FA metabolism-Brar Flashcards
how is triacylglycerol formed? How does this differ in different tissues?
o G3P + fatty acyl CoA →lysophosphatidic acid + Fatty acylCoA–> phosphatidic acid (DAG phosphate) .
• Enzyme = acyltransferase
o Dephosphorylation of phosphatidic acid produces a diacylglycerol.
• Enzyme = phosphatase
o Another fatty acyl CoA reacts with the diacylglycerol to form a triacylglycerol (enzyme: acetyltransferase)
G3P comes from:
- liver: Glycerol is converted to G3P by glycerol kinase
- adipose: G3P made from glucose via dihydroxyacetone phosphate (adipose doesn’t have glycerol kinase)
what is the function of LPL?
Lipoprotein lipase (LPL) cleaves the triacylglycerols in VLDL (and chylomicrons) forming fatty acids and glycerol --> to then be taken up into cells for storage of triacylglycerols -the fatty acids enter the adipose cells and form triacylglycerols in the same way as the liver and --- -the glycerol is taken up by the liver and reused because Adipose cells lack glycerol kinase
LPL is secreted by adipose cells when the insulin/glucagon ratio is elevated (fed state)
where are triacylglycerols produced and how are they transported?
Triacylglycerols are produced in the smooth endoplasmic reticulum of the liver
They are packaged along with cholesterol, phospholipids and proteins to form VLDL
Microsomal triglyceride transfer protein (MTP) is required for VLDL assembly
MTP also required for chylomicron assembly
The major protein in VLDL is apoB-100
VLDL is processed in the Golgi complex and secreted into to the bloodstream by the liver
correlation between LDL and heart disease?
Strong correlation with blood LDL levels and heart disease
High HDL levels are associated with decreased risk for heart disease
HDL is thought to be able to remove lipids from plaques and transport it back to the liver for processing –> less lipids in circulation
How does hormone sensitive lipase function? What effects will insulin, glucagon and epinephrine have on hormone sensitive lipase?
During fasting cAMP levels rise in adipose cells due to the decrease in insulin (normally inhibits FA release in the fed state) and rise in glucagon
Increase in glucagon causes an increase in cAMP which activates PKA which will stimulate lipolysis and stimulates FA release
Protein kinase A phosphorylates hormone sensitive lipase to produce a active form of the enzyme
Hormone sensitive lipase cleaves a fatty acid from a triacylglycerol
Other lipases complete the process of liberating fatty acids and glycerols into the blood
insulin: decrease cAMP–> no PKA –> no phosphorylation of hormone sensitive lipase to activate it–> no FA liberation in the fed state
glucagon and epinephrine: in fasting, cause an increase in cAMP –> activate PKA–> phosphorylate hormone sensitive lipase to activate it –> FA and glycerol liberation into the blood
what are glycerophospholipids and sphingolipids and what are they sources/precursors of?
FA’s from the diet are the major precursors of glycerophospholipids (GPL) and sphingolipids
GPL’s are components of lipoproteins, bile and lung surfactant
GPL’s are also the source of poly unsaturated fatty acids (PUFA’s), especially arachidonic acid which serve as the precursors of eicosanoids
Ether GPL’s have an alkyl group joined to carbon 1 of the glycerol backbone (platelet activating factor)
Sphingolipids=important in cell membrane and cell health
Biological effects at low concentration
essential fatty acids
linoleic acid has Tm of -5 o C (omega 6)
alpha-linolenic acid has Tm of -11 o C (omega 3)
double bonds lower the melting point
essential fatty acids
linoleic acid has Tm of -5 o C (omega 6)
alpha-linolenic acid has Tm of -11 o C (omega 3)
Dietary lipids and their affects on cholesterol
Saturated FA’s: Myristic acid and palmitic acid elevate cholesterol levels more
Monounsaturated FA’s: Lower both cholesterol and LDL with modest or no effect on HDL
Olive oil high in oleic acid
Polyunsaturated FA’s: Linoleic acid is major dietary PUFA for humans
N-6
Principally linoleic acid
Lowers both LDL and HDL
Required for membrane fluidity and synthesis of eicosanoids
N-3
Principally alpha-linolenic acid
Little effect on LDL and HDL
Varied effects include Reduction of BP, Treating infection, Treating psoriasis, Anti-inflammatory, antithrombotic
- they are natural ligands for PPARs (peroxisome proliferator activation receptors)
Trans Fatty acids:
• Thought to promote CV disease.
• Raise LDL levels.
• Mechanisms not clear.
Regulation of FA synthesis
acetyl CoA carboxylase converts AcetylCoA --> malonyl-CoA--> --> palmitic acid activated by citrate inhibited by palmitoyl-CoA inhibited by Protein kinase A Indirectly inhibited by insulin
in the fed state–> AcCoA carboxylase will be inhibited by insulin so FA will not be formed
Function of hypoglycin A
Hypoglycin A inhibits acyl CoA dehydrogenase=shuts down beta oxidation of FA
The rare amino acid (or is it an alkaloid?)
is heat labile and found in unripe akee fruit
Leads to fasting hypoglycemia
Symptoms include vomiting, convulsions and coma
Affects people with low levels of acyl CoA DH severely
carnitine deficiency
in the liver, leads to hypoketotic hypoglycemia during periods of extended fasting (FA metabolism problem).
during fasting, FA beta oxidation is used to generate acetyl CoA for ketogenesis and ATP for gluconeogenesis
==> carnitine deficiency compromises these because it cannot transport FA into the mitochondria for beta oxidation to take place
beta oxidation defects compromise tissues which rely heavily on oxidation of FA for energy: skeletal muscle and liver (during fasting)
Medium Chain acyl CoA DH deficiency
Most common inherited defect in the -oxidation sequence
Affected enzyme catalyzes the first reaction in -oxidation of medium chain (C5-C12) fatty acids
Short chain and long chain FA use two other dehydrogenase enzymes for the same reaction
Patients present with fasting hypoglycemia during infancy or childhood
Often during an infectious illness when the child eats little
Many cases go undiagnosed and some infants die during their first hypoglycemic attack (under circumstances suggesting sudden infant death syndrome)
Most common in NW Europe where a single mutation is responsible for 90% of cases
Refsum Disease
o Recessively inherited defect of peroxisomal α-oxidation
o Causes the accumulation of phytanic acid
• Branched chain FA is derived from phytol
• Phytol is a constituent of chlorophyll which accumulates in the fat of ruminants
o The β carbon is methylated so α-oxidation is needed to shorten phytanic acid by one carbon.
o This is followed by a round of β-oxidation which yields propionyl CoA rather than acetyl CoA.
o Refsum disease characterized:
• By slowly progressive peripheral neuropathy
• Weakness
• Muscle wasting
• Retinitis pigmentosa: degeneration of the retina. It affects night vision and peripheral vision, and eventually can lead to blindness.
• Cerebellar ataxia
o Neurological damage is irreversible so treatment must start early.
o Patients usually respond to dietary restriction of green vegetables and reduced amounts of ruminant milk and meat.
• Apo AI(Milano)
o Apolipoprotein AI Milano factor.
o Differs from native Apo AI in that arginine is replaced by a cysteine residue.
• This allows a disulfide linked dimer to be formed.
o Thought to help increase the transport of cholesterol from plaques to liver for reprocessing.
