Lipids Part 1

Lipids - Part 1

Learning Objectives

• Identify the types of lipids and their biological functions.
• Fatty Acids (FA).
  • Describe their structure, composition, and physiological roles.
  • Understand fatty acid nomenclature.
  • Name the essential fatty acids.
• Phospholipids:
  • Describe their structure and function.
  • Explain their synthesis and degradation processes.
• Glycolipids (Glycosphingolipids):
  • Describe their structure and physiological relevance, give examples.
• Eicosanoids:
  • Name the eicosanoids, understand their structure and physiological roles.
• Cholesterol and Steroid Hormones:
  • Describe their structure and physiological significance.
• Lipoproteins:
  • Name the different lipoproteins and compare their structure.
  • Explain where the different lipoproteins are generated and their main function.

Terminology/Abbreviations

• Amphipathic/Amphiphilic
• Anionic group
• Carboxyl group
• Cholesterol
• Eicosanoids
• Exocytosis
• Hydrophilic
• Hydrophobic
• Lipophilic
• Lipophobic
• Monosaccharides
• Nonpolar
• Phosphatase
• Phospholipases
• Phospholipids (PL)
• Polar
• Steroids
• Surfactant
• SCFA (short chain fatty acid)
• MCFA (medium chain fatty acid)
• LCFA (long chain fatty acid)
• SFA (saturated fatty acid)
• USF (unsaturated fatty acid)
• TAG (Triacylglycerol or triglycerides)
• FFA (Free fatty acids)

What are Lipids?

• A chemically diverse group of mainly water-insoluble (hydrophobic) organic molecules.
• Soluble in non-polar solvents such as ether, chloroform, benzene, and other lipids.
• Components of plant and animal tissues.
• Body lipids are generally found compartmentalized (because of hydrophobicity):
  • Membrane-associated lipids.
  • Droplets of triacylglycerol in adipocytes.
  • Transported in blood plasma associated with transport proteins (lipoproteins, albumin).

Lipids - Biological Functions

• Major source of energy for the body (stored in adipocytes).
• Provide:
  • Structural elements for biological membranes.
  • Hydrophobic barriers → compartmentalization.
  • Protection against physical trauma (cushioning action).
• Thermal and electrical insulators.
• Metabolic regulators → i.e., associated with liposoluble vitamins regulating enzymes (coenzyme function).
• Important for controlling body homeostasis → main component of prostaglandins and steroid hormones.

Lipids - Structure

• Carbohydrates vs Lipids:
  • Hydrophilic/Lipophobic: water-loving = polar molecule.
  • Hydrophobic/Lipophilic: water-fearing = nonpolar molecule.
  • Some lipids are Amphipathic (having both hydrophilic and hydrophobic parts) - Phospholipids!

Common Lipids

Molecules with high physiological and metabolic relevance:

• Saturated and unsaturated fatty acids (SFA and UFA).
• Mono-, di- and triacylglycerol (MAG, DAG, TAG) – glycerides.
• Neutral fats (e.g., Waxes, ceramide).
• Cholesterol.
• Phospholipids (PL).
• Glycolipids.
• Lipoproteins (LP).
• Steroids (i.e., sexual hormones, adrenal gland hormones).
• Eicosanoids (prostaglandins, thromboxanes, leukotrienes).
• Ketone bodies.
• Fat-soluble vitamins (A, D, E, K).

Fatty Acids - Relevance

Fatty acids are the building blocks of lipids:

• Exist free in the body (small amount).
• As fatty acyl esters (combination of a fatty acid with an alcohol such as glycerol; i.e., triacylglycerol TAG).
• Provide energy for the cells: during a fast period, fatty acids are released from adipose tissue (TAG) and transported to tissues bound to plasma albumin → beta-oxidation: energy production in most tissues → i.e., liver and muscle.
• Structural components: phospholipids and glycolipids in the plasma membrane.
• Hormone precursors: prostaglandins (hormone-like molecule).
• Energy reserve/storage: TAG in white adipose tissues.

Fatty Acids - Structure

• Consists of a hydrophobic hydrocarbon chain with a terminal carboxyl group (-COOH), which ionizes at physiological pH to –COO- (polar).
  • Anionic group is hydrophilic, giving the FA its amphipathic nature.
• In long-chain-length FA (LCFA), the hydrophobic portion is dominant, making them highly water-insoluble.
• They must be associated with a protein for blood plasma circulation → mainly albumin and lipoproteins.
• > 90% of FA circulating in blood plasma are in esterified form (TAG, PL and cholesteryl esters) contained in lipoprotein particles.

Fatty Acids - Saturation

• No double bonds → Saturated.
• One or more double bonds → unsaturated (mono or poly).
  • Cis double bonds cause the FA to bend or kink in that position and play important roles in plasma membrane structure.
  • Two or more double bonds are always spaced at 3-carbon intervals.
  • Addition of double bonds decreases the melting temperature ($T_m$) of a FA.

Fatty Acids - Nomenclature

• Carbon atoms are numbered starting with carbonyl carbon = C1.
  • Number before the colon indicates number of carbons in the chain.
  • Number after colon describes numbers and positions (relative to carboxyl end) of double bonds.
• Carbon 2, the carbon to which the carboxyl group is attached, is also called the α-carbon.
• Carbon 3 is the β-carbon.
• Carbon 4 is the γ-carbon.
• Carbon of the methyl group (R-CH3): ω-carbon.
• Double bonds in a fatty acid can also be named using the ω-carbon as a reference.
  • Arachidonic acid: is referred to as an ω-6 fatty acid because the first double bond is six carbons from the ω end.

Fatty Acids - Chain Length

• 2-5 carbons is short (SCFA).
• 6-12 carbons is medium (MCFA).
• 13-21 carbons is long (LCFA).
• ≥ 22 carbons is very long (VLCFA).
• Longer FA (≥ 22 carbons) are mainly found in the brain.

Essential Fatty Acids

• Linoleic acid (ω-6 fatty acid) is the precursor of arachidonic acid, the substrate for eicosanoids synthesis.
• α-linolenic acid (ω-3 fatty acid) is important for growth and development, also eicosanoids synthesis.
• Essential for the metabolism and cannot be synthesized in the body (humans and most animals).
• Different species will have different requirements (quantity and ratio); i.e., most species will require 5:1 to 10:1 (ω-6:ω-3).
• Must be absorbed from the diet.
• Source of essential FA are nuts, seeds, vegetable oils, algae, fish oils.

Essential Fatty Acid Pathways

• Omega-6 oils:
  • Linoleic acid (18:2w6)
    • Sources: safflower, sunflower, sesame, canola, hemp, grape seed, corn, soybean, chia, pumpkin, walnut, wheat germ, rice bran
    • Delta 6-desaturase enzyme
      • Requires B6, magnesium, and zinc; inhibited by trans-fatty acids, saturated fats, and alcohol
    • Gamma-linolenic acid (18:3w6)
    • Elongase enzyme
      • Adds 2 more carbon units to chain
    • Dihomo-gamma-linolenic acid (20:3w6)
    • Delta 5 desaturase enzyme
      • Prefers omega-3 oils; requires vitamin C, niacin, and zinc
    • Arachidonic acid (20:4w6)
      • Cyclooxygenase
      • Lipoxygenase
      • Prostaglandins of 2 series [unfavorable] inflammatory
      • Leukotrienes
• Omega-3 oils:
  • Alpha-linolenic acid (18:3w3)
    • Sources: flax, hemp, chia, walnut, soy, canola, pumpkin, black currant
    • Stearidonic acid (18:4w3)
      • Sources: Black currant
    • Eicosatetraeonic acid (20:4w3)
    • Eicosapentaenoic acid (20:5w3)
      • Sources: cold water fish
        • Salmon, tuna, trout, sardine, mackerel, etc.
      • Cyclooxygenase
      • Lipoxygenase
      • Prostaglandins of 3 series [favorable]
      • Less inflammatory
      • Leukotrienes
    • (22:5w3)
    • Docosahexaenoic acid (22:6w3)

Partial Hydrogenation of Cooking Oils

• Vegetable oils such as corn and olive oil are composed mainly of TAG with unsaturated FA and thus are liquid at room temperature.
• TAG containing only saturated FA, such as tristearin, the major component of beef fat, are solid at room temperature.
• Cis-formation: high energy, more polar, less symmetry, less tight packing → low melting point.
• Trans-formation: low energy, less polar, more symmetry, more like saturated bond, less rigid, can be packed tighter → high melting point.
• FYI: Partial hydrogenation of the unsaturated fat converts some of the cis double bonds into trans double bonds by an isomerization reaction.
• Although edible, consumption of trans fats has been shown to increase the risk of coronary artery disease.
• Raises levels of LDL lipoprotein (‘bad cholesterol’), lowers HDL (good cholesterol), promotes systemic inflammation.

Lipids - Eicosanoids

• Eicosanoids are lipid derivatives, signaling molecules, extremely potent compounds that have a wide range of effects.
  • Physiologic (i.e., inflammatory response).
  • Pathologic (i.e., hypersensitivity).
• Produced in very small amounts in most tissues → acting locally.
• Also classified as local hormones.
• They are not stored and have extremely short half-lives.

Lipids - Eicosanoids (PGs, TXs, and LTs)

• Derived from essential fatty acids.
• Arachidonic acid is the main immediate precursor, and it is:
  • Part of membrane phospholipids.
  • Not an essential fatty acid, but can become limited (as it is derived from essential FA).
  • Some mammals (e.g.; cats) lack or have very limited ability to synthesize arachidonic acid.
• Derived from ω-3 and ω-6 polyunsaturated FA with 20 carbons (eicosa = 20).

Lipids - Eicosanoids (PGs, TXs, and LTs) - Functions

• PGs (Prostaglandin):
  • Pain and fever response.
  • Action on reproductive and gastrointestinal tract.
  • Action on bronchopulmonary tone and vascular smooth muscle tone (mostly vasodilation).
  • Regulation of hormones, calcium movement, inflammation.
• TXs (thromboxane):
  • Synthesized primarily in platelets (thrombocytes).
  • Promote platelet homeostasis (inhibition/promotion of blood clot formation).
• LTs (leukotriene):
  • Synthesized primarily in leukocytes (macrophages, neutrophils, eosinophils, and mast cells).
  • Mediators of allergic response and inflammation.
  • Synthesis is not inhibited by NSAIDS (e.g., Meloxicam, Ibuprofen).

Phospholipids - Structure

• Lipid compounds in which a polar phosphate head group and two nonpolar fatty acid tails are joined by a glycerol backbone.
• The phosphate group can link with different polar heads (molecules such as serine or choline).
• Amphipathic in nature:
  • Hydrophilic head (polar): phosphate group + polar head (serine is a polar amino acid with an alcohol function).
  • Long, hydrophobic tail containing FA or FA-derived hydrocarbons (orange).

Phospholipids - General Structure

• Glycerol + Fatty acid + Phosphate + Alcohol (polar group) + Fatty acid.

Phospholipids - Functions

• In membranes, their hydrophobic parts are connected to the nonpolar parts of other membrane molecules such as glycolipids, proteins, and cholesterol.
• The hydrophilic (polar) head points outward to the aqueous environment.
• Membrane phospholipids can also store intracellular messenger molecules or serve as ‘anchors’.
• Nonmembrane phospholipids are important components of lung surfactants and detergent-like molecules (bile).
• Phospholipids are the main lipids of cell membranes.

Phospholipids in Aqueous Environment

• Orientation of phospholipids in an aqueous environment:
  • Liposome
  • Lipid-bilayer

Phospholipids - Classes

Two different classes of phospholipids, both essential for membranes and cell signaling:

1. Glycerophospholipids contain glycerol as their backbone.
   • Constitute the majority of PL and are prevalent in membranes.
2. Sphingophospholipids contain sphingosine as their backbone.
   • Sphingosine is derived from serine and palmitate and has attached a long-chain-length unsaturated FA (LCFA) hydrocarbon tail.
   • Sphingomyelin is the main one → is an important component of the myelin sheath of nerve fibres.

Glycerophospholipids and Sphingophospholipids

Glycerophospholipids:

• Phosphatidylserine
• Phosphatidylcholine (major component of lecithin)
• Phosphatidylethanolamine (cephalin)
• Phosphatidylinositol
• Phosphatidylglycerol

Sphingophospholipid:

• Sphingomyelin

More Phospholipids - Glycerophospholipids

• Phosphatidic acid (PA) is the precursor of glycerophospholipids, esterified to different alcohols (polar head).
• Phosphatidic acid (PA) = hydrophobic tail + glycerol backbone + phosphate.
• Alcohol = polar head.
• Serine + PA → Phosphatidylserine.
• Ethanolamine + PA → Phosphatidylethanolamine (cephalin).
• Choline + PA → Phosphatidylcholine (also called lecithin, present in lung surfactant).
• Inositol + PA → Phosphatidylinositol (important to regulate intracellular signaling, lipid transportation, and vesicular trafficking).
• Glycerol + PA → Phosphatidylglycerol (also present in lung surfactant).

More Phospholipids with Physiological Relevance

• Cardiolipin: component of the inner mitochondrial membrane (relevant for maintenance of electron transport chain complexes), also important for blood clotting.
• Platelet-activating factor (PAF): activates inflammatory cells, platelets aggregation, involved in hypersensitivity, anaphylactic reactions.

Phospholipids - Synthesis

• All cells except erythrocytes can synthesize phospholipids.
• Glycerophospholipids are synthesized from cell cytosolic precursors:
  • Fatty acyl CoA (fatty acid + CoA).
  • Glycerol-3-phosphate (glycolysis intermediate).
• Synthesis occurs in sER membrane.
• Modification of lipid structure occurs in the Golgi apparatus.
• Fate: composition of membranes or secreted in vesicles.

Phospholipids - Synthesis (Steps)

1. Two fatty acids linked to coenzyme A (CoA) are joined to glycerol-3-phosphate, yielding phosphatidic acid.
2. An enzyme then converts phosphatidic acid to diacylglycerol.
3. The attachment of different polar head groups to diacylglycerol results in formation of:
   • Phosphatidylcholine.
   • Phosphatidylethanolamine, or.
   • Phosphatidylserine.

Phospholipids - Degradation

• Phospholipases → Degradation of phospholipids.
• Can be found in all tissues and pancreatic juice.
• Phospholipases are present in many toxins and venoms such as snake and bee venoms.
• Many pathogenic bacteria also produce these enzymes to dissolve cell membranes and facilitate the spread of infection.

Glycolipids and Glycosphingolipids

• Glycolipids contain both carbohydrate and lipid components → the main role is to maintain the stability of the cell membrane and to facilitate cellular recognition.
• Glycosphingolipids (a subclass of glycolipids) contain:
  • Ceramide (backbone structure)
    • In which a LCFA (fatty acid unit) is attached to sphingosine.
  • Carbohydrate (sugar unit).

Glycosphingolipids - Structure & Function

• Do not contain phosphate - unlike phospholipids (such as sphingomyelin).
• The polar head function is provided by a mono- or oligosaccharide attached directly to the ceramide by an O-glycosidic bond.
• Essential compounds of all membranes in the body:
  • High concentrations in nerve tissue (i.e., galactocerebroside).
  • Outer parts of the plasma membrane - where they interact with the extracellular environment (antigenic/recognition function).
• Important for regulation of cellular interactions, growth, and development.

ABO Blood Group Antigens are Glycosphingolipids

• If the terminal sugar on the glycan is N-Acetylgalactosamine (GalNAc) = the blood group is A.
• If the terminal sugar on the glycan is galactose (Gal) = the blood group is B.
• If neither GalNAc or Gal are present = the blood group is 0.

Lipids - Cholesterol and CE

• Cholesterol:
  • Is a very hydrophobic compound.
  • Consists of four fused hydrocarbon rings (A-D) called the ‘steroid nucleus’.
  • Can be taken in diet or synthesized in the body “cholesterol de novo synthesis”.
  • Structural component of all cell membranes (modulating fluidity).
• Cholesteryl esters (CE):
  • Most plasma cholesterol is in an esterified form (with FA attached at carbon 3).
  • Makes them even more hydrophobic.
  • For transport must be associated in a lipoprotein.
  • CE are not found in membranes; they are present only in low levels in association with lipoproteins.

Lipids - Cholesterol

• Cholesterol is a sterol → a type of lipid.
• Performs many essential functions:
  • Structural component of cell membranes and lipoproteins.
  • Precursor of bile acid, steroid hormone, and vitamin D.
• An appropriate supply of cholesterol is essential for the cells of the body.
• It is biosynthesized by all animal cells and is an essential structural component of animal cell membranes.

Lipids - Cholesterol Homeostasis

• The liver is central in the control of the body’s cholesterol homeostasis.
• Cholesterol enters the liver from many sources:
  • Dietary.
  • Cholesterol de novo synthesis (by the liver and by extrahepatic tissues).
• Disturbances in this delicate balance can lead to deposition of cholesterol in tissues and dangerous plaque formations.

Lipids - Steroid Hormones

• Cholesterol is the precursor for all classes of steroid hormones:
  • Glucocorticoids (e.g., cortisol).
  • Mineralocorticoids (e.g., aldosterone).
  • Sex hormones (e.g., estrogens, progestins, and androgens).
• Steroid hormones are transported in the blood from sites of synthesis to target organs.
• Because of hydrophobicity, must be attached to plasma proteins, such as albumin.

Lipids - Plasma Lipoproteins

• Are spherical macromolecular complexes of lipids and proteins (apolipoproteins).
• Include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
• They differ in lipid and protein composition, size, density, site of origin, and function.
• They function to keep their component lipids soluble for transport in plasma and provide an effective transport mechanism of lipids to and from tissues.
• During pathological conditions, humans and other animal species can experience a gradual deposition of lipids (specially cholesterol) in tissues and blood vessels.

Lipoproteins - Overview

• Abnormalities in lipoprotein metabolism generally occur at the site of their production or at the site of their utilization/degradation.