Neuronal Lipid Metabolism Overview

Lipids are organic molecules with diverse structures, playing crucial roles in various biological processes. They are classified into five main types: fatty acids, triacylglycerols, phospholipids, sterol lipids, and sphingolipids.

Fatty acids are the basic building blocks of all lipids. They consist of a carbon chain ending with a carboxyl group. Their classification is based on the length of their chain and the presence or absence of double bonds.

Saturated fatty acids have only single bonds between carbon atoms, while unsaturated fatty acids contain double bonds. Polyunsaturated fatty acids (PUFAs) play a vital role in signaling and membrane structure in the brain.

Fatty acid elongation is a process that extends the carbon chain of fatty acids. It mostly occurs in the endoplasmic reticulum and involves a series of condensation, reduction, and dehydration reactions.

Desaturation is the process that introduces double bonds into the fatty acid chain, modifying its structure and function. Enzymes like ∆9, ∆5, ∆6 desaturases and FADS3 are crucial for this process.

Fatty acid synthesis occurs in the cytosol of lipogenic tissues. While the brain can synthesize most saturated and monounsaturated fatty acids, it heavily relies on dietary sources for PUFAs.

Acetyl-CoA is converted to malonyl-CoA through a carboxylation reaction catalyzed by acetyl-CoA carboxylase (ACC). This is the rate-limiting step in fatty acid synthesis, and it is irreversible.

Fatty acid synthase (FAS) is a homodimer found in the cytoplasm with multiple domains and catalytic sites. It facilitates the cyclical process of fatty acid synthesis, adding two carbons to the chain in each cycle.

Fatty acid transport is crucial, especially for PUFAs, as the brain heavily relies on dietary sources. Fatty acids are transported in the bloodstream and then cross the blood-brain barrier through both passive and active mechanisms.

Passive diffusion describes the movement of fatty acids across membranes without energy expenditure. It is dependent on lipophilicity and size; shorter fatty acids pass more readily.

Active transport involves specialized protein carriers that use energy to move fatty acids across membranes. Primarily, FATP, fatty acid translocase, FABPs, and caveolae contribute to this mechanism.

Triacylglycerols (TAGs) are the primary storage form of lipid precursors. They are composed of a glycerol backbone with three fatty acid chains. Variations in structure arise from the composition of these fatty acid chains.

TAG synthesis primarily happens in adipose tissue and the liver but also occurs in other tissues like skeletal muscle and the brain. It follows two major pathways: glycerol-3-phosphate and monoacylglycerol.

TAG breakdown, also known as lipolysis, is essential for releasing fatty acids. Lipases like ATGL and HSL catalyze this process, breaking down TAGs into diacylglycerol, monoacylglycerol, and finally, free fatty acids and glycerol.

Lipoproteins are complexes that package TAGs, cholesterol esters, and fat-soluble vitamins for transport in the bloodstream. They are classified based on their density: HDL, LDL, IDL, and VLDL.

Phospholipids are a diverse group of lipids with various roles in the body, particularly in the brain. They are characterized by a glycerol backbone, hydrophobic fatty acid tails, hydrophilic head groups, and a phosphate group.

Phospholipid synthesis primarily occurs in the ER. The Kennedy pathway, utilizing CDP-choline and CDP-ethanolamine, is the major route for synthesizing phosphatidylcholines and phosphatidylethanolamines.

Phospholipid transport involves various mechanisms: soluble transport proteins shuttle lipids between compartments, vesicles carry lipids, and close membrane contact facilitates transfer.

Sterol lipids, primarily cholesterol, are essential for brain function. They have a tetracyclic ring structure with a hydroxyl group and a hydrocarbon chain, making them amphipathic.

Cholesterol synthesis occurs through the mevalonate pathway, a multi-step process with HMG-CoA reductase as the rate-limiting enzyme. It begins with acetyl-CoA and ends with cholesterol.

Cholesterol transport involves packaging into lipoproteins like HDL and VLDL, which deliver cholesterol to different tissues. Intracellular transport relies on carrier proteins and vesicular trafficking.

Sphingolipids are a diverse group of lipids characterized by a sphingosine backbone. Ceramides are the simplest form, while sphingomyelins have a phosphocholine group and glycosphingolipids have sugar residues attached.

Sphingolipid synthesis begins at the ER and involves a multi-step process that converts palmitoyl CoA and serine to ceramide. Different enzymes like ceramide synthases and CGT further modify this molecule.

Sphingolipid transport is a complex process involving both vesicular and non-vesicular mechanisms. For instance, CERT is a non-vesicular protein that transports ceramide specifically for sphingomyelin synthesis.

The brain relies heavily on glucose for energy, but fatty acid oxidation contributes approximately 20% of its total energy requirement. This process is mainly carried out by astrocytes.

Fatty acid oxidation involves a series of reactions that convert fatty acids into acetyl-CoA, which then enters the Krebs cycle to generate ATP. This process occurs in the mitochondria and involves several enzyme complexes.

Carnitine palmitoyltransferases (CPTs) are crucial for fatty acid oxidation, transporting fatty acyl-CoAs across mitochondrial membranes. CPT1 is the rate-limiting step, regulated by malonyl-CoA levels.

β-oxidation is the main pathway for fatty acid oxidation, occurring in the mitochondrial matrix. It generates ATP through a cyclic process of four reactions, producing reducing equivalents (NADH, FADH2), acetyl-CoA, and a shorter fatty acyl derivative.

Peroxisomes also participate in fatty acid oxidation, specifically for branched and very long-chain fatty acids. This process involves β-oxidation and α-oxidation, which removes a single carbon from fatty acids.

Fatty acid oxidation is regulated by cellular energy levels. Low ATP levels activate AMPK, inhibiting lipogenesis. Transcription factors like PPARα and CREB also play a role in regulating this pathway.

Ketone bodies are fatty acid derivatives produced in the liver under conditions of low glucose. They are transported in the bloodstream to peripheral tissues, like the brain, where they are used as an alternative energy source.

Lipids play a vital role in forming structural components of cellular membranes. Phospholipids, sterol lipids, and sphingolipids are major contributors to membrane structure due to their amphipathic nature.

Phospholipids, specifically phosphatidylcholine, are abundant in cell membranes and contribute to their fluidity and structural integrity. Their unique molecular geometry affects membrane curvature and permeability.

Phosphatidylethanolamine, a minor phospholipid, contributes to membrane curvature and fluidity. It is enriched in arachidonic acid, a precursor to signaling molecules like prostaglandins and anandamides, important for neuronal signaling.