Lipids and Fatty Acids - Part 1 (Properties and Biological Roles)
Lipids: Overview and Core Roles
Lipids come from three sources (lecture, notes, book) and have two main functional categories: structural and signaling roles.
Structural role: lipids form membranes and boundaries that separate intracellular and extracellular environments.
Signaling role: lipids act as signaling molecules that can trigger cascades in cells; hormones and vitamins often have lipid components and function in cascades.
Vitamin D originates from cholesterol and acts as a hormone; lipid signaling can be hormonal in nature.
Lipids that contain fatty acids serve as storage lipids (e.g., triacylglycerols) and as membrane lipids (e.g., phospholipids). Some lipids show strong biological activity and signaling properties.
Two major lipid groups in membranes: phospholipids (lipids with phosphate) and sphingolipids; glycolipids (galactosides, cerebrosides, gangliosides) are also important but do not contain phosphate.
The inner mitochondrial membrane is rich in cardiolipin (a phospholipid) that is important for electron transport and oxidative phosphorylation.
Cholesterol modulates membrane properties and membrane solubility.
Steroid hormones derive from cholesterol; they regulate processes such as smooth muscle tone and pain; cholesterol is also the precursor to vitamin D (cholecalciferol). Warfarin is a vitamin K antagonist used as an anticoagulant.
Membranes are not just barriers; they host receptors and control the selective transport of ions and molecules, enabling cellular responses to external stimuli.
The Fluid Mosaic Model (Sanger–Nicholson) describes membranes as dynamic and mosaic-like, with lipids and proteins able to diffuse laterally.
The membrane can be a reservoir for signaling molecules; phospholipids can be precursors to signaling cascades (e.g., phosphatidylinositol-derived signals).
Fatty Acids: Structure, Saturation, and Nomenclature
Fatty acids in humans are typically even-numbered carbon chains.
Saturation vs. unsaturation:
Saturated fatty acids have no double bonds.
Unsaturated fatty acids have one or more cis double bonds (cis configuration is the common natural form); trans double bonds are less common in nature and are often produced industrially.
Double bonds create kinks in the chain, reducing tight packing and affecting membrane fluidity; more unsaturation generally means lower melting point and greater membrane fluidity at a given temperature.
Example considerations (common naming vs. potential transcription errors):
Palmitic acid: C_{16}:0 (saturated).
Oleic acid: C_{18}:1\,\Delta 9 (monounsaturated, cis at position 9).
Linoleic acid: C_{18}:2\,\Delta 9,12 (polyunsaturated, ω-6).
Linolenic acid: C_{18}:3\,\Delta 9,12,15 (polyunsaturated, ω-3).
Important correction from lecture notes: Palmitic acid is not C{16}:1\,\Delta9 (that would be palmitoleic acid). Palmitic is C{16}:0; palmitoleic is C_{16}:1\,\Delta9.
Nomenclature: Delta (Δ) vs. Omega (ω)
Delta (Δ) numbering:
Indicates the position of double bonds from the carboxyl end (the A/B ends), e.g., C_{18}:1\;\Delta9.
Omega (ω) numbering:
Indicates the position of the first double bond counting from the methyl end; e.g., ω-3 means the first double bond is at the third carbon from the methyl end.
Common examples:
Oleic acid: C_{18}:1\,\Delta9 (ω-9, effectively also ω-9 if you count from the other end).
Linoleic acid: C_{18}:2\,\Delta9,12 (ω-6).
Linolenic acid: C_{18}:3\,\Delta9,12,15 (ω-3).
Essential fatty acids:
Linoleic acid: ext{18:2}, \omega-6
Alpha-linolenic acid: ext{18:3}, \omega-3
The body cannot introduce double bonds beyond Δ9 for certain fatty acids, which is part of why linoleic and alpha-linolenic acids are essential; the downstream products (e.g., arachidonic acid) require dietary supply or elongation/desaturation steps.
Essential Fatty Acids and Metabolic Fate
Essential fatty acids (EFAs):
Linoleic acid (LA): ext{18:2}, \omega-6
Alpha-linolenic acid (ALA): ext{18:3}, \omega-3
Derived/related fatty acids:
Arachidonic acid (AA): ext{20:4}, \omega-6, a key precursor for eicosanoids (prostaglandins, thromboxanes, leukotrienes).
Some fatty acids can be elongated/desaturated to form longer polyunsaturated fatty acids (e.g., EPA, DHA in the ω-3 family).
Why EFAs matter: humans cannot synthesize certain double bonds beyond Δ9 for specific chains, making dietary EFAs essential for proper membrane function and production of signaling molecules.
Fatty Acids and Energy Yield: Why Fats are Energy-Dense
Energy content:
Carbohydrates: 4\ \text{kcal/g}
Fatty acids (as triglycerides): 9\ \text{kcal/g}
Triacylglycerols (TAGs) store energy in adipose tissue; energy is released by lipolysis, releasing fatty acids that undergo beta-oxidation in mitochondria.
Beta-oxidation and oxidative phosphorylation:
Beta-oxidation breaks down fatty acids in the mitochondria to acetyl-CoA units.
Acetyl-CoA enters the TCA cycle, and reduced cofactors feed the electron transport chain, driving oxidative phosphorylation to produce ATP.
Activation of hormone-sensitive lipase (HSL) triggers breakdown of TAGs to release glycerol and free fatty acids for energy.
Triacylglycerols vs Membrane Lipids: Structural and Energy Considerations
Triacylglycerols:
Primarily energy storage.
Glycerol backbone with three fatty acid chains; high energy content per gram.
Stored with osmotic considerations; packs as droplets in adipose tissue.
Membrane lipids:
Primarily phospholipids and cholesterol; form the fluid bilayer.
Balance between saturated and unsaturated fatty acids influences membrane fluidity and phase behavior.
Plant (vegetable) fats tend to have more unsaturated fatty acids, while many animal fats are more saturated; this affects their physical state at room temperature and membrane properties.
Cholesterol affects membrane rigidity and plasma membrane properties, contributing to membrane solubility and organization.
Phospholipids and Sphingolipids: Structure and Roles in Membranes
Phospholipids contain phosphate groups and are divided into two major classes:
Glycerophospholipids: derived from glycerol; contain phosphate and various head groups (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol).
Sphingolipids: built on a sphingosine backbone (not glycerol); may carry a phosphate (e.g., sphingomyelin) or be glycosphingolipids (e.g., cerebrosides, gangliosides).
Glycolipids (glycosphingolipids) include cerebrosides and gangliosides; important for cell recognition and signaling but do not contain phosphorus.
Cardiolipin (a special phospholipid with four acyl chains) is particularly abundant in the inner mitochondrial membrane and is important for electron transport chain function.
Phosphatidylinositol Signaling and Membrane Dynamics
Phosphatidylinositol and its phosphorylated derivatives (phosphoinositides) act as signaling lipids.
Phosphatidylinositol 4,5-bisphosphate (PIP2) is a key signaling lipid on the inner leaflet of the plasma membrane.
Signaling cascade via phospholipase C (PLC):
PIP2 is hydrolyzed by PLC to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3):
ext{PIP}2 ightarrow ext{DAG} + ext{IP}3
DAG remains in the membrane and activates protein kinase C (PKC); IP3 diffuses into the cytosol and triggers Ca^{2+} release from the endoplasmic reticulum, increasing intracellular calcium and activating downstream enzymes.
This signaling pathway is central to many cellular responses, including T cell activation and other immune signaling events.
Membrane Architecture and Receptors
Membranes define cellular boundaries, regulate permeability, and host receptors that respond to external signals.
The membrane is a dynamic, semi-fluid mosaic of lipids and proteins—not a static barrier.
Receptors are specific to ligands and are embedded in or associated with the membrane, enabling selective responses.
Internal compartmentalization allows separation of oxidative from reductive processes and protects genetic material and other sensitive components (nucleus, mitochondria, etc.).
Inner membrane lipid composition (e.g., cardiolipin) supports electron transport and energy production.
Cholesterol, Vitamins, and Hormonal Roles of Lipids
Cholesterol as a membrane component helps modulate fluidity and membrane organization; it is also a precursor to steroid hormones.
Steroid hormones (derived from cholesterol) regulate diverse physiological processes, including smooth muscle tone and inflammatory responses; they can influence signaling cascades that intersect with lipid metabolism.
Vitamin D synthesis begins with cholesterol; sunlight converts precursors to cholecalciferol (Vitamin D3), which acts as a hormone after activation.
Warfarin: a vitamin K antagonist used as an anticoagulant; vitamin K is essential for the activation of certain clotting factors, tying lipid biology to coagulation pathways.
Membranes are impermeable barriers but can be selectively permeable via receptors, channels, and transporters tuned to the cell’s needs.
Medical and Nutritional Implications of Lipids
Unsaturated vs. saturated fats influence membrane fluidity and the physical state of fats at room temperature; unsaturated fats tend to be more fluid.
Trans fatty acids (industrial trans fats) are associated with adverse cardiovascular outcomes; they tend to behave more like saturated fats in membranes and can disrupt normal function.
Essential fatty acids (EFAs) are required in the diet and include:
Linoleic acid (LA): 18:2, \omega-6
Alpha-linolenic acid (ALA): 18:3, \omega-3
Arachidonic acid (AA): 20:4, \omega-6; a pivotal precursor for eicosanoids (prostaglandins, thromboxanes, leukotrienes) that participate in pain, fever, and inflammatory responses.
The balance of ω-3 and ω-6 fatty acids influences inflammatory status and cardiovascular health.
Vitamin K and warfarin link lipid metabolism to coagulation pathways; alterations in membrane lipids can affect signaling pathways that modulate clotting factors and inflammation.
Quick Reference: Key Notations and Examples
Fatty acid notations:
Palmitic acid: C_{16}:0 (saturated)
Stearic acid: C_{18}:0 (saturated)
Oleic acid: C_{18}:1\,\Delta9 (monounsaturated)
Linoleic acid: C_{18}:2\,\Delta9,12\ (\,\omega-6)
Linolenic acid: C_{18}:3\,\Delta9,12,15\ (\,\omega-3)
Arachidonic acid: C_{20}:4\,\Delta5,8,11,14\ (\,\omega-6)
Signaling cleavage example:
\text{PIP}2 \xrightarrow{PLC} \text{DAG} + \text{IP}3
Energy yields:
\text{Energy from fat} = 9\ \text{kcal/g}
\text{Energy from carbohydrate (glucose)} = 4\ \text{kcal/g}
Key membrane lipid roles:
Phosphatidylinositol (PI) and phosphoinositides (e.g., PIP2) are signaling lipids.
Cardiolipin is abundant in the inner mitochondrial membrane and supports electron transport.
Cholesterol modulates membrane properties and serves as a precursor to steroid hormones and vitamin D.
Connections to Foundational Principles
Energy metabolism: Lipids store more energy per gram than carbohydrates, making fats a major energy reservoir, especially during fasting or prolonged exercise.
Structure–function: The specific saturation level and chain length of fatty acids influence membrane fluidity, permeability, and the function of membrane proteins and receptors.
Signaling networks: Lipids are not inert components; they actively participate in signaling cascades, often at the membrane, linking metabolism to gene expression and cellular responses.
Homeostasis and disease: EFAs and balance of ω-3/ω-6 fatty acids influence inflammation, cardiovascular risk, and neurological health; industrial trans fats negatively impact cardiovascular outcomes.
Notes and Nuances from the Lecture
The lecturer emphasizes the two-part structure of the topic: Part I covers fatty acids and their medical/biological consequences; Part II will review lipids in organelles, especially membranes.
Membranes are described as boundaries that enable selective transport and signaling, with receptors enabling response to specific hormones and signals.
The lecture stresses that some phospholipids act as signaling precursors (e.g., PIP2 cleavage generating DAG and IP3) and that this is relevant in processes like T cell activation.
A reminder about nomenclature corrections: common student-friendly examples include that palmitic acid is 16:0, oleic 18:1 Δ9, linoleic 18:2 Δ9,12, and linolenic 18:3 Δ9,12,15, with ω designations (ω-3, ω-6) reflecting the position of the first double bond from the methyl end.
The practical health messages touched on include essential fatty acids, the consequences of trans fats, and the role of lipids in vitamin D production and steroid hormones.