Introduction to Lipids

Introduction to Lipids

• Lipids include chemically diverse compounds.
• Lipids are defined by their insolubility in water.
• Lipids' biological functions are as diverse as their chemistry.
• Fats and oils are the main way organisms store energy.
• The structural elements of biological membranes include phospholipids and sterols.
• Lipids play key roles as enzyme cofactors, electron carriers, light-absorbing pigments, hydrophobic anchors for proteins, “chaperones”, emulsifying agents, hormones, and intracellular messengers.

Lipid Solubility

• Lipids are marginally soluble (at best) in water.
• Lipids are readily soluble in organic solvents like chloroform, and acetone.
• Fats and oils exemplify lipid solubility, but solubility doesn't fully define lipids' chemical nature.
• Lipids share structural similarities, mainly with a preponderance of nonpolar groups.

Lipid Classification

• Lipids are classified into two main groups based on their chemical nature.
• One group consists of open-chain compounds with polar head groups and long nonpolar tails, including: fatty acids, triacylglycerols, sphingolipids, phosphoacylglycerols, and glycolipids.
• The second group comprises fused ring compounds known as steroids.
• An important steroid representative is cholesterol.

Fatty Acid Structure

• A fatty acid has a long hydrocarbon chain ("tail") and a terminal carboxyl group ("head").
• Under physiological conditions, the carboxyl group is normally ionized.
• Fatty acids are abundant in biological systems.
• Fatty acids are rarely free; they're typically esterified to glycerol or other backbone structures.
• Most natural fatty acids contain an even number of carbon atoms, usually 14 to 24.
• Marine organisms contain fatty acids with an odd number of carbon atoms.

Saturated and Unsaturated Fatty Acids

• Fatty acids are either saturated or unsaturated.
• Saturated fatty acids have all single carbon-carbon bonds.
• Unsaturated fatty acids have one or more double bonds in the hydrocarbon chain.
• Fatty acids with a single double bond are monounsaturated.
• Fatty acids with more than one double bond are polyunsaturated.

Naming Fatty Acids

• Fatty acids are named three ways: systematic name, common name, and shorthand notation.
• For example, an 18-carbon chain fatty acid with no double bonds is octadecanoic acid (systematic), stearic acid (common), or 18:0 (shorthand).

Natural Abundance and Configuration of Fatty Acids

• Unsaturated fatty acids are more abundant than saturated ones, especially in higher plants.
• The most common unsaturated fatty acid is oleic acid (18:1Δ9), with a double bond between carbons 9 and 10.
• The number of double bonds ranges from one to four.
• Bacteria rarely have more than one double bond in fatty acids.
• Double bonds in fatty acids are usually in the cis configuration.

Fatty Acid Packing and Structure

• Saturated fatty acid chains form ordered, rigid arrays under certain conditions.
• Unsaturated fatty acids prevent close packing and produce flexible, fluid aggregates.

Essential Fatty Acids

• Mammals cannot synthesize some fatty acids.
• Essential fatty acids include linoleic and α-linolenic acids.
• They must be obtained from plant sources in the diet.
• Arachidonic acid can be synthesized from linoleic acid in mammals, but is not found in plants.
• Essential fatty acids serve as precursors for eicosanoid synthesis, such as prostaglandins.
• Eicosanoids are compounds that exert diverse hormone-like effects.

Fatty Acids and Health

• Cardiovascular disease is correlated with diets high in saturated fatty acids.
• Diets higher in unsaturated fatty acids, especially polyunsaturated ones, may reduce the risk of heart attacks and strokes.
• Vegetable oils usually contain more unsaturated fatty acids than animal oils and fats.
• Palm oil is low in polyunsaturated fatty acids but high in saturated palmitic acid.
• Coconut oil is high in both saturated lauric and myristic acids and contains little unsaturated fatty acid.

Cis vs. Trans Fatty Acids

• Most unsaturated fatty acids in nature are cis fatty acids.
• Trans fatty acids are formed by bacteria via double-bond migration and isomerization, or by partial hydrogenation.
• Bacterial reactions produce trans fats in ruminant animals.
• Butter, milk, cheese, and ruminant meat contain modest quantities of trans fats (2% to 8% by weight).
• Margarine and processed fats from partially hydrogenated oils have substantial levels of trans fats.
• Chronic consumption of processed foods containing partially hydrogenated vegetable oils can contribute to cardiovascular disease.
• Trans fatty acids elevate plasma LDL cholesterol and triglycerides while lowering HDL cholesterol.

Triacylglycerols (Triglycerides)

• A significant number of fatty acids in plants and animals exist as triacylglycerols.
• Triacylglycerols are a major energy reserve.
• They are the principal neutral derivatives of glycerol.
• Triacylglycerols consist of glycerol esterified with three fatty acids. If all three fatty acid groups are the same, it's a simple triacylglycerol.
• Examples of simple triacylglycerols are tristearoylglycerol (tristearin) and trioleoylglycerol (triolein).
• Mixed triacylglycerols contain two or three different fatty acids.
• Animal triacylglycerols are found primarily in adipose tissue (body fat), a storage site for lipids.

Mono- and Diacylglycerols

• Monoacylglycerols and diacylglycerols exist, but are far less common than triacylglycerols.
• Most natural plant and animal fat has mixtures of simple and mixed triacylglycerols.

Acylglycerol Hydrolysis and Saponification

• Acylglycerols can be hydrolyzed by heating with acid or base, or by treatment with lipases.
• Hydrolysis with alkali is called saponification which yields salts of free fatty acids and glycerol. This is how soap is made.
• Early soap production: potassium hydroxide (potash) from wood ashes was used to hydrolyze animal fat.
• Soaps precipitate in hard water with Mg2+ and Ca2+ ions, which makes them less useful than modern detergents.

Phosphoglycerides (Glycerophospholipids)

• A 1,2-diacylglycerol with a phosphate group esterified at carbon atom 3 of the glycerol backbone is a glycerophospholipid.
• Glycerophospholipids are also known as a phosphoglyceride or a glycerol phosphatide.
• These lipids are a large, important class of natural lipids found throughout the cell.
• Phosphoglycerides are essential components of cell membranes.

Phosphatidic Acid

• Phosphatidic acid is the parent compound for glycerol-based phospholipids.
• It consists of sn-glycerol-3-phosphate with fatty acids esterified at the 1- and 2-positions.
• Phosphatidic acid is found in small amounts in most natural systems.
• Phosphatidic acid is an important intermediate in the biosynthesis of common glycerophospholipids.

Phosphatide Head Groups

• In phosphoglycerides, polar groups are esterified to the phosphoric acid moiety.
• The phosphate and the esterified polar group make up the "head" group.
• Phosphatides with choline or ethanolamine are phosphatidylcholine (lecithin) or phosphatidylethanolamine.
• Phosphatidylcholine and phosphatidylethanolamine are common biological membrane components.
• Other common head groups include glycerol, serine, and inositol.

Diphosphatidylglycerol (Cardiolipin)

• Diphosphatidylglycerol is another glycerol phosphatide found in many tissues.
• It was first observed in heart tissue.
• A phosphatidylglycerol is esterified through the C-1 hydroxyl group of the glycerol moiety to the phosphoryl group of another phosphatidic acid molecule.
• Phosphatides vary depending on the fatty acids esterified to the glycerol group.

Sphingolipids

• Sphingolipids make up another class of lipids found in biological membranes.
• Sphingosine, an 18-carbon amino alcohol, forms the backbone of these lipids, rather than glycerol.
• A fatty acid joins to sphingosine via an amide linkage, forming a ceramide.
• Sphingomyelins are phosphorus-containing sphingolipids, especially important in nervous tissue in higher animals.
• Sphingomyelin is formed by phosphorylcholine or phosphorylethanolamine esterification to the 1-hydroxy group of a ceramide.

Glycosphingolipids

• Glycosphingolipids like sphingomyelins are important components of muscle and nerve membranes.
• They consist of a ceramide with one or more sugar residues in a β-glycosidic linkage at the 1-hydroxyl moiety.
• Neutral glycosphingolipids contain only neutral, uncharged sugar residues.

Cerebrosides, Sulfatides, and Gangliosides

• When a single glucose or galactose binds to a ceramide, the molecule is a cerebroside.
• A sulfatide forms when a sulfate is esterified at the 3-position of galactose.
• Gangliosides consist of a ceramide backbone with three or more sugars esterified, including sialic acid (like N-acetylneuraminic acid).
• These are acidic glycosphingolipids with a net negative charge at neutral pH.

Glycosphingolipid Function and Diseases

• Glycosphingolipids have important cellular functions, despite being present in small amounts in membranes.
• Glycosphingolipids at cell surfaces determine elements of tissue and organ specificity.
• Cell-cell recognition and tissue immunity depend on specific glycosphingolipids.
• Gangliosides are present in nerve endings, and involved in nerve impulse transmission.
• Genetic diseases cause an accumulation of specific glycosphingolipids due to enzyme deficiencies.
• In Tay-Sachs disease, ganglioside GM2 accumulates in the brain, causing blindness, and self-mutilation.

Waxes

• Waxes are esters of long-chain alcohols with long-chain fatty acids.
• Waxes have a weakly polar head group (the ester moiety) and a long nonpolar tail (hydrocarbon chains).
• Waxes typically contain saturated fatty acids.
• Alcohols in waxes can be saturated or unsaturated, and may include sterols (e.g., cholesterol).
• Waxes are water-insoluble due to their hydrocarbon composition.
• Waxes confer water-repellant character to animal skin, plant leaves, and bird feathers
• A polished apple's glossy surface results from a wax coating.
• Examples include:
• Carnauba wax: Palm tree in Brazil, used for high-gloss finishes.
• Lanolin: Wool wax used in cosmetics; Oil of Olay uses it.

Lipid Bilayers in Biological Membranes

• Biological membranes have phosphoglycerides and glycolipids.
• Steroids are present in eukaryotes; cholesterol is used in animal membranes; phytosterols are used in plants.
• In the lipid bilayer, polar head groups are in contact with water, and nonpolar tails are in the interior.
• The bilayer arrangement is held together by noncovalent interactions such as van der Waals forces and hydrophobic interactions.
• The bilayer surface is polar and contains charged groups.
• The nonpolar interior of a bilayer has saturated and unsaturated fatty acid chains and the fused-ring system of cholesterol.

Asymmetry and Fluidity of Lipid Bilayers

• Lipid bilayer inner and outer layers contain lipid mixtures, but their compositions differ.
• Larger molecules tend to appear in the outer layer.
• Smaller molecules tend to occur in the innter layer.
• The distribution of lipid types (phosphatidylcholine, phosphatidylethanolamine, cholesterol) varies widely among membranes in cells (e.g., rat liver).
• Hydrocarbon bilayer interior arrangement can be ordered/rigid or disordered/fluid, which depends on composition.
• Saturated fatty acids' linear hydrocarbon chains allow for close packing and rigidity.
• Unsaturated fatty acids (kinks) don't allow close packing and cause greater bilayer fluidity.
• The presence of cholesterol may enhance order & rigidity by stabilizing the extended straight-chain arrangement of saturated fatty acids.

Membrane Lipids in Plants vs. Animals

• Plant membranes have a higher percentage of polyunsaturated fatty acids compared to animal membranes.
• Cholesterol is characteristic of animal membranes, rather than plant membranes.
• Animal membranes are less fluid than plant membranes as a result.
• Prokaryotes have no steroids, so they are the most fluid.
• Plant sterols can act as natural cholesterol blockers, interfering with cholesterol uptake.

Terpenes

• Lipids formed from combinations of two or more molecules of 2-methyl-1,3-butadiene, also known as isoprene (C5).
• Monoterpene: Two isoprene units (C10)
• Sesquiterpene: Three isoprene units (C15)
• Diterpene: Four isoprene units (C20)
• Isoprene units link in straight-chain/cyclic molecules, usually head to tail.
• Monoterpenes occur in all higher plants; sesquiterpenes and diterpenes are less widely known.
• Triterpenes are C30 terpenes that include squalene and lanosterol, precursors of cholesterol and other steroids.
• Tetraterpenes (C40) are rare, but they include carotenoids, a class of colorful photosynthetic pigments.
• β-Carotene is a precursor of vitamin A.
• Lycopene is found in tomatoes, similar to β-carotene.
• Polyprenols are long-chain polyisoprenoid molecules with a terminal alcohol.
• Dolichols consist of 16-22 isoprene units that function to carry carbohydrates in the biosynthesis of glycoproteins in animals
• Polyprenyl groups serve to anchor certain proteins to biological membranes.

Steroids

• Steroids are mainly of a eukaryotic origin, and are derivatives of cyclopentanoperhydrophenanthrene.
• Cholesterol is the most abundant steroid in animals and classified as a sterol because of its C3-OH group and its branched aliphatic side chain.
• Cholesterol is a major component of animal plasma membranes (30-40 mol %).
• The polar OH group of cholesterol gives a weak amphiphilic character.
• Its fused ring system provides greater rigidity.
• Cholesterol is an important determinant of membrane properties.
• Abundant in blood plasma lipoproteins; 70% is esterified to long-chain fatty acids as cholesteryl esters.

Steroid Hormones

• Cholesterol is the metabolic precursor of steroid hormones.
• Steroid hormones regulate a variety of physiological functions including sexual development and carb metabolism.
• Plants contain little cholesterol, but have stigmasterol and β-sitosterol.
• Steroids in animals encompass androgens, estrogens, progestins, glucocorticoids, mineralocorticoids, and bile acids.

Androgens and Estrogens

• Androgens (testosterone) and estrogens (estradiol) mediate the development of sexual characteristics/function.

Progestins, Glucocorticoids, and Mineralocorticoids

• The progestins (progesterone) participate in the menstrual cycle and pregnancy control.

• Glucocorticoids (cortisol) participate in carb, protein, & lipid metabolism.

• Mineralocorticoids regulate salt (Na, K, Cl) balances.

Bile Acids

• The bile acids (cholic and deoxycholic acid) are detergent molecules secreted in bile from the gallbladder.
• Bile acids assist in dietary lipid absorption in the intestine.

Fat-Soluble Vitamins

• Some vitamins are lipid-soluble.
• These have different functions and are hydrophobic for solubility.

Vitamin A (Retinoids)

• Retinoids are a family of molecules pertaining to retinol (vitamin A) that are pivotal for vision, reproduction, growth, & epithelial tissue maintenance.
• Retinoic acid is derived from dietary retinol oxidation.
• Retinoic acid mediates retinoid actions except for vision, which depends on retinal.

Vitamin A Forms

• Vitamin A refers to biologically active molecules (retinoids); these can be natural or synthetic.
• Retinol: a primary alcohol a β-ionone ring with a long unsaturated side chain; retinyl ester in animal tissues.
• Retinal: an aldehyde derived from retinol oxidation; it interconverts with retinol.
• Retinoic acid: the acid from retinal oxidation.
  • It can't be reduced and doesn't give rise to either retinal or retinol.
• β-Carotene: plant foods/oxidatively cleaved to yield two retinal molecules.
• Vitamin A from β-carotene is only 1/12 as active in humans.

Absorption & Transport of Vitamin A

• Retinyl esters hydrolyze into retinol and fatty acids in the intestine.
• Retinol is re-esterified to long-chain fatty acids, and it becomes part of chylomicrons in the lymphatic system.
• Chylomicron remnants containing retinyl esters are stored in the liver.
• Retinol is released by the liver with plasma retinol binding protein (RBP).
• Retinol-RBP attaches to receptors on peripheral tissues, where it moves to the nucleus to act like steroid hormones.

Mechanism of Vitamin A Action

• Retinol is oxidized to retinoic acid.
• Retinoic acid binds with high affinity to specific receptor proteins present in the nucleus of target tissues, including epithelial cells.
• The activated retinoic acid–receptor complex interacts with nuclear chromatin to regulate retinoid-specific RNA synthesis.
• The specific retinoic acid–receptor proteins are part of the superfamily of transcriptional regulators (steroid and thyroid hormones & 1,25-dihydroxycholecalciferol).

Forms of Vitamin A & Their Functions

• Vitamin A's form determines its usage.
• Visual Cycle: as a visual pigment in rod & cone cells (rhodopsin).
• Growth: deficiency slows growth rate and bone development in children.
• Reproduction: supporting in spermatogenesis of male and fetal resorption prevention in female.
• Retinoic Acid in the function of the cell differs.
  • It is inactive with reproduction and in the visual cycle.
  • It does promote growth and differentiation of the epithelial cells.
• Thus, only with retinoic acid animals from birth are blind and sterile.

Vitamin A's Relation to Epithelial Cells, Distribution, & Requirements

• Epithelial Cells: Essential for normal differentiation of epithelial tissues and mucus secretion.

• Distribution: preformed Vitamin A is from Liver, kidney, cream, butter, & egg yolk, where carotenes are in yellow and dark green vegetables and fruits which will serve as precursors of the vitamin.

• Requirement of Vitamin A:

• In adults: RDA is 900 retinol activity equivalents (RAE) for males and 700 RAE for females.

• In comparison, 1 RAE = 1 mg of retinol, 12 mg of β-carotene, or 24 mg of other carotenoids.

Vitamin A - Clinical Indications

• Differing retinoids has distinct therapeutic applications.
• Retinol are supplements.
• It's precursor is used as a dietary supplement.
• Several therapeutic applications for dermatology.

Clinical Indications and Deficiencies

• Use as Vitamin A: (as retinol or retinyl esters)
• In treating: "vitamin deficient" patients.
• First sign: Night Blindness; increased visual threshold
• Leads to irreversible visual cell loss
• Severe deficiency: Xerophthalmia (conjunctiva & cornea dryness). - Untreated condition forms opaque scar tissue which results in blindness.
• Region: Most common most frequently seen tropical children (developing).
• Occurence: 500,000+ children in the tropical world.
• Suffers in being xerophthalmia caused by Vitamin A diets.

Clinical Indications with Dermatology

• Acne & Psoriasis: Can have retinoid related problems.
  • Mild cases of acne: Darier disease & keratosis all affect skin aging
  • Treatment with topical application of tretinoin.
  • Tretinoin is toxic for systemic administration so only used topically.

Vitamin A (Retinoids) Toxicity

• 1. Vitamin A: Can produce hypervitaminosis A toxic syndrome,
  • Prevent: Over 7.5 mg/day use of it
  • Shown with skin which comes dry & pruritic (due to decreased keratin synthesis)
  • Nervous system: A rise in intracranial pressure with tumor mimicking.
  • Prevent: pregnant patients ingesting excessive vitamin amounts, teratogenically.
• 2. Isotretinoin: Absolutely contraindication; severe teratogenic cystic acne in women with childbearing potential.
  • Initiation: Pregnancy must be excluded before treatment.
  • Prolonged conditions lead to hyperlipidemia/increased LDL/HDL.
  • Risk: cardiovascular

Vitamin Basics

• D: "Sterols hormone like" & active molecule dihydroxycholecalciferol binds selective intracellular protein.
  • Molecule-Receptor complex acts: select stimu & gene transciption.
    • Actions: regulates calcium phosphorus plasma levels.

Distribution

• Distribution D: Plant based = Ergocalciferol D2: Animal based = cholecalciferol D3, Chemical differnece? presence/absence methyl double bond addition
• Precursor: intermediate synthesis dermis & epidermis exposed = cholecalciferol.
  • Limited to sunlight.

Vitamin Metabolism

• Active Form Formation: diOH-D3 active two sequential hydroxylation reaction. First: cat liver-25 position liver-25 hydroxy cholecalciferol: predominant D plasma storage form. Second: 25 OH-D3: hydroxy cholecalciferol 1 hydroxylase kidney- resulting diOH-D3 calcitriol 2 "regulation": DiOH-D3 most potent metabolite Tightened level: plasma phosphate and Calcium ions (28.24), Hydroxylase activated 1 By lowered low plasma phosphate or INDIRECTLY low calcium PTH release: Low Ca: causes elevated PTH OH-D3. 1-Hydroxylase also lowered.

Vitamin Function Diets and AI

• Overall D: maintain adequte plasma calcium levels

Function by: 1: increase calcium intake intestine 2: minimize calcium kidney loss 3: stimulating bone if necessary Effect D intestine: diOh-D3 stimulation absorption and phosphate Enters cell - cytosol complex/selective dna uptake enhanced synth Actions: typical steroid bone action DiOh3, stim synth cal and phosphate bone- PTH Results: Bone important mobil plasma levels

Distribution & Needs

Vitamin D: Fatty Fish, Liver, and Yolk Artificial if fortified 200 to age 50 400-600 after indications demineral bone kids/osteo adults: soft bones osteom: frac Insufficient consumption in sunlight in kids and elderly Lower latitude and sunlight. intake is and increased

Vitamin Implications and Toxicity

• Serum levels increased as reduced strength increased muscle/bone.
• Ostero: Renal lack active D calcitriol effect.
• HypoPTH: Absence causes HYPOcalc PTH.
• Side: vitamin store and high weeks or months

Vitamin implications with blood levels

• K: Main role: translate modified cloth factors.

• Coenzymes is needed by glut residues in the proteins.

• Forms as K include: plants (phylloquin K1), gutflora (menaquin K2), Synthetic K: menadione, is available A Functions K:

• Gla glut: prothrombin in hepatic requires for all synthesized Enzyme: dependent carboxyl glut resid Mature Clot factor requires subsequent: Hydroquin sensitive inhibition to Dicumarol, anti clot natrual and warfarin (synthetic)

• prothrom platelet: Ca chelator and carboxyl and phospholipids clot At platet increased to conversions.

Vitamin Clinical and Toxicity

• Gla residues - OTHER present: osteocal bone Clots involved

Distrub required k: leafy greggs spinach yoke Gut flora make vitamin Al is daily for men (120 Mg) and women (90)

Indication K 1 Deficiency: not used Intest synth or diet Gut decreased by antibiotics/endogenous then hypoclot geratric K in Newborn due Steril needs and milk so get single K toxicity synthetic K : membrane due: use synth over k k toxcit: set for the vitamins The D Vitamins to keep in mind

A. Distribution & Requirements of Vitamin E

• E: made from tocoferols
• tocopherol action: anti cell oxidize fats acids/free

Distribution and requirements made available

• Plant Oil Rich: moderate meats liver
• -toco: is 15 mg adults vitamin E needs poly

B. And C of A

• Vitamin E deficient in infants.
• Defect transport absorb:
• The signs: -Erythro sensitive
• membranes in cell

Vitamin E Clinical Aspects

• is not recommeneded heart related issues like cardo
• Not only received high E but had stroke vitamin least is all has 300 Mg

Eicosanoids basics

• Made from Hormone and cell hormone released Variety: fertility fever blood gastric etc