Lipids are the main component of cellular membranes. They are highly diverse in structure, and the distribution of different lipids and their species (membrane lipid composition) varies at the organism, cell type, organelle, membrane, bilayer-leaflet and membrane subdomain level. Understanding the biological relevance of this diversity and why there are so many lipid-related genetic diseases represent a fundamental challenge in biology.
The enzymes carrying out the vast majority of lipid metabolic pathways have now been identified, enabling the use of genetics to modify experimental lipid composition. However, detailed analyses of enzyme functions and results from genetic modification experiments reveal that most lipid levels are regulated by a complex contribution from various pathways, making the functional analysis of genetic defects challenging.
Lipid composition affects membrane physical properties, the biological relevance of which is becoming clearer. For example, polyunsaturated fatty acids in glycerophospholipids reduce membrane rigidity and affect processes that accompany membrane deformation.
Lipid composition affects membrane protein functions, such as ion channels. However, the mechanisms by which lipids affect protein conformation and activity are still not fully understood.
Chemical biology tools enable proteome-wide identification of lipid-interacting proteins, potentially revolutionizing our understanding of lipid functions. However, further breakthroughs will be required to understand how proteins are functionally affected by lipid composition.
A few examples of mechanisms that cells use to sense lipid composition have now been discovered. Sensing is important not only for maintaining lipid homeostasis but also for sensing cellular metabolic status and coordinating it with various cell functions, such as cell growth.
Cellular membranes are formed from a chemically diverse set of lipids present in various amounts and proportions. A high lipid diversity is universal in eukaryotes and is seen from the scale of a membrane leaflet to that of a whole organism, highlighting its importance and suggesting that membrane lipids fulfil many functions. Indeed, alterations of membrane lipid homeostasis are linked to various diseases. While many of their functions remain unknown, interdisciplinary approaches have begun to reveal novel functions of lipids and their interactions. We are beginning to understand why even small changes in lipid structures and in composition can have profound effects on crucial biological functions.
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The authors thank the members of the Riezman laboratory for helpful discussions and funding from the Japanese Society for the Promotion of Science (T.H.), the Swiss National Science Foundation (H.R.) and the National Centre for Competence in Research in Chemical Biology (H.R.).
The authors declare no competing financial interests.
Inherited diseases of lipid metabolism (XLSX 18 kb)
List of enzymes and their localizations. (XLSX 23 kb)
Tissue distributions of enzymes. (XLSX 130 kb)
Analysis of tissue-specific regulation of lipid-related genes (PDF 175 kb)
Effect of lipid structures on lateral heterogeneity in membranes (PDF 757 kb)
Isomeric molecules that have the same molecular formula but different structures.
- Membrane contact sites
Regions where two organelles are in close proximity, typically at a distance of less than 30 nm, where nonvesicular exchange of lipids is proposed to occur.
- Lipid mediators
Lipids with signalling functions, such as the eicosanoids, which are derived from arachidonic acid released from the membrane and serve as ligands for their receptors.
- Lipid droplets
Organelles where the excess of triglycerides, cholesteryl esters and acylceramides is stored.
- Protein lipidation
A post-translational modification of proteins encompassing a covalent attachment of a lipid.
- Sphingoid base
The structural backbone of sphingolipids, which also acts as one of the hydrophobic chains.
A mitochondria-specific (in mammals) glycerophospholipid with four acyl chains, the malfunction of which is involved in Barth syndrome.
- Membrane nanodomains
Lateral heterogeneities in membranes, often very small and dynamic, where lipids are postulated to have important roles affecting membrane properties and function.
Glycerophospholipids with a vinyl-ether bond at the sn-1 position, which depend upon peroxisomes for their synthesis.
In terms of enzymology, the ability of an enzyme to utilize a broad range of substrates.
A situation where different molecules (for example, enzymes) have (at least partially) overlapping functions.
- ENCODE Project
(Encyclopaedia of DNA Elements). An international collaboration with the objective of comprehensively elucidating functional elements in the human genome.
- Mead acid
A polyunsaturated fatty acid (20:3 n-9) that can be synthesized endogenously in mammals, which is produced under polyunsaturated fatty acid insufficiency.
- Omega end
In fatty acid nomenclature, the end of a fatty acid that has a methyl group. The other end with a carboxyl group is called the alpha end.
- Sjögren–Larsson syndrome
A genetic disease with skin and neurological problems, caused by mutations in a fatty aldehyde dehydrogenase involved in sphingolipid degradation.
- Hereditary sensory and autonomic neuropathy
A genetic disease affecting the nervous system characterized by a loss of pain sensation, among other symptoms.
Ceramides with another fatty acid O-esterified at the ω-end of the N-acyl chain.
A group of proteins involved in membrane fusion.
Multinucleated cell type generated by cell fusion that has a role in bone resorption.
- Liquid-ordered domains
A state of membrane lipids where hydrophobic chains are ordered but lateral diffusion is still high.
- Sertoli cells
Testicular cells that assist spermatogenesis.
A non-apoptotic cell death triggered by overaccumulation of peroxidized lipids.
- Nuclear receptors
A family of proteins that serve as transcriptional regulators in the nucleus upon ligand binding.
- BAR domain
A protein domain that has the ability to bind and/or to induce a specific curvature in membranes.
- Annular lipids
Lipids that stick to the surface of membrane protein transmembrane regions with fairly weak interactions, being in rapid exchange with the bulk of membrane lipids.
- Nonannular lipids
Lipids that bind strongly to, or are buried in, membrane protein transmembrane regions.
- Tor complex 2
(TORC2) Protein kinase complex that contains the target of rapamycin subunit that responds to nutritional and other signals and acts as a central regulator of protein and lipid synthesis and cell proliferation.
- AMP-activated protein kinase
(AMPK). An important protein kinase that senses energy status by binding to AMP and that is activated upon glucose deprivation to regulate several biosynthetic pathways.
The negative log10 of the acid dissociation constant of a molecule.
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Harayama, T., Riezman, H. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol 19, 281–296 (2018). https://doi.org/10.1038/nrm.2017.138
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