Triacylglycerol Phospholipid Sphingolipid Metabolism Flashcards
What is the function of TG?
Energy source for metabolic fatty acids
Where is TG produced?
Liver and adipose tissue
How is TG synthesized?
- By a pathway containing a phosphatidic acid intermediate where Glycerol-3P reacts with FA1CoA and FA2CoA
- Dephosphorylation produces diacylglycerol reacting with FA3CoA to form TG
What is the source of glycerol-3-P in the liver?
- phosphorylation of glycerol by glycerol kinase
or - reduction of dihydroxyacetone phosphate (glycolysis(
What is the source of glycerol-3-P in adipose tissue?
- glycolysis (dihydroxyacetone phosphate)
because adipose does not have glycerol kinase
How is TG incorporated into VLDL?
TG produced in the smooth ER of the liver is packaged with cholesterol, phospholipids, proteins (ApoB-100) synthesized in the RER and Golgi complex and secreted into the bloody by the liver
How is FA in VLDL converted to storage TG in adipose tissue?
Ie what happens in the fed state?
- In the fed state, when insulin/glucagon ratio is high, adipose cells synthesize and secrete lipoprotein lipase (LPL)
- LPL breaks down the TG located in VLDL and chylomicrons to FA
- The FA enter adipose cells and form FACoA
- This reacts with glycerol-3-P to form TG that is added to other TG formed from glucose
What happens to TG in the fasted state?
- In the fasted state, when there is low insulin and high glucagon, cAMP increases
- cAMP activates protein kinase A
- PKA phosphorylates HSL (hormone sensitive lipase) which activates it
- Activated HSL initiates lipolysis
What are some functions of glycerophospholipids?
- major component of cellular membrane
- component of blood lipoproteins, bile, lung surfactant
- source of polyunsaturated fatty acids, particularly arachidonic acid, that serve as precursors of the eicosanoids
How are glycerophospholipids synthesized?
first mechanism
- Glycerpl-3-P reacts with fatty acyl CoA to form phosphatidic acid
- phosphatidic acid is cleaved by a phosphatase to form DAG
- DAG interacts with an activated headgroup
READ THE SLIDE (11) FOR FORMATION OF DIFFERENT TYPES OF GLYCEROPHOSPHOLIPIDS
How are glycerophospholipids synthesized?
second mechanism
- Glycerpl-3-P reacts with fatty acyl CoA to form phosphatidic acid
- Phosphatidic acid reacts with CTP to form CDP-diacylglycerol
- CDP-diacylglycerol interacts with an activated headgroup
What is the molecule that drives both mechanism of glycerophospholipid synthesis?
CTP - cytidine triphosphate
How are glycerophospholipids degraded?
Phospholipases which are located in cell membranes or lysosomes
What does phospholipase A1 do?
Removes the fatty acyl group on C1 of the glycerol moiety
What does phospholipase A2 do?
Removes the fatty acid of C2
What does phospholipase C do?
Cleaves the bond joining C3 of the glycerol moiety to phosphate
What does phospholipase D do?
Cleaves the bond bw the phosphate and head gorup
What is the biological importance of C2 fatty acid obtained from degradation of glycerophospholipid?
It is frequently arachidic acid which is removed by phospholipase A in response to signals for the synthesis of eicosanoids, playing important roles in inflammatory responses & other physiological functions
What other role does phospholipase C have?
Hormonal stimuli activate phospholipase C, which hydrolyzes PIP2 to produce DAG and IP3. These 2nd messengers are involved in signaling pathways that regular a variety of cell functions including Ca+ homeostasis
How do lung surfactants work?
it is found in epithelial cells lining the inside of the alveoli and reduces surface tension of water/fluid on the surface of the sac
W/o lung surfactant, ten times the normal pressure is needed for re-inflation
What is infant respiratory distress syndrome?
- IRDS occurs sue to problem in lung surfactant production or secretion
- Diagnosis is made in utero through sample of amniotic fluid
- Low ratio of phosphatidyl choline (PC)/sphingomyelin indicates a deficient in lung surfactant and is predictive of IRDS in newborn
- Treatment = administration of synthetic corticosteroids 48-72 hours prior to delivery to stimulate fetal synthesis of lung surfactant
How is ether glycerophospholipids synthesized?
- A fatty acyl CoA reacts with C1 of DHAP forming a fatty ester which is exchanged for a fatty alcohol to produce the ether linkage
- The keto group of C2 of DHAP moiety is reduced and esterified to a fatty acid and C3 dephosphorylated
- Addition of the head group proceeds by a series of reactions analogous to those for synthesis of phosphatidylethanolamine
- Formation of a double bond between C1 and C2 of the alkyl group produces a plasmalogen
Where is ethanolamine plasmalogen found?
It is found in myelin and choline plasmalogen in heart muscle
What is the structure of platelet activating factor (PAF)
Similar to choline plasmalogen except:
an acetyl group replaces the fatty acyl group at C2 of the glycerol moiety and he alkyl group on C1 is saturated
What are the functions of sphingolipids?
- Components of the plasma membranes (CNS and brain has high amts in the myelin membrane surround axons, essential for rapid conduction of impulses)
- Provide receptors for pathogenic bacteria and bacterial toxins
- Sever as antigen determinants of the ABO blood groups
- Serve in intercellular communication
What are the two stages sphingolipids biosynthesis occurs?
- Formation of ceramide (in SER)
2. Attachment of different head groups to ceramide (in Golgi)
How are different sphingolipids formed?
- Ceramide reacts with phosphatidylcholine to form sphingomyelin
- Ceramide reacts with UDP sugars to form cerebrosides. Galactocerebroside may react with 3’-phosphoadenosine 5’-phosphosulfate to form sulfatides
- Additional sugars may be added to ceramide to form globosides or gangliosides which are produces by the addition of NANA (an acid) ad branches from the oligosaccharide chains
Where are sphingolipids degraded?
lysosomes
How do exoglycosidases degrade sphingolipids?
catalyze hydrolysis of specific carbohydrate head groups sequentially from outside in
How do sphingomyelinase degrade sphingolipids?
cleaves the phospho-choline group
How do Arylsulfatase A degrade sphingolipids?
it is a sulfatidase
How do ceramidase degrade sphingolipids?
cleaves bw acyl groups and sphingosine
What are sphingolipidoses?
inherited diseases that are characterized by pathologic accumulation of particular sphingolipids in cells of affected individuals
the inherited mutations, that results in a missing/defective enzyme, plays a role in the degradation of sphingolipids
List some examples of sphingolipidoses and their deficiency
- Tay-Sachs disease - lack of enzyme hexosaminidase A
- Gaucher’s disease - deficiency in beta-glucosidase
- Niemann-Pick disease - deficiency of sphingomyelinase
- Farber’s disease - deficiency of ceraminidase
