1. Complex lipid metabolism

2. Complex lipids
Complex lipids on hydrolysis yield one or more fatty acids, an alcohol, and some other type of compounds
They are categorized in:
Phospholipids
Glycolipids (also called cerebrosides due to their existence in cerebrum of the brain)

3. 1. Phospholipids are: major constituents of all cell membranes
components of bile
anchor some proteins in membranes
signal mediators
components of lung surfactant
components of lipoproteins

4. Properties of phospholipids
Phospholipids are amphipathic molecules
Head group = alcohol attached via phosphodiester linkage to either:
diacylglycerol (glycerophospholipid) or
sphingosine (sphingophospholipid = sphingomyelin).

5. Cellular membranes are composed of phospholipids and sphingolipids
Glycerophospholipids and sphingolipids spontaneously self-associate in water to form bilayer vesicles (i.e., closed membranes)
Bilayers are permeability barriers that enclose cells and cell organelles

6. Types of phospholipids
The simplest glycerophospholipid is phosphatidic acid (PA)
It consists of glycerol, phosphate, and 2 fatty acyl chains in ester linkages

7. Other glycero-phospholipids derived from PA include:

8. Cardiolipin is found in mitochondrial membranes

9. Phospholipids are distributed asymmetrically in the plasma membrane
Outside
Inside

10. Plasmalogens
Plasmalogens have an ether-linked hydrocarbon chain at C-1 of glycerol, instead of ester-linked fatty acid.
For example,
1. phosphatidalethanolamine (abundant in nerve tissue)
2. Phosphatidalcholine (abundant in heart muscle) is the other quantitatively significant ether lipid in mammals.

11. Plasmalogens
Platelet-activating factor (PAF) is a plasmalogen (a phosphatidalcholine) with an acetyl group at C-2 of glycerol
It has potent physiologic actions (platelet activation; inflammatory responses; bronchoconstriction)

12. Sphingolipids
Sphingomyelin contains sphingosine with a long-chain fatty acid attached in amide linkage ( = ceramide)
Ceramide plus a phosphocholine group constitutes a sphingomyelin
Ceramide is also the core component of glycosphingolipids

13. Sphingomyelin
Sphingomyelin is present in plasma membranes and in lipoproteins
It is very abundant in myelin
Sphingomyelin is abundant in specialized plasma membrane microdomains called lipid rafts

14. Lipid rafts
Lipid rafts are specialized microdomains in the plasma membrane that are rich in sphingomyelin and cholesterol
GPI-linked proteins accumulate in lipid rafts
Lipid rafts appear to function in signaling

15. Phospholipid synthesis
Recall synthesis of PA as an intermediate of TG synthesis
It involves glycerol-P and two fatty acyl CoA molecules

16. Phospholipid biosynthesis
Glycerophospholipid synthesis involves activated intermediates:
CDP-alcohol + diacylglycerol or
CDP-diacylglycerol + alcohol
Synthesis occurs in the ER of almost all cells

17. Synthesis of PC
Choline can be made from ethanolamine by transfer of 3 methyl groups from S-adenosyl-methionine (SAM)
Choline is an essential nutrient
De novo synthesis of PC from PS involves a decarboxylation to give PE followed by three methylation steps

18. SAM is S-adenosylmethionine:
a methyl group donor for many biochemical reactions

19. Synthesis of PS & PI PS is made by a base exchange reaction:
PE + serine PS + ethanolamine
PI is synthesized from CDP-diacylglycerol and myoinositol
PI often has arachidonate in the C-2 glycerol position

20. Role of phosphatidylcholine in lung surfactant
The synthesis of dipalmitoylphosphatidylcholine (DPPC, or dipalmitoyl lecithin) is very important in lung functioning.
DPPC, made and secreted by type II pneumocytes , is a major lipid component of lung surfactant, which is the extracellular fluid layer lining the alveoli.
Surfactant serves to decrease the surface tension of this fluid layer, reducing the pressure needed to reinflate alveoli, thereby preventing alveolar collapse (atelectasis).

21. Surfactant is a complex mixture of lipids (90%) and proteins (10%), with DPPC being the major component for reducing surface tension.
Respiratory distress syndrome (RDS) in preterm infants is associated with insufficient surfactant production and/or secretion and is a significant cause of all neonatal deaths in Western countries.

22. The respiratory distress syndrome (RDS) of a premature infant
Note: Lung maturation can be accelerated by giving the mother glucocorticoids shortly before delivery. Why?
RSD which is due to an insufficient amount of surfactant can also occur whose surfactant- producing pneumocytes have been damaged (an adverse side effect of immunosuppressive medication or chemotherapeutic drug use.

23. Roles of phosphatidylinositol
PI can provide arachidonate for eicosanoid synthesis
2. Signal transduction across membranes
PI anchors some enzymes to the
plasma membrane through a glycan chain

24. 2 . Signal transduction across membranes
Ach, NE, Serotonin

25. Phosphatidylinositol 4,5-bisphosphate (PIP2) participates in hormonal signal transduction via activated phospholipase C formation of inositol-P3 and diacylglycerol, followed by mobilization of Ca+2 and activation of protein kinase C.

26. 3. PI anchors some enzymes to the plasma membrane through a glycan chain
Examples include alkaline phosphatase and acetylcholine esterase
(an enzyme of the postsynaptic membrane that degrades the neurotransmitter acetylcholine)

27. Degradation of phospholipids:
Phospholipases allow degradation & Remodeling of Phosphoglycerols
Long-chain saturated fatty acids are found predominantly in the 1 position of phospholipids.
Polyunsaturated acids (eg, the precursors of prostaglandins) are incorporated more into the 2 position, which is frequently arachidonic acid.
Phospholipase A1 removes the fatty acyl group on carbon 1 of the glycerol moiety, and phospholipase A2 removes the fatty acid on carbon 2.
Removal of the fatty acid moiety from C1 or C2 produces a lysophosphoglyceride, which is the substrate of lysophospholipases.

28. Phospholipases allow degradation & Remodeling of Phosphoglycerols
Lysophospholipid can be attacked by lysophospholipase, forming the corresponding glyceryl phosphoryl base, which in turn may be split by a hydrolase liberating glycerol 3- phosphate plus base.
Alternatively lysophospholipid, which in turn may be reacylated by acyl-CoA in the presence of an acyltransferase (Remodeling).
Lysophosphatidylcholin
may be
formed by an alternative
route
that
involves lecithin:
cholesterol
acyltransferase (LCAT).
LCAT is found in plasma and catalyzes the transfer of a fatty acid residue from the 2 position of lecithin to cholesterol to form cholesteryl ester and lysolecithin.

29. 1. Synthesis of sphingomyelin
Sphingomyelin is made from:
palmitoyl CoA + serine sphingosine
sphingosine + FA CoA ceramide
ceramide + CDP-choline sphingomyelin

30. Sphingomyelin degradation
Sphingomyelin is degraded in lysosomes by sphingomyelinase to give ceramide,
and ceramidase to give sphingosine
Niemann-Pick disease is due to sphingomyelinase deficiency

31. 2. Glycolipids
Glycolipids are derivatives of ceramides and sphingosine with carbohydrate directly attached to ceramide
In contrast to sphingomyelin they do not have a phosphocholine group
Glycolipids are essential components of cell plasma membranes (outer leaflet), but are most abundant in nervous tissues
Outside
Inside

32. Roles of glycolipids
Glycolipids have important roles in cell interactions, growth, and development
They are very antigenic (e.g., blood group antigens);
act as surface receptors for some toxins and viruses.

33. Glycolipid structure — cerebrosides
The carbohydrate component is linked by an O-glycosidic bond to ceramide
Cerebrosides contain a single sugar (Glu or Gal) or few sugars; they are abundant in brain and myelin

34. Glycolipid structure — gangliosides
Gangliosides are acidic glycosphingolipids
They contain oligosaccharides with terminal, charged N-acetyl neuraminic acids (NANA)
Depending on the number of NANA sugars, gangliosides are designated M, D, T, Q (e.g., GM)
Ganglioside GM2

35. Glycolipid synthesis
Synthesis of glycosphingolipids takes place in the ER and Golgi by the sequential addition of sugars by specific glycosyltransferases
The sugars are activated: UDP-Glu, UDP-Gal, CMP-NANA
Sulfate groups are added last by a sulfotransferase using PAPS (3'-phosphoadenosine-5'-phosphosulfate)

36. Glycolipid degradation
Degradation of glycosphingolipids occurs in lysosomes after endocytosis of membrane portions
A series of acid hydrolases participate in the degradation
Degradation is sequential in the order: last on, first off

37. Glycolipid degradation
Sphingolipidoses result from deficiencies of specific degradative enzymes
They are diagnosed by accumulation of specific sphingolipid, enzyme activity measurements, and histologic examination of affected tissue

38. Some sphingolipidoses

40. Fabrazyme® = α-galactosidase A

41. Eicosanoids Eicosanoids are specialized FA
They include prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT)
Eicosanoids have strong hormone-like actions in the tissues where they are produced
Eicosanoids are not stored and are very unstable

42. Eicosanoid synthesis
Dietary linoleic acid is the precursor. It is elongated and further desaturated to 20-carbon, 3, 4, or 5 double bond FAs
Arachidonate, 20:4 (5, 8, 11, 14), is the precursor of many eicosanoids
Arachidonate is normally part of membrane phospholipids (especially phosphatidylinositol).
Arachidonate is released by a specialized phospholipase A2

43. Synthesis of prostaglandins from arachidonate
The free arachidonic acid is oxidized and cyclized in the ER by endoperoxide synthase ( = PGH2 synthase)
This enzyme has two activities – cyclooxygenase (COX) and peroxidase
Initially yields PGH2
Subsequent steps lead to thromboxane A2 and various prostaglandins

44. Synthesis of leukotrienes from arachidonate
Leukotrienes are produced from arachidonic acid via a different enzyme: lipoxygenase

46. Biological actions of eicosanoids
Biologic actions of eicosanoids are diverse in various organs:
vasodilation, constriction, platelet aggregation, inhibition of platelet aggregation, contraction of smooth muscle, chemotaxis of leukocytes, release of lysosomal enzymes
Excess production symptoms: pain, inflammation, fever, nausea, vomiting

47. Some major polyunsaturated fatty acids
Name
Structure
Type
Significance
Linoleate
18:2(9,12)
ω-6
Essential FA
Linolenate
18:3(9,12,15)
ω-3
Arachidonate
20:4(5,8,11,14)
Prostaglandin precursor

48. Linoleate (18:2) (ω-6) arachidonate (AA) (20:4) (ω-6)
Metabolism of linoleate versus linolenate into polyunsaturated fatty acids (PUFAs):
Linoleate (18:2) (ω-6) arachidonate (AA) (20:4) (ω-6)
Linolenate (18:3)(ω-3) eicosapentanoic acid (EPA) (20:5) (ω-3)
and
docosahexanoic acid (DHA) (22:6) (ω-3)

49. Omega-3 fatty acids
EPA & DHA are precursors for different eicosanoids than arachidonate
When we were evolving, dietary ratio of ω-6 FA (linoleate) to ω-3 FA (linolenate) was about 1:1 to 2:1
Currently it is about 10:1 to 20:1 in Western diets
Fish oils have high content of ω-3 FA

50. Inhibitors of prostaglandin synthesis
Corticosteroids (e.g., cortisol) inhibit at the level of phospholipase A2
Antiinflammatory drugs (NSAIDS) like indomethacin & ibuprofen reversibly inhibit COX
Aspirin irreversibly inactivates COX

51. Cyclooxygenase
There are at least two isozymes of PGH2 Synthase (COX-1 and COX-2)
COX-1 is constitutively expressed at low levels in many cell types
Specifically, COX-1 is known to be essential for maintaining the integrity of the gastrointestinal epithelium.

52. Cyclooxygenase
COX-2 expression is stimulated by growth factors, cytokines, and endotoxin
COX-2 levels increase in inflammatory disease states such as arthritis and cancer
Up-regulation of COX-2 is responsible for the increased formation of prostaglandins associated with inflammation

53. Next generation NSAIDs
Older NSAIDs inhibit both COX-1 & COX-2:
acetylsalicylate (Aspirin®, Anacin®, etc.)
ibuprofen (Motrin IB®, Advil®, etc.)
Newer generation drugs are specific COX-2 inhibitors:
Celebrex®
Vioxx®