Phospholipids and Lipid Mediators

phospholipids, glycolipids, cholesterol

3 major classes of membrane lipids

glycerophospholipids

ether glycerolipids

sphingomyelin

3 main types of phospholipids

glycerol-3-phosphate

Synthesis of complex lipids from fatty acids begins with —

In most tissues G-3-P is derived from glycolysis through reduction of DHAP by G3PDH

In the liver it can also be derived from glycerol phosphorylation by glycerol kinase

How G3P is derived in most tissues (and an additional way in the liver

cytosolic surface of the smooth ER

activated

All membrane lipid syntheses occurs on the — and involves some form of an — compound

Phosphatidate (phosphatidic acid)

The key intermediate in complex lipid synthesis

mitochondrial inner membrane

Cardiolipin is found almost exclusively in the —.

Treponema pallidum (bacterium that causes syphilis)

Cardiolipin is the antigen recognized by antibodies against —

more flexible than regular phospholipids allowing interactions with respiratory chain complexes and mitochondrial substrate carriers

high unsaturated fatty acid content makes it prone to reactive oxygen species–induced damage

Following mild mitochondrial damage, cardiolipin redistributes to the outer mitochondrial membrane and serves as a recognition signal for sequestration by autophagosomes

Cardiolipin:

flexibility

saturation effect

mitochondrial damage

S-adenosyl methionine

phosphatidylethanolamine —> phosphatidylcholine

cytidine diphosphate

phosphatidylethanolamine & phosphatidylcholine are activated by conjugating to —

pulmonary surfactant

Dipalmitoyl lecithin (Dipalmitoyl phosphatidylcholine, DPPC) is a major component of —.

surfactant

DPPC (Dipalmitoyl)

Premature babies (esp <28 wk) often do not have sufficient levels of — and suffer from respiratory distress syndrome (RDS). Administration of — alleviates symptoms.

PIP₂

Activated phospholipase C hydrolyzes — to produce 2^nd messengers, IP₃ and DAG

peroxisomes

Plasmologen synthesis begins in —

ether

lipases

Plasmologens contain an — linkage resistant to —

myelin

Ethanolamine plasmalogens are found in —

cardiac

Choline plasmalogens are found in — tissue

antioxidants, signaling molecules

Plasmalogens can act as — and —

ether, acetyl

Platelet activating factor is an — analogue of phosphatidylcholine and has — group at sn-2 which increases solubility in blood

very low (10^-12)

GPCR

Platelet activating factors functions at — concentrations and acts as a ligand for a —

Allergic and inflammatory responses, targeting WBC (mediator of anaphylactic shock)

Induces platelet aggregation,

Smooth muscle contraction, decreases cardiac output

Contributes to atheromas, coronary artery disease

Functions of platelet activating factor

sphingosine (instead of glycerol)

Backbone of sphingolipids

palmitoyl-CoA and serine

Sphingosine is derived from — and —

Ceramide

— is created by addition of very long chain FA to N of serine

Sphingomyelin

— is created in an exchange reaction with phosphatidylcholine (PC) that donates phospho-choline

outer leaflet of the plasma membrane

Sphingolipids are almost exclusively located in the —

sugar

In glycolipids, at least 1 — is present

cerebroside

glucose or galactose

The simplest glycolipid and the single sugar residue it contains

sulfatide

Sulfation of cerebroside creates

globosides

Glycolipids with 2-4 sugars called:

vascular and immune

Sphingosine-1-phosphate is a major regulator of these 2 systems

intra: 2nd messenger or is exported from cells

extra: ligand for GPCRs

How sphingosine-1-phosphate acts intra- and extracellularly

embryonic

Sphingosine kinase is essential for the — development of the brain and the vascular system

sphingosine kinase

sphingosine —> sphingosine-1-phosphate

scramblase, phagocytes

In apoptotic cells, low ATP reduces ATPase activity and increased — activity resulting in phosphatidylserine presence on outer surface where it serves as an “eat me” signal recognized by receptors on —.

inner: Phosphatidylethanolamine, Phosphatidylserine, Phosphatidylinositol

(PE, PS, PI)

outer: Phosphatidylcholine (PC), sphingolipids

Typical makeup of lipids in inner and outer leaflet of plasma membrane

fever, vasoconstriction (blood pressure), airway constriction (asthma), arthritis and platelet function

Eicosanoids have roles in:

20

near

short (they are chemically unstable)

eicosanoids usually have — carbons and act — site of synthesis. Their lifespan is —

GPCR

Eicosanoid type of receptor

phospholipase A₂

Physical injury in addition to hormonal or neuronal stimulus can result in the release of unsaturated fatty acid from sn2 of phospholipids by —

removes phospho-head group

generates diaceylglycerol (+IP₃)

Phospholipase C removes —, generating —

alcohol side chain (choline)

phosphatidic acid

Phospholipase D removes —, generating

Inhibiting phospholipase A₂

How corticosteroids reduce inflammation

Removes acyl chain from C2

Phospholipase A₂ function

prostaglandins

leukotrienes

epoxides

3 major group of eicosanoids generated from free poly-unsaturated FAs

arachidonate + O₂ —> prostaglandin G₂ —> prostaglandin H₂ —> eicosanoids (this step is tissue specific)

Arachidonate —> eicosanoids overview (COX pathway)

cyclooxygenase (COX)

arachidonate + O₂ —> prostaglandin G₂

peroxidase

prostaglandin G₂ —> prostaglandin H₂ (+H₂O)

platelet aggregation, gastric mucus secretion, renal homeostasis

COX-1 produces low prostaglandin levels for physiological responses such as —

inducible

constitutive

COX-2 is an — isoform but is — in nervous system

inflammation/pain, expressed in macrophages, monocytes, kidney.

Induced by a variety of inflammatory stimuli, cytokines and mitogens.

COX-2 is involved in —

Irreversibly inhibits COX enzymes

How aspirin works

steroids inhibit phospholipase A₂

NSAIDs inhibit COX-1 and COX-2 (specificity varies)

Steroids vs NSAIDs

avoids clotting and ulcer side effects of a dual inhibitor

long term use for chronic inflammation increases MI and stroke risk

Benefit of a COX-2 specific inhibitor and long term effects

very short, seconds to minutes

Half life of eicosanoids

oxidation of C15 hydroxyl group

Prostaglandins are inactivated by —

prostaglandins (+ prostacyclin and thromboxanes)

leukotrienes and lipoxins

epoxides

3 major groups of eicosanoids

Shifts arachidonic acid to production of leukotrienes, which are potent mediators of bronchoconstriction, airway inflammation, and increased mucus secretion.

Also, inhibition of prostaglandin PGE2, which normally has protective effects in the airways like bronchodilation and anti-inflammatory action.

Why are asthma patients sensitive to NSAIDs

Suppression of Thromboxane A2, a potent promoter or platelet aggregation and vasoconstriction

Triggering the synthesis of lipoxins which are anti-inflammatory and pro-resolving.

Cardiovascular benefit of low dose aspirin

leukotrienes

5-lipoxygenase pathway makes —

epoxide

cysteinyl leukotriene

Leukotriene synthesis: 5-lipooxygenase generates a peroxide that is converted to an — (4 DBs is most potent), then to a — via addition of glutathione

SPMs—specializied pro-resolving lipid mediators

Potent molecules for preventing and/or resolution of acute inflammation typically formed in resolution phase to prevent chronic inflammation

Role of Lipoxin A₄ and B₄

diet

Because eicosanoids are derived from essential FAs, — impact inflammatory response.

Omega-3 and omega-6 FAs compete for COX enzymes.

Omega-6 produces more inflammatory eicosanoid compounds

Omega-3 produces less inflammatory (less potent) eicosanoid compounds and SPMs

Omega-3 vs omega-6 effect on inflammation

resolvins, protectins, maresins

Types of SPMs