2. The Lipids are a heterogeneous group of compounds which
are relatively insoluble in water, but freely soluble in
nonpolar organic solvents like benzene, chloroform, ether,
hot alcohol, acetone,etc.
Lipids are classified based on their chemical nature
3. Simple lipids
Compound lipids
Derived lipids
Lipids complexed to other compounds
4. Compound lipids are esters of fatty acids containing groups
in addition to an alcohol and a fatty acid.
Compound lipids are phospholipids, glycolipids and other
complex lipids.
5. Glycolipids
Glycolipids are widely distributed in every tissue of the body,
particularly in nervous tissue such as brain.
They occur particularly in the outer leaflet of the plasma
membrane, where they contribute to cell surface
carbohydrates.
6. The major glycolipids found in animal tissues are
glycosphingolipids.
They contain ceramide and one or more sugars.
Ceramide + Glucose ----- Glucocerebroside
Ceramide + Galactose ---Galactocerebroside
7. Globosides ( ceramide oligosaccharides )
They contain two or more hexoses or hexosamines, attached
to a ceramide molecule.
Ceramide + Galactose + Glucose -- Lactosyl ceramide
Lactosyl ceramide is a component of erythrocyte membrane.
8. Gangliosides
They are formed when ceramide oligo-saccharides have at
least one molecule of NANA ( N-acetyl neuraminic acid ) (
Sialic acid) attached to them.
Ceramide – Glucose – galactose – NANA ; this is designated
as GM3 ( ganglioside M3 ).
9. Gangliosides contribute to stability of paranodal junctions
and ion channel clusters in myelinated nerve fibres.
Autoantibodies to GM1 disrupt lipid rafts, paranodal or nodal
structures, and ion channel clusters in peripheral motor
nerves.
10. A specific ganglioside on intestinal mucosal cell binds to the
b subunit of the Cholera toxin when the a subunit enters the
cell.
It keeps the level of cellular cAMP raised by inhibition of
GTPase activity of the G protein.
Gangliosides also act as receptors for other toxins like tetanus
toxin, and toxins of viral pathogens.
11. Sulpholipids or sulfatides
These are formed when sulfate groups are attached to
ceramide oligosaccharides.
Sulphated Cerebrosides
Sulphated globosides
Sulphated Gangliosides
All these complex lipids are important components of
membranes of nervous tissue.
12. Synthesis of Glycosphingolipids
synthesis of glycosphingolipids occurs primarily in the Golgi
apparatus by sequential addition of glycosyl monomers
transferred from UDP-sugar donors to the acceptor
molecule.
13.
14.
15.
16. Degeneration of Glycosphingolipids
Glycosphingolipids are internalized by endocytosis.
All of the enzymes required for the degrative process are
present in lysosomes, which fuse with the endocytotic
vesicles.
The lysosomal enzymes hydrolytically and irreversibly cleave
specific bonds in the glycosphingolipid.
17. Failure of degradation of these compounds results in
accumulation of these complex lipids in CNS.
This group of inborn errors is known as lipid storage
diseases.
18. Lipid storage diseases
They are called as spingolipidoses.
Gaucher’s disease
most common lysosomal storage diseases
enzyme deficiency – Beta glucosidase
19. lipid accumulating – Glucosylceramide
Clincal symptoms
3 types – adult, infantile, juvenile
Hepatosplenomegaly, erosion of long bones, moderate
anemia, mental retardation in infants
20. Niemann- pick disease
enzyme deficiency – sphingomyelinase
lipid accumulating – sphingomyelin
Clinical symptoms
severe CNS damage, mental retardation,
hepatosplenomegaly, cherry rod spot in macula
neurodegenerative course ( type A )
death occurs by 2 years of age
21. Krabbe’s disease
Globoid cell dystrophy
enzyme deficiency – Beta galactosidase
lipid accumulating – Galactosylceramide
Clinical symptoms
severe mental retardation, total absence of myelin in CNS,
Globoid bodies in white matter
22. Metachromatic leukodystrophy
enzyme deficiency – arylsulfatase
lipid accumulating – 3-sulfogalactosylceramide
Clinical symptoms
Mental retardation and psychologic disturbances in adults,
demyelination, neurological deficit, difficulty in speech and
optic atrophy, progressive paralysis, dementia in adult form,
nerves stain yellowish-brown with cresyl violet –
metachromasia
23. Fabry’s disease
enzyme deficiency – alpha galactosidase
lipid accumulating – Globotriaosylceramide
Clinical symptoms
progressive renal failure, death by 5 years of age, skin rash,
purplish papules appear, X – linked inheritance
24. Tay-Sachs disease
enzyme deficiency – Hexosaminidase A
lipid accumulating – GM2 Ganglioside
Clinical symptoms
Incidence 1 in 6000 births
mental retardation, blindness, cherry red spot in the macula,
muscular weakness, progressive deterioration, death by 3-4
years
25. Generalized gangliosidoses
enzyme deficiency – Beta-galactosidase
lipid accumulating – Ganglioside (GM1)
Clinical symptoms
mental retardation, hepatosplenomegaly, skeletal
deformities, foam cells in bone marrow, cherry-red macula in
the retina
27. Sandhoff’s disease
enzyme deficiency – Hexosaminidase A and B
lipid accumulating – Globoside
Clinical symptoms
neurological deficit, mental retardation
28. Farber disease
enzyme deficiency – Ceramidase
lipid accumulating – ceramide
Clinical symptoms
hoarseness, dermatitis, subcutaneous nodules of lipid-laden
cells, tissues show granulomas, skeletal deformation, painful
and progressive joint deformity, mental retardation, fatal in
early life
29.
30. Laboratory diagnosis
A specific sphingolipidosis can be diagnosed by measuring
enzyme activity in cultured fibroblasts or peripheral
leukocytes, or by analysis of DNA.
Histologic examination of the affected tissue is also useful.
31.
32.
33. Shell-like inclusion bodies are seen in Tay-Sachs disease and
a wrinkled tissue paper appearance of the cytosol is seen in
Gaucher disease.
All these diseases can be diagnosed prenatally by
amniocentesis and culture of amniotic fluid cells.
34. Lysosomal storage diseases are diagnosed by quantitative
enzyme assay.
Carriers are best diagnosed by DNA analysis of the common
mutations.
35. Treatment
Replacement of deficient enzyme has been tried in Gaucher’s
disease, with limited success.
Gaucher disease and Fabry disease are treated by
recombinant human enzyme replacement therapy, but the
monetary cost is extremely high.
36. Gaucher disease has also been treated by bone marrow
transplantation.
Other promising approaches are substrate deprivation
therapy to inhibit the synthesis of sphingolipids and
chemical chaperone therapy.
Gene therapy for lysosomal disorders is also currently under
investigation.
