Lipids of Physiological Significance By Dr. Reem Sallam

Objectives To know what is the definition of lipids To understand the major functions of lipids To know the basic structure of FA To understand the difference between saturated and unsaturated FA To be familiar with some examples of FA of physiologic importance To know the essential FAs Reem Sallam, MD, PhD

Objectives, continued… To understand the nature, types, and use of KBs To understand the mechanism of diabetic ketoacidosis (DKA) To know the different categories of complex lipids (phospholipids, glycolipids) To be introduced briefly to some of the medical application of lipids of physiological significance To know the difference between different lipoprotein particles. Reem Sallam, MD, PhD

What are lipids? What are their main functions?

They can be extracted from tissues by nonpolar solvents. Lipids are heterogeneous group of H2O-insoluble (hydrophobic) organic molecules. They can be extracted from tissues by nonpolar solvents. In the body, they are generally compartmentalized, or transported in plasma in association with protein (albumin), or as lipoproteins. Reem Sallam, MD, PhD

Reem Sallam, MD, PhD

Functions of lipids: Main source of energy Provide hydrophobic barrier (partitioning) Special functions: Regulatory or coenzyme function (fat-soluble vitamins) Control of body homeostasis ( PGs & steroid hormones) Reem Sallam, MD, PhD

Fatty Acids

Structure of FAs pKa 4.8 Predominant in LCFAs Reem Sallam, MD, PhD

FA Free (unesterified) fatty acids (FFA, low levels in tissues) Esterified (fatty acyl esters) in: TAG CE PL In Plasma FA are either: Esterified >90% of FA in plasma Contained in LP particles FFA Carried by albumin Their levels can be v high (e.g in fasting) Are on their way from their origin (TAG of AT or circulating LP) to their target (tissues) to perform various functions Reem Sallam, MD, PhD

Functions of FA When oxidized (by many tissues, especially liver & muscle)  energy Structural components of membrane lipids (e.g PL & GL) When attached to certain intracellular protein  the ability of proteins to associate w/ membranes Precursors of hormone-like PG (Arachidonic acid) Storage form of fuel (TAG in AT) Reem Sallam, MD, PhD

Saturated vs Unsaturated FA Saturated = No DB Unsaturated = DB DB nearly always cis DB are spaced @ 3-C intervals DB:  ↓Tm  ↑ fluid nature FA chain length  ↑Tm  ↓ fluid nature The presence of DB in the LCFA in membrane  maintain the fluid nature of membrane lipids kink (bend) Reem Sallam, MD, PhD

Examples of physiologically important FA 20 carbons 4 DB Reem Sallam, MD, PhD

Essential FA Dietary essential in human Linoleic acid -Linolenic acid If deficient in diet (rare condition)  scaly dermatitis, visual & neurologic abnormalities) Linoleic acid 18:2(9,12) -6 FA The precursor of arachidonic acid (the substrate of PG synthesis) -Linolenic acid 18:3(9,12,15) -3 FA The precursor of other -3 FA important for growth & development Reem Sallam, MD, PhD

Arachidonic acid as an -6 FA Is only essential if linoleic acid is deficient in the diet. Reem Sallam, MD, PhD

Prostaglandins

Oxidation & Cyclization of arachidonic acid by PG endoperoxide synthase

TriAcylGlycerol (TAG)

Acylglycerol Fat Oil solid @ RT liquid @ RT kink (bend) TAG = Neutral Fat Saturated or Unsaturated Typically saturated Typically unsaturated Reem Sallam, MD, PhD

Storage of TAG The 1ary site of TAG synthesis is the liver TAG are only slightly soluble in H2O TAG coalesce within adipocytes  cytosolic oily droplets (nearly anhydrous; the major energy reserve of the body) Reem Sallam, MD, PhD

Ketone Bodies

What are KBs? * mitochondrial

KB: An alternate fuel for cells Organic acids Soluble in aqueous solution; no special carrier is needed (LP nor albumin) Either functional (metabolized: Acetoacetate,  (or 3)-OH butyrate) or non metabolized side product : Acetone: volatile  can be released in the breath. Transported in blood to the peripheral tissues. In peripheral tissues (extra-hepatic: sk. M., ♥ m., renal cortex, brain) they are converted to Ac. CoA Ac. CoA can be oxidized (TCA)  Energy Produced by liver (when the [Ac. CoA] > liver capacity to oxidize Ac. CoA Their use is  [KB] in blood If blood [KB] ↑ enough, they pass BBB  used by the brain for energy production (KB spare Glc) Reem Sallam, MD, PhD

Steroids

Cholesterol & Cholesterol ester Reem Sallam, MD, PhD

Complex Lipid

Phospholipids

What are phospholipids? Polar, ionic, amphipathic Composed of an alcohol, DAG or sphingosine

What are the functions of PL? Phospholipids What are the functions of PL? The predominant lipids in cell membranes Reservoir for intracellular messengers Anchors of some proteins to cell membranes Component of lung surfactant Components of bile (detergent property  solubilization of cholesterol)

Phopholipids A- Glycerophospholipids PA + Ser = PS PA + EA = PE: cephalin PA + C = PC: lecithin PA + I = PI PA + Glycerol = PG Plasmalogens & PAF 2 PA + Glycerol = Cardiolipin (diphosphotidylglycerol)

Phopholipids B- Sphingophospholipids: sphingomyelin Sphingosine (an amino alcohol) + LCFA = Ceramide Ceramide + Phosphoryl Choline = Sphingomyelin Sphingomyelin is an important constituent of the myelin of nerve fibers in CNS

Role of PC in lung surfactant Dipalmitoyl-phosphatidylcholine (DPPC), made & secreted b type II pneumocytes is the major lipid component of lung surfactant. Lung surfactant is the extracellular fluid layer lining the alveoli Surfactant is a complex mixture of lipids (90%), & proteins (10%), DPPC is the major component to ↓ the surface tension (ST) of this fluid layer  preventing alveolar collapse (atelectasis) ~ 32 weeks of gestation there is a major shift from Sphingomyelin (S) to Lecithin (L; DPPC) synthesis in the pneumocytes of the fetus. L/S in amniotic fluid  2 is evidence of maturity.

Infantile Respiratory distress syndrome (RDS) RDS in preterm infants is associated with insufficient surfactant production &/or secretion RDS is a major cause of all neonatal deaths in Western countries. Can we accelerate lung maturation? Yes. giving the mother glucocorticoids shortly before delivery natural or synthetic surfactant (by intratracheal instillation; preventive & therapeutic in infant with RDS)

Adult Respiratory distress syndrome In adult whose surfactant-producing pneumocytes have been damaged or destroyed (e.g. by infection or trauma)

Role of phosphatidylinositol (PI) in signal transmission across membranes

PIP2

Glycolipids

Types of Glycosphingolipids: Neutral glycosphingolipids: cerebrosides (mainly present in the brain & peripheral nervous tissue Acidic glycosphingolipids: Gangliosides (contains NANA; sialic acid) Medical importance: several lipid storage disorders involve the accumulation of NANA-containing glycosphingolipids in cells (e.g.Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease) Sulfatides: sulfoglycosphingolipids: cerebrosides containing S-Gal, found predominantly in nerve tissue & kidney

Neutral glycosphingolipid (glalactocerbroside)

Acidic Glycosphingolipids Galactocerebroside 3-S

Acidic Glycosphingolipids Ganglioside GM2

Serum Lipoproteins; size & density Bad Cholesterol Good Cholesterol