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Review
. 2018 Jan 23:11:10.
doi: 10.3389/fnmol.2018.00010. eCollection 2018.

Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease

Timothy J Tracey  1 , Frederik J Steyn  2 , Ernst J Wolvetang  1 , Shyuan T Ngo  1   2   3
Affiliations
Review

Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease

Timothy J Tracey et al. Front Mol Neurosci. .

Abstract

Lipids are a fundamental class of organic molecules implicated in a wide range of biological processes related to their structural diversity, and based on this can be broadly classified into five categories; fatty acids, triacylglycerols (TAGs), phospholipids, sterol lipids and sphingolipids. Different lipid classes play major roles in neuronal cell populations; they can be used as energy substrates, act as building blocks for cellular structural machinery, serve as bioactive molecules, or a combination of each. In amyotrophic lateral sclerosis (ALS), dysfunctions in lipid metabolism and function have been identified as potential drivers of pathogenesis. In particular, aberrant lipid metabolism is proposed to underlie denervation of neuromuscular junctions, mitochondrial dysfunction, excitotoxicity, impaired neuronal transport, cytoskeletal defects, inflammation and reduced neurotransmitter release. Here we review current knowledge of the roles of lipid metabolism and function in the CNS and discuss how modulating these pathways may offer novel therapeutic options for treating ALS.

Keywords: amyotrophic lateral sclerosis; glycosphingolipid; lipid metabolism; mitochondria; neuronal metabolism.

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Figures

Figure 1
Figure 1
The structure of individual lipid classes affects their intracellular localization. Triacylglycerols (TAGs) consist of three fatty acid chains attached to a glycerol backbone. As TAG synthesis occurs in the endoplasmic reticulum (ER), a large proportion of TAGs are found within this compartment. A significant proportion is also stored in specialized intracellular organelles known as lipid droplets. The subclasses of phospholipids are synthesized through a number of pathways. Phosphatidylcholine and phosphatidylinositol are largely localized to the ER, while phosphatidylserine, phosphatidylglycerol and phosphatidylethanolamine are mainly to localized to the mitochondria and its associated membranes. Sterol lipids, such as cholesterol, are highly concentrated at the plasma membrane. Sphingolipids are also largely localized to the plasma membrane. This is particularly the case for sphingomyelin and glycosphingolipids. As major components of lipid rafts, sphingolipid concentration at the plasma membrane is kept high.
Figure 2
Figure 2
Fatty acid synthesis is a cyclical process that utilizes a unique multifunctional enzyme complex. Glucose is metabolized to acetyl CoA through the standard glucose metabolic pathway. Acetyl CoA is then carboxylated by acetyl CoA carboxylase (ACC) to form malonyl CoA. This carboxylation step is the rate limiting process in fatty acid synthesis. Malonyl CoA and unreacted acetyl CoA undergo transacylation to form malonyl ACP and acetyl ACP respectively. These intermediates enter fatty acid synthase (FAS), where four reactions take place; condensation, reduction, dehydration, and a second reduction. The four reactions add two carbons to the original carbon chain—in this case malonyl ACP. In humans, this cycle is typically repeated six more times, using the product from the end of the cycle as the input molecules for the next cycle, producing palmitoyl ACP; a 16 carbon product. A thioesterase enzyme then terminates the carbon chain at the thioester bond, forming palmitic acid.
Figure 3
Figure 3
All phospholipid subclasses are derived from phosphatidic acid via a variety of synthetic pathways. Phosphatidylcholine is synthesized via two pathways. The major pathway is the Kennedy pathway and involves the addition of CDP-choline to the phosphatidic acid derivative diacylglycerol. Phosphatidylcholine can also be synthesized through the action of phosphatidylethanolamine N-methyltransferase (PEMT), which converts phosphatidylethanolamine to phosphatidylcholine. Phosphatidylethanolamine is also synthesized via the Kennedy pathway, where the multifunctional enzymes catalyze the addition of CDP-ethanolamine to diacylglycerol. Phosphatidylethanolamine can also be synthesized by phosphatidylserine decarboxylase. Phosphatidylserine is synthesized from CDP-diacylglycerol, phosphatidylcholine, and phosphatidylethanolamine via phosphatidylserine synthase. Phosphatidylinositol is derived from the CDP-diacylglycerol by phosphatidylinositol synthase. Phosphatidylglycerol is synthesized from CDP-diacylglycerol via a multistep process involving phosphatidylglycerol phosphate synthase, and phosphatidylglycerol phosphate phosphatase. Cardiolipin can then be synthesized from phosphatidylglycerol via cardiolipin synthase.
Figure 4
Figure 4
Cholesterol synthesis occurs through diverging pathways for different neuronal cell types. Cholesterol synthesis acts through the mevalonate pathway. Acetyl CoA is converted to 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). HMG CoA is then converted to mevalonate via HMG-CoA reductase, and this is the rate limiting step in cholesterol synthesis. Via a complex series of reactions that involve multiple enzymes and reaction steps, mevalonate is converted to squalene. Squalene is converted to lanosterol in an essential cyclization process. From here, the Kandutsch-Russel pathway, which is favored by neuronal cells, produces cholesterol from lanosterol, while the Bloch pathway synthesizes cholesterol that is favored by glial cells. After cholesterol is synthesized, it can be further metabolized into vitamin D, steroid hormones, or bile acids, or it may be incorporated into cellular membranes.
Figure 5
Figure 5
Neuronal sphingolipid synthesis takes place across multiple cellular compartments. Sphingolipid synthesis begins at the cytosolic leaflet of the ER. Via a series of reactions, palmitoyl CoA and serine are converted to ceramide. A portion of this ceramide is transported to the luminal leaflet of the ER, where ceramide galactosyltransferase (CGT) converts the ceramide to galactosylceramide; an essential neuronal sphingolipid. Another portion of this ceramide is transported to the Golgi complex, where it is converted to either glucosylceramide on the cytosolic side of the Golgi via glucosylceramide synthase, or to sphingomyelin on the luminal side by sphingomyelin synthase. Transport of ceramide from the ER to the Golgi complex is facilitated by either ceramide transfer protein (CERT) or vesicular transport.
Figure 6
Figure 6
Fatty acid oxidation is a major contributor to reactive oxygen species production, which is increased in amyotrophic lateral sclerosis (ALS). Although fatty acids are not the obligate substrate for energy production in the cell, β-oxidation of fatty acids generates a substantial amount of reactive oxygen species as a by-product. In turn, these promote a number of harmful oxidative effects including lipid peroxidation, protein oxidation, DNA damage, and apoptosis. As neurons are not effectively equipped to deal with oxidative stress, these harmful effects are multiplied, contributing to neurodegeneration.
Figure 7
Figure 7
Dysregulated lipid metabolism exerts a multifaceted effect on neurons in ALS. Dysregulation of neuronal lipid metabolism in ALS impacts energy use, structural integrity and signaling processes. Increased use of lipid as an energy substrate leads to increased oxidative stress. This exacerbates inflammation, mitochondrial dysfunction, metabolic dysfunction and excitotoxicity. Altered lipid metabolism also disrupts intracellular lipids leading to cytoskeletal defects and the denervation of neuromuscular junctions. Finally, changes in lipid metabolism impacts the composition of lipid rafts. This disrupts signaling processes that are crucial in regulating neurotransmitter synthesis and release, cytoskeletal integrity and intracellular transport.
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