Lipids 1 2024-1 PDF

Cellular Biology & Homeostasis LIPIDS – PART 1 VP 2024 Clara Camargo, DVM LEARNING OBJECTIVES 1. Understand the structure, composition and physiological relevance of lipids 2. Fatty acids: a) Describe the structure and composition b) Understand nomenclature c) Understand physiological relevance d) N...

Cellular Biology & Homeostasis LIPIDS – PART 1 VP 2024 Clara Camargo, DVM LEARNING OBJECTIVES 1. Understand the structure, composition and physiological relevance of lipids 2. Fatty acids: a) Describe the structure and composition b) Understand nomenclature c) Understand physiological relevance d) Name the essential fatty acids 3. Describe the structure and function of phospholipids 4. Describe the synthesis and degradation of phospholipids 5. Understand what are glycolipids, the structure and physiological relevance (glycosphingolipids) 6. Understand the structure and physiological relevance of eicosanoids 7. Briefly describe the structure and physiological relevance of cholesterol, lipoproteins and steroid hormones LIPIDS - 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): o Membrane associated lipids o Droplets of triacylglycerol in adipocytes o Transported in blood plasma associated with transport proteins (lipoproteins, albumin) LIPIDS Diverse 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 VERSUS LIPIDS  Hydrophilic/Lipophobic water loving = polar molecule Versus:  Hydrophobic /Lipophilic From: Silbernagl & Despopoulos. Color Atlas of Physiology Phospholipids! (water fearing) = nonpolar molecule Some lipids are Amphipathic (having both hydrophilic and hydrophobic parts) COMMOM 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) GLYCEROPHOSPHOLIPID SPHINGOGLYCOLIPID From: Harvey and Ferrier. Biochemistry Phospholipids (PL) Glycolipids Lipoproteins (LP) Sphingolipids/Sphingoglycolipids Steroids (i.e., cortisol, sexual hormones, aldosterone) Eicosanoids (prostaglandins, thromboxanes, leukotrienes) Ketone bodies Fat-soluble vitamins (A,D,E,K) simple FATTY ACIDS - Relevance Fatty acids are the building blocks of lipids  exist free in the body (small amount), and  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 STRUCTURAL ASPECTS  One or more double bonds  unsaturated (mono or poly) Cis double bonds cause the FA to bend or kink in that position  No double bonds  Saturated o 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 (Tm) of a FA From: Harvey and Ferrier. Biochemistry 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 reference Arachidonic acid: is referred to as an ω-6 fatty acid because the first double bond is six carbons from the ω end From: Harvey and Ferrier. Biochemistry ω end Arachidonic acid FATTY ACIDS - Nomenclature 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 From: Harvey and Ferrier. Biochemistry ESSENTIAL FATTY ACIDS 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 Linoleic acid (ω-6 fatty acid)  is the precursor of arachidonic acid, the substrate for eicosanoids synthesis α-linolenic acid (ω-3 fatty acid)  important for growth and development, also eicosanoids synthesis 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  In membranes, their hydrophobic parts are connected to the nonpolar parts of other membrane molecules such as glycolipids, proteins, and cholesterol Phospholipids are the main lipids of cell membranes  The hydrophilic (polar) head point 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 in aqueous environment Orientation of phospholipids in an aqueous environment Water Lipidbilayer Water Water Phospholipid Liposome Water PHOSPHOLIPIDS - Classes Two different classes of phospholipids, both essential for membranes and cell signaling: 1. Glycerophospholipids contain glycerol as their backbone Constitute 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 Fatty acid Fatty acid G L Y C E R O L Sphingosine Fatty acid Phosphatidylserine Glycerophospholipids: Phosphatidylcholine (major component of lecithin) Phosphatidylethanolamine (cephalin) Phosphate Alcohol Phosphatidylinositol Phosphatidylglycerol Phosphate Choline Sphingophospholipid: Sphingomyelin PHOSPHOLIPIDS GLYCEROPHOSPHOLIPIDS: PHOSPHATIDIC ACID + ALCOHOL GROUP Phosphatidic acid (PA) is the precursor of glycerophospholipids, esterified to different alcohols (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 intracelluar signaling, lipid transportation and vesicular trafficking) Glycerol + PA  Phosphatidylglycerol (also present in lung surfactant) From: Harvey and Ferrier. Biochemistry 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 From: Harvey and Ferrier. Biochemistry PHOSPHOLIPIDS - Synthesis Essentially all cells except erythrocytes can synthesize phospholipids Glycerophospholipids are synthesized from cell cytosolic precursors (fatty acyl CoA and glycerol-3-phosphate) sER Synthesis of phospholipids occurs in sER membrane  modification in the Golgi apparatus  then will compose membranes of organelles or will be secreted in vesicles From: Harvey and Ferrier. Biochemistry PHOSPHOLIPIDS - Synthesis 1. Two fatty acids linked to coenzyme A (CoA) are joined to glycerol-3-phosphate, yielding phosphatidic acid 2. A phosphatase then converts phosphatidic acid to diacylglycerol 3. The attachment of different polar head groups to diacylglycerol results in formation of phosphatidylcholine, phosphatidylethanolamine, or phosphatidylserine From: The Cell: A Molecular Approach. 2nd edition 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 Bacterial Sphingomyelinases and Phospholipases as Virulence Factors. FYI https://www.ncbi.nlm.nih.gov/pmc/artic les/PMC4981679/ From: Harvey and Ferrier. Biochemistry GLYCOLIPIDS AND GLYCOSPHINGOLIPIDS Glycolipids contain both carbohydrate and lipid components → main role is to maintain the stability of the cell membrane and to facilitate cellular recognition  Glycosphingolipids (a subclass of glycolipids) contain:  Carbohydrate (sugar unit) and  Ceramide derivative in which a LCFA (fatty acid unit) is attached to the amino alcohol sphingosine GLYCOLIPIDS AND GLYCOSPHINGOLIPIDS From: Harvey and Ferrier. Biochemistry Glycosphingolipids Unlike PL (i.e., sphingomyelin) they do not contain phosphate. 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 Found in high concentrations in nerve tissue Structure of a neural glycosphingolipid → galactocerebroside Can be located in outer parts of the plasma membrane, where they interact with extracellular environment (antigenic/recognition function)  Important for regulation of cellular interactions, growth and development A B O BLOOD GROUP ANTIGENS ARE GLYCOSPHINGOLIPIDS Sphingosine Ceramide Fatty acid 0 - antigen Gluc Gal If neither GalNAc or Gal are present = the blood group is 0 GalNAc Gal Fuc Sphingosine Karl Landsteiner Nobel Price 1930 Picture: Wikipedia Fatty acid A - antigen Gluc Gal GalNAc Gal GalNAc If the terminal sugar on the glycan is NAcetylgalactoseamine (GalNAc) = the blood group is A Fuc Sphingosine Fatty acid B - antigen Gluc Gal GalNAc Gal Fuc Gal If the terminal sugar on the glycan is galactose (Gal) = the blood group is B LIPIDS – Eicosanoids Lipid derivatives, signaling molecules, extremely potent compounds that have a wide range of effects physiologic (inflammatory response) and pathologic (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 Arachidonic acid LIPIDS - Eicosanoids PROSTAGLANDINS (PG), THROMBOXANES (TX) AND LEUKOTRIENES (LT) Derived from ω-3 and ω-6 polyunsaturated FA with 20 carbons (eicosa = 20) Arachidonic acid is the main immediate precursor  It is part of membrane phospholipids  It is 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 LIPIDS - Eicosanoids PGs (Prostaglandin) Pain and fever response FYI 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 From: Harvey and Ferrier. Biochemistry 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) Structure of cholesterol and its ester From: Harvey and Ferrier. Biochemistry 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 The liver is central in the control of the body’s cholesterol homeostasis  Cholesterol enters liver from many sources  dietary  cholesterol de novo synthesis (by the liver and by extrahepatic tissues)  Essential component of bile (bile salts)  Disturbances in this delicate balance can lead to deposition of cholesterol in tissues and dangerous plaque formations From: Harvey and Ferrier. Biochemistry LIPIDS - Steroids hormones Cholesterol is the precursor for all classes of steroid hormones:  Glucocorticoids (e.g. cortisol) FYI D D D  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 From: Harvey and Ferrier. Biochemistry LIPIDS Plasma Lipoproteins https://www.youtube.com/watch?v=9dghtf7Z7fw Are spherical macromolecular complexes of lipids and proteins (apolipoproteins) Include chylomicrons, very-low-density lipoproteins (VLDL), low-densitylipoproteins (LDL) and high-density lipoproteins (HDL) They differ in lipid and protein composition, size, density, and site of origin They function to keep their component lipids soluble for transport in plasma and provide effective transport mechanism of lipids to and from tissues Humans and other animal species can experience gradual deposition of lipids (specially cholesterol) in tissues and blood vessels From: Harvey and Ferrier. Biochemistry Lipoproteins Overview From: Harvey and Ferrier. Biochemistry Abnormalities in lipoprotein metabolism generally occur at the site of their production or at the site of their utilization