaptic junctions and synaptic plasticity.

8 citations

Journal ArticleDOI
TL;DR: It is highlighted that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context.
Abstract: Lipid droplets are highly dynamic intracellular organelles that store neutral lipids such as cholesteryl esters and triacylglycerols. They have recently emerged as key stress response components in many different cell types. Lipid droplets in the nervous system are mostly observed in vivo in glia, ependymal cells and microglia. They tend to become more numerous in these cell types and can also form in neurons as a consequence of ageing or stresses involving redox imbalance and lipotoxicity. Abundant lipid droplets are also a characteristic feature of several neurodegenerative diseases. In this minireview, we take a cell-type perspective on recent advances in our understanding of lipid droplet metabolism in glia, neurons and neural stem cells during health and disease. We highlight that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context. The mechanistic understanding of context-dependent lipid droplet functions in the nervous system is progressing apace, aided by new technologies for probing the lipid droplet proteome and lipidome with single-cell type precision.

7 citations

Journal ArticleDOI
22 Dec 2022-Cells
TL;DR: In this article , the role of LDLR in the NaIO3-induced model of dry AMD was investigated, and LDLR loss leads to lipid accumulation and impaired retinal function, which may contribute to the development of AMD.
Abstract: Lipid peroxidation from oxidative stress is considered a major contributor to age-related macular degeneration (AMD). The retina is abundant with circulating low-density lipoproteins (LDL), which are taken up by LDL receptor (LDLR) in the RPE and Müller cells. The purpose of this study is to investigate the role of LDLR in the NaIO3-induced model of dry AMD. Confluent primary human RPE (hRPE) and LDLR-silenced ARPE-19 cells were stressed with 150 µM tert-butyl hydroperoxide (tBH) and caspase 3/7 activation was determined. WT and Ldlr −/− mice were administered NaIO3 (20 mg/kg) intravenously. On day 7, fundus imaging, OCT, ERG, and retinal thickness were measured. Histology, TUNEL, cleaved caspase 3 and lipid accumulation were assessed. Treatment of hRPE with tBH markedly decreased LDLR expression. Caspase 3/7 activation was significantly increased in LDLR-silenced ARPE-19 cells treated with tBH. In Ldlr −/− mice, NaIO3 administration resulted in significant (a) retinal thinning, (b) compromised photoreceptor function, (c) increased percentage of cleaved caspase 3 positive and apoptotic cells, and (d) increased lipid droplet accumulation in the RPE, Bruch membrane, choroid, and sclera, compared to WT mice. Our findings imply that LDLR loss leads to lipid accumulation and impaired retinal function, which may contribute to the development of AMD.

4 citations

Journal ArticleDOI
01 Jul 2022-Cells
TL;DR: The results revealed remarkable differences in the expression and spatial distribution of lipids detected in the scent glands of muskrats during the different reproductive statuses, and elucidates that the seasonal changes in the lipid metabolism may affect the functions of the scent gland in muskrat.
Abstract: As a typical seasonal breeding animal, male muskrats have a pair of scent glands that can emit musky odor substances to attract females during the breeding period. The present study aimed to visualize the differences in the distribution of lipids in the scent glands of muskrats during their different reproductive statuses by imaging mass spectrometry and quantitative real-time PCR (qRT-PCR). The results revealed remarkable differences in the expression and spatial distribution of lipids detected in the scent glands of muskrats during the different reproductive statuses. In addition, the expression levels of lipid molecules PC (32:0) and LysoPC (16:0) were found to be significantly higher in the breeding season than in the non-breeding season. Moreover, the mRNA expression levels of lipid synthesis enzyme Pemt and Pla2g4b were higher in the breeding season than in the non-breeding season, and there were positive correlations between the expression intensities of lipid molecules and the expression levels of Pemt and Pla2g4b. The present study investigates the changes and distribution of the endogenous lipid in the scent glands of muskrats and elucidates that the seasonal changes in the lipid metabolism may affect the functions of the scent glands in muskrats.

3 citations

Journal ArticleDOI
TL;DR: In this paper , a non-invasive assay using Raman spectroscopy for in vitro diagnosis and visualization of cerebral ischemia/reperfusion injury and protective effects of ferulic acid was developed.
Abstract: Ischemic stroke is a major cause of mortality with complicated pathophysiological mechanisms, and hematoxylin and eosin (HE) staining is a histochemical diagnosis technique heavily relying on subjective observation. In this study, we developed a noninvasive assay using Raman spectroscopy for in vitro diagnosis and visualization of cerebral ischemia/reperfusion injury and protective effects of ferulic acid. By establishing a middle cerebral artery occlusion (MCAO) model in Sprague-Dawley male rats, we found effective interventions by ferulic acid using the neurological function score and HE staining. Raman spectra of neuronal and neuroglial cells exhibited significant intensity changes of protein, nucleotide, lipid, and carbohydrate at 780, 814, 1002, 1012, 1176, 1224, 1402, 1520, 1586, 1614, and 1752 cm-1. Cluster vector analysis highlighted the alterations at 1002, 1080, 1298, 1430, 1478, 1508, 1586, and 1676 cm-1. To evaluate the levels of neuron injury and intervention performance, a random forest model was developed on Raman spectral data and achieved satisfactory accuracy (0.9846), sensitivity (0.9679-0.9932), and specificity (0.9945-0.9989), ranking peaks around 1002 cm-1 as key fingerprint for classification. Spectral phenylalanine-to-tryptophan ratio was the biomarker to visualize neuronal injury and intervention performance of ferulic acid with a resolution of 1 μm. Our results unravel the biochemical changes in neuronal cells with cerebral ischemia/reperfusion injury and ferulic acid treatment, and prove Raman spectroscopy coupled with machine learning as a power tool to classify neuron viability and evaluate the intervention performance in pharmacological research.

3 citations

References
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Journal ArticleDOI
01 Dec 1994-Nature
TL;DR: The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Abstract: The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.

12,394 citations

Journal ArticleDOI
TL;DR: How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functions of their individual membranes?
Abstract: Throughout the biological world, a 30 A hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?

5,720 citations

Journal ArticleDOI
TL;DR: The mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, and all of the known ROS-producing sites and their relevance to the mitochondrial ROS production in vivo are discussed.
Abstract: Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

2,893 citations

Journal ArticleDOI
TL;DR: In this article, the authors quantified the biological sources of hepatic and plasma lipoprotein TAG in NAFLD patients, using stable isotopes for four days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipid TAG.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD Patients (5 male and 4 female; 44 ± 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia Of the TAG accounted for in liver, 590% ± 99% of TAG arose from NEFAs; 261% ± 67%, from DNL; and 149% ± 70%, from the diet The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids DNL was elevated in the fasting state and demonstrated no diurnal variation These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD

2,870 citations

Journal ArticleDOI
29 Feb 2008-Science
TL;DR: It is found that cargo is segregated into distinct subdomains on the endosomal membrane and that the transfer of exosome-associated domains into the lumen of theendosome did not depend on the function of the ESCRT (endosomal sorting complex required for transport) machinery, but required the sphingolipid ceramide.
Abstract: Intraluminal vesicles of multivesicular endosomes are either sorted for cargo degradation into lysosomes or secreted as exosomes into the extracellular milieu. The mechanisms underlying the sorting of membrane into the different populations of intraluminal vesicles are unknown. Here, we find that cargo is segregated into distinct subdomains on the endosomal membrane and that the transfer of exosome-associated domains into the lumen of the endosome did not depend on the function of the ESCRT (endosomal sorting complex required for transport) machinery, but required the sphingolipid ceramide. Purified exosomes were enriched in ceramide, and the release of exosomes was reduced after the inhibition of neutral sphingomyelinases. These results establish a pathway in intraendosomal membrane transport and exosome formation.

2,818 citations