Semester 2: Metabolism of lipids Flashcards
Mobilization of triacylglycerols store in adipose tissue
- Glucagon, adrenalin, ACTH attaches to receptor
- Activates Gs -> adenylyl cyclase -> ATP to cAMP -> PKA
- Phosphorylation of Perilipin and HSL (hormone sensitive lipase)
- CGI dissociates from Perilipin then associates with ATGL (adipocyte triglyceride lipase)
- TG -> DG + FA
- HSL: DG -> MG + FA
- MGL (monoglycerol lipase): MG -> glycerol + FA
How are fatty acids carried in the bloodstream?
Bound to albumin
Activation of fatty acids
FA + ATP + CoA Acyl-CoA + PPi + AMP
Takes place in cytosol
Transport of fatty acids into mitochondria: Acyl-Coa synthetase
- In outer mitochondrial membrane
- Catalyzing: Fatty acids -> Fatty acyl-CoA (ATP+CoA -> AMP+PPi)
Transport of fatty acids into mitochondria: Carnitine-acyltransferase I
- Outer mitochondrial membrane
- Catalyzing: Fatty acyl-CoA + carnitine -> CoA-SH + Acylcarnitine
- Inhibitor: Malonyl CoA
Transport of fatty acids into mitochondria: Carnitine-acyltransferase II
- Inner mitochondrial membrane
- Catalyzing: Acylcarnitine into matrix, carnitine to intermem. space
- CoA-SH + acylcarnitine -> acyl-CoA that can enter beta-ox.
How to convert glycerol to glycolysis intermediate?
Glycerol -> glycerol-3-p -> dihydroxyacetone phosphate
enzymes: glycerol kinase, glycerol-p-dehydrogenase
What is PPAR?
Peroxisome proliferator/activated receptors - nuclear receptor - transcription factor
PPARalpha
- In muscle, adipose tissue, liver
- Regulates the transcription of fatty acid transporters, CPTI and II + acyl-CoA dehydrogenase
Ketone bodies
1) Acetoacetate
2) D-beta-hydroxybutyrate
3) Acetone
When does ketogenesis occur?
When there is a high rate of fatty acid oxidation
Lipogenesis, enzyme?
Fatty acid synthase - has 7 active sites for different reactions in separate domains
Cofactor requirements for fatty acid synthase
- NADPH
- ATP
- Mn2+
- Biotin
- HCO3-
Where does beta-ox. occur?
Mitochondrial matrix
Where does lipogenesis occur?
Cytosol
Committed step in lipogenesis
Formation of malonyl-CoA from acetyl-CoA (+bicarbonate)
Via acetyl-CoA carboxylase (prosthetic group: biotin)
Reactions catalyzed by acetyl-CoA carboxylase
- Transfer of carboxyl group to biotin (ATP-dep.) - Biotin (E1) carboxylase
- –> Activated CO2 is moved to transcarboxylase active site - Transfer of activated carboxyl group from biotin to acetyl-CoA
Source of NADPH for fatty acid synthesis
1) Malate + NADP -> Pyruvate + NADPH+H (by malic enzyme)
2) Glucose-6-p -> Ribulose-5-p (PPP) - Makes two NADPH
Lipids transported from intestines in ….
Chylomicrons
Lipids transported from liver in…
VLDL
Apolipoprotein of VLDL
B-100, Apo Cs
Apolipoprotein of LDL
Apo B (B-100)
Apolipoprotein of Chylomicrons
Apo As and Cs, E, B-48
HDL is synthesized and secreted in..
Both liver and intestine
Function of SRB1
- (Scavenger receptor class B member 1)
- Is a HDL receptor - accepts cholesterol from HDL
- HDL3 can accept cholesterol from tissue via this R.
Function of ABCA1
Mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (apo-A1 and apoE), which then form nascent high-density lipoproteins (HDL)
Role of LDL
Supply cholesterol and cholesterol esters to many tissues
Role of HDL
Removes free cholesterol from tissues and transport it to the liver
Cholesteryl ester formation in HDL
Phosphatidylcholin (lecithin) + cholesterol –> lysolecithin + cholesteryl ester (by Lecithin-cholesterol acyl transferase (LCAT))
Function of StAR
Steroidogenic acute regulatory protein is essential for transport of cholesterol to inner mitochondrial membrane
Cortisol inactivation done by..
11betaOHSDH2 (cofactor: NAD)
Cortisol activated by…
11betaOHSDH1 (cofactor: NADPH)
Cushing syndrome
Excess cortisol
Adrenal cortex insufficiency
Lack of cortisol
Side effects of glucocorticosteroids
- Osteoclastogenesis increases –> increased bone resorption
- Osteoblastogenesis decreases –> decreased bone formation
- Increased apoptosis of osteocytes –> decreased bone formation
= osteoporosis
Congenital adrenal hyperplasia
Defect in cortisol synthesis
- Most frequent: Partial or complete deficiencies of 21hydroxylase, or 11beta hydroxylase
From arachidonic acid we will further get:
1) Cyclooxygenase pathway –> prostaglandins, thromboxanes
2) Lipoxygenase pathway –> lipoxins, leukotrienes
Cyclooxygenase catalyzes what reaction?
Arachidonic acid –> PGG2
Peroxidase catalyzes what reaction?
PGG2 –> PGH2
Where can we find TXA2 and what is its function?
Platelets, increases calcium –> Platelet aggregation + vascular smooth muscle contraction
Where can we find PGI and what is its function?
Endothelial cells, cAMP increase –> Platelet aggregation + vascular smooth muscle contraction
Where can we find PGD2 and what is its function?
Mast cells
- Increases calcium –> pulmonary vasoconst. + bronchoconstriction
- Increases cAMP –> vasodilation, relaxation of GI and uterus muscle
Prostaglandin F2alpha
Inc. Ca2+ –> smooth muscle cell contr. in bronchi, vessel wall, uterus, GI tract
Prostaglandin E2
Protection of gastric mucosa, bronchodilation etc.
COX-1
- Mostly in cytosol
- Narrow substrate-binding site (completely blocked by aspirin)
- PG products secreted
COX-2
- Mostly in nuclear mem.
- Less inhibition by aspirin than COX1 due to wider substrate binding site
What does aspirin do?
Inhibits cyclooxygenase enzymes by acetylating Ser. Inactivates COX1, switches catalytic activity of COX2
Dioxygenase enzyme
Arachidonic acid –> 5-HPETE
Dehydrase enzyme
5-HPETE –> LTA4
LTA4 hydrolase enzyme
LTA4 –> LTB4
Rate limiting step in fatty acid oxidation
Transport of carnitine-acylcarnitine (via CPT1)
Acetyl-CoA dehydrogenase
Palmitoyl CoA + FAD+ –> Trans-delta2-enoyl-CoA + FADH2
Enoyl-CoA hydratase
Trans-delta2-enoyl-CoA + H2O–> L-beta-hydroxyacyl-CoA
Beta-hydroxyacyl-CoA dehydrogenase
L-beta-hydroxyacyl-CoA + NAD+ –> beta-ketoacyl-CoA + NADH+ H
Acyl-CoA acetyltransferase (thiolase)
Beta-ketoacyl-CoA + CoA-SH –> (C14) Acyl-CoA (myristoyl-CoA) + Acetyl-CoA
1 step of ketone body formation: thiolase
2 acetyl-CoA —> Acetoacetyl-CoA + CoA-SH
HMG-CoA synthase
Acetoacetyl-CoA –> HMG-CoA
Acetyl-Coa + H2O -> CoA-SH
HMG-CoA lyase
HMG-CoA –> Acetoacetate + acetyl-CoA
Final reaction in ketone body formation: Acetoacetate to…
- Beta-hydroxybutyrate (beta-hydroxybutyrate dehydrogenase, uses NADH)
- Acetone (Acetoacetate decarboxylase, releasing CO2)
Beta-ketoacyl-CoA transferase
Acetoacetate –> Acetoacetyl-CoA
Succinyl-CoA -> succinate
Where can we find ACAT2?
Enterocytes, hepatocytes
Where can we find ACAT1?
Kuppfer cells, macrophages
HMG-CoA reductase
HMG CoA –> Mevalonic acid + CoA
- (In cholesterol synthesis)
- Uses 2NADPH+ 2H+
How is cholesterol transferred to HDL?
1) passive diffusion
2) via SR-BI
3) via ABCA1
Coenzymes for bile acid synthesis
NADPH, NAD, CoA
LXR receptor
- liver x receptor
- ligand: oxysterol
- inc. bile acid synthesis
- inc. cholesterol efflux
- dec. LDL receptors
FXR
- farnesoid x receptor
- ligand: bile acids
- inc. bile acid reabsorption
- inc. LDL receptor
SHP
Dec. bile acid synthesis