Lectures 25/26: Lipid Metabolism Flashcards
Atherosclerosis
When normal lipid delivery systems are overwhelmed, lipoproteins end up in wrong spot
Lipids are deposited in arterial wall
Lipoprotein particles
Water-insoluble fat is packaged into soluble lipoproteins
Amphipathic
Phospholipid, cholesterol, apolipoproteins
Hydrophobic
Triacylglycerols
Cholesteryl esters
Chylomicron
Mainly triglycerides
Density ~0.94
Proteins: apoB48, apoCII, poE
Transport triacylglycerols from intestine to adipose and other tissues
After TG are taken up, remaining chylomicron remnant is taken up by liver
Very-Low-Density lipoproteins
Half triacylglycerol
Density ~0.94-1
Proteins: apoB48, apoCII, poE
Transport TG form the liver to the adipose and other tissues
TG are taken up, remaining lipoproteins are mainly cholesterol and are LDL
Low-Density lipoproteins
Almost half cholesterol
Density ~1-1.063
Protein: apoB100
Peripheral tissue takes up to get cholesterol
LDL not taken up by peripheral tissue is cleared by the over
If LDL levels are too high, LDL can deposit cholesterol into arterial walls
High-Density lipoprotein
Mostly protein, 1/4 cholesterol
Proteins: apoA1, apoE
Transport cholesterol from tissues to liver
Cholesterol is excreted from liver
High HDL levers counteract the cholesterol deposition by LDL
Lipid metabolism
Triacylglycerols contain fatty acids attached to a glycerol backbone
Fatty acids are broken down into acetyl-CoA, which feeds into the citric acid cycle
Triacylglycerol synthesis
Glycerol-3-phosphate and fatty acyl CoA Most in liver (VLDL secretion) and adipose tissue (storage) Energy storage TG is overflow pathway: excess nutrients No feedback inhibition of TG synthesis
Glycerol kinase
In liver
Phosphorylates glycerol to glycerol-3-phosphate
Glyceroneogenesis
Adipose tissue: they do not have glycerol kinase
Gluconeogenesis that stops at glycerol-3-phosphate: when glucose is not available, gluconeogenesis to DHAP, then DHAP is reduced to glycerol-3-phosphate
Cannot be active at the same time as glycolysis
Acyl CoA synthetase
Source for fatty acyl-CoA
Glycerol-3-phosphate
Precursor for TG and glycerophospholipids
Derived form glycolysis, or DHAP reduced during glycerneogenesis, or synthesized form glycerol
Mitochondrial dehydrogenase
Reduces DHAP to glycerol-3-phosphate
Fatty acid activation
Binding of fatty acids to CoA
Fatty acid + Co-ASH + ATP = Fatty acyl-CoA + AMP + ppi
Lipoprotein lipase
Hydrolyzes TG in capillaries before transport inside cell
Fatty acids are taken up by cells
Glycerol remains in blood stream: water soluble, taken up by liver
Adipose tissue: storage
Muscle: energy
Adipocyte
Adipose tissue
Takes up fatty acids
Activates with CoA
Fatty actyl-CoA are esterified with glycerol-3-phosphate to give triacylglycerides
Hydrolysis of triacylglycerols in adipose tissue
When body requires energy
Fatty acids and glycerol are secreted into the bloodstream
Adipose triglyceride lipase (ATGL)
Catalyses lipolysis when energy stores are mobilized
Fatty acids excreted and bound to albumin, sent to muscle and liver
Glycerol sent to liver
Hormone sensitive lipase
Catalyses lipolysis when energy stores are mobilized
Fatty acids excreted and bound to albumin, sent to muscle and liver
Glycerol sent to liver
Glycerol
Used in liver: glycolysis or gluconeogenesis depending on hormones present
Can be made during chylomicron uptake into adipose tissue or during lipolysis in adipose tissue
Glycerol kinase synthesizes it into glycerol-3-phosphate
Glycerol-3-phosphate
Processed by glycerol-3-phosphate dehydrogenase to dihydroxyacetone phosphate: this can be used in glycolysis or gluconeogenesis
Fatty acid oxidation
Breakdown of fatty acids in the mitochondrial matrix
Each reaction cycle removes 2 caron from the carboxyl end of the carbon chain
Also called beta-oxidation (broken at the beta end)
1NADH and 1 QH2
Regulated at transport step of fatty acids in mitochondria
Produces acetyl-CoA to enter TCA cycle
Requires oxygen
Step 1 of fatty acid oxidation: activation
Activated in cytosol through conjugation to CoA: CoASH
ATP hydrolyzed to AMP and pyrophosphate ppi
Step 2: import into mitochondria
Fatty acyl groups are transferred via carnitine
Carnitine deficiency slows down/prevents fatty acid oxidation
Beta oxidation
Fatty acids degraded to acetyl-CoA
Cycle of 4 reactions, each cycle removes 2 carbons as acetyl-CoA from the carboxyl end of the fatty acid
Total energy yield: 35NADH and 17QH2=139 ATP
Beta oxidation: first oxidation
Transfer of two electrons to FAD prosthetic group to form FADH2
Transfer of electrons from FADH2 to Q to form QH2
Saturated fatty acyl-coA is oxidized to 2,3-enoyl with C=C double bond
Catalyzed by a dehydrogenase
Beta oxidation: hydration
Hydrates catalyzes the addition of water to the double bond
Hydroxy group formed
Beta oxidation: second oxidation
Hydroxygroup oxidized to ketogroup
Electrons are transferred to NAD forming NADH
Catalyzed by a dehydrogenase
Beta oxidation: cleavage, thiolysis
Catalyzed by thiolase
Release of acetyl CoA and an acyl-CoA chain that is 2 carbons shorter
Shortened acyl-CoA chain undergoes the next round of oxidation
Oxidation of very long fatty chains
Oxidation in peroxisomes to medium-chain fatty acids which are then oxidized in mitochondria
Peroxisomal fatty acid oxidation does not yield ATP
Adrenoleukodystrophy
Genetic defects in peroxisomal transports leads to build up of very long chain fatty acids
Oxidation of unsaturated fatty acid
Additional enzyme are required to degrade the carbon chain around double bonds
Odd numbered double bonds require an isomerase
Even numbered bonds require dehydrogenase
Energy yield is lower than from saturated fatty acids
Oxidation of odd chain fatty acids
Yields propionic acid, which is covered to succinyl CoA: glycogenic
After last beta oxidation, propionyl-CoA remains, carboxylation and isomeration yields succinyl-CoA
Some odd-chain fatty acids and propionic acid are generated by intestinal bacteria
Vitamin B12 deficiency
Neurological damage because of accumulation of odd-chain fatty acids in neuronal membranes
Fatty acid synthesis
In liver, adipose tissue, som other tissues
Synthesis from acetyl-coA, needs NADPH, systolic
Not identical to oxidation
Excess fatty acid synthesis can contribute to inappropriate fat accumulation
Step 1 of fatty acid synthesis: transport
Transfer of acetyl-CoA into cytosol from mitochondria
Transports as citrate (costs ATP)
Citrate ligase cleave citrate to oxaloacetate and acetyl-CoA in cytoplasm
Cytosolic malic enzyme produces NADPH
Step 2 of fatty acid synthesis: activation
Acetyl-CoA carboxylase catalyzes first committed step of fatty acid synthesis
Rate limiting step
Uses one ATP to make malonyl CoA
Malonyl CoA
Inhibits carnitine palmitoyltransferase: import of fatty acids into mitochondria for oxidation
Fatty acid synthase
Catalyzes the synthesis of saturated fatty acids up to 16 carbons long
540kD protein
To identical polypeptide sequences
Six active sites per polypeptide
Acts as tether and prosthetic group for acyl group of growing chain
Acyl carrier protein
Fatty acid synthase
Binds and activates acyl groups similar to CoA
Step 3 of fatty acid synthesis: elongation
Intermediates attach to carrier protein
Two carbons at a time
Elongases
Makes fatty acids longer than C16 in ER or mitochondria
Addition of C2 units using acetyl CoA or malonyl CoA
4 step reaction
Requires 1NADH and 1NADPH
Desaturases
Introduction of double bonds to fatty acids
Animals only have 4, 5, 6, and 9 denatures
No insertion of double bond beyond C9 counting carboxygroup
Denaturation coupled with elongation moves double bond down the chain
delta4-desaturase
Double bond at 4 carbons from carboxyl group
delta5-desaturase
Double bond at 5 carbons from carboxygroup
Linoleum acid
Essential fatty acid
Animals cannot synthesize
delta12-desaturation: only in plants
Longer omega-6 and 3 fatty acids are made form linoleic and alpha-linolenic acid: essential
Inhibition of fatty acid metabolism
From malonyl-CoA: to carinitine
From fatty acid: to acetyl-CoA carboxylase
Ketone bodies
Synthesized by liver from acetyl-CoA when glucose is scarce and can be used as fuel by the brain
Metabolites: acetoacetate, 3-hydrobutyrate and acetone
Ketogenesis
From acetyl-CoA in liver
Observed after several days of fasting, when fatty acids are far higher than carbohydrates, and in type 1 diabetes
Liver misses an enzyme of ketone catabolism, so it synthesizes but does not break down ketones
Cholesterol synthesis
Synthesized from acetyl CoA
Requires NADPH and ATP
Dietary uptake and endogenous synthesis are balanced
HMG CoA reductaste
Target of cholesterol-lowering drugs, statins
Convers HMG CoA to mevalonate
Cholesterol
Incorporated into membrane, esterified for storage/packaging into VLDL, converted to bile acids and steroid hormones
Unesterified cholesterol can be cytotoxic: intercalates into membrane and disturbs their function
Cellular cholesterol levels must be tightly controlled
Endocytosis of lipoproteins
Mediated by specific receptors that recognize the apolipoprotein
LDL receptor
Located in all cells
Recognize ApoB, ApoE of LDL and VLDL remnants
Without protein part, lipoproteins are not taken up
Efflux of cholesterol
Can be transferred to HDL to reduce cellular cholesterol content
Mediated by transmembrane protein ABCA1
Cardiovascular Risk
Positive correlation with serum LDL, LDL/HDL ratio and serum cholesterol with cardiovascular risk
Negative correlation with serum HDL
Nile red
Stains fat lesions red
High fat, high cholesterol diet leads to increase lesion area and occlusion of arterial lumen
Chronic endothelial injury
Hyperlipidemia Hypertension Hyperinsulinemia Skiing Hemodynamic factors Toxins Viruses Immune reactions
Atheroma formation
Initial changes in endothelial lining of artery
Monocytes adhere to endothelial cells
Infiltration of monocytes into intimate
Differentiation into macrophages
Causes: increased permeability for LDL, entry and retention of LFL into intimate, mild oxidation of LDL, uncontrolled uptake of LDL into macrophages and foam cell formation
Unstable plaques
Smooth muscle cells migrate into intimate and proliferate
Further accumulation of lipids
Increased synthesis of extracellular matrix: hardening of artery
Beginning of cell death
Plaque rupture
Cell death: formation of necrotic core Calcium deposition Cholesterol crystal formation Plaque instability Plaque rupture
Lecithin-acyl CoA transferase (LCAT)
Activated by ApoA1
Esterifies cholesterol to cholesterol ester
Cholesterol ester forms hydrophobic core
