Lectures 25/26: Lipid Metabolism Flashcards

1
Q

Atherosclerosis

A

When normal lipid delivery systems are overwhelmed, lipoproteins end up in wrong spot
Lipids are deposited in arterial wall

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2
Q

Lipoprotein particles

A

Water-insoluble fat is packaged into soluble lipoproteins

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3
Q

Amphipathic

A

Phospholipid, cholesterol, apolipoproteins

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4
Q

Hydrophobic

A

Triacylglycerols

Cholesteryl esters

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5
Q

Chylomicron

A

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

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6
Q

Very-Low-Density lipoproteins

A

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

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7
Q

Low-Density lipoproteins

A

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

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8
Q

High-Density lipoprotein

A

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

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9
Q

Lipid metabolism

A

Triacylglycerols contain fatty acids attached to a glycerol backbone
Fatty acids are broken down into acetyl-CoA, which feeds into the citric acid cycle

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10
Q

Triacylglycerol synthesis

A
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
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11
Q

Glycerol kinase

A

In liver

Phosphorylates glycerol to glycerol-3-phosphate

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12
Q

Glyceroneogenesis

A

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

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13
Q

Acyl CoA synthetase

A

Source for fatty acyl-CoA

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14
Q

Glycerol-3-phosphate

A

Precursor for TG and glycerophospholipids

Derived form glycolysis, or DHAP reduced during glycerneogenesis, or synthesized form glycerol

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15
Q

Mitochondrial dehydrogenase

A

Reduces DHAP to glycerol-3-phosphate

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16
Q

Fatty acid activation

A

Binding of fatty acids to CoA

Fatty acid + Co-ASH + ATP = Fatty acyl-CoA + AMP + ppi

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17
Q

Lipoprotein lipase

A

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

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18
Q

Adipocyte

A

Adipose tissue
Takes up fatty acids
Activates with CoA
Fatty actyl-CoA are esterified with glycerol-3-phosphate to give triacylglycerides

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19
Q

Hydrolysis of triacylglycerols in adipose tissue

A

When body requires energy

Fatty acids and glycerol are secreted into the bloodstream

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20
Q

Adipose triglyceride lipase (ATGL)

A

Catalyses lipolysis when energy stores are mobilized
Fatty acids excreted and bound to albumin, sent to muscle and liver
Glycerol sent to liver

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21
Q

Hormone sensitive lipase

A

Catalyses lipolysis when energy stores are mobilized
Fatty acids excreted and bound to albumin, sent to muscle and liver
Glycerol sent to liver

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22
Q

Glycerol

A

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

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23
Q

Glycerol-3-phosphate

A

Processed by glycerol-3-phosphate dehydrogenase to dihydroxyacetone phosphate: this can be used in glycolysis or gluconeogenesis

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24
Q

Fatty acid oxidation

A

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

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25
Step 1 of fatty acid oxidation: activation
Activated in cytosol through conjugation to CoA: CoASH | ATP hydrolyzed to AMP and pyrophosphate ppi
26
Step 2: import into mitochondria
Fatty acyl groups are transferred via carnitine | Carnitine deficiency slows down/prevents fatty acid oxidation
27
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
28
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
29
Beta oxidation: hydration
Hydrates catalyzes the addition of water to the double bond | Hydroxy group formed
30
Beta oxidation: second oxidation
Hydroxygroup oxidized to ketogroup Electrons are transferred to NAD forming NADH Catalyzed by a dehydrogenase
31
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
32
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
33
Adrenoleukodystrophy
Genetic defects in peroxisomal transports leads to build up of very long chain fatty acids
34
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
35
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
36
Vitamin B12 deficiency
Neurological damage because of accumulation of odd-chain fatty acids in neuronal membranes
37
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
38
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
39
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
40
Malonyl CoA
Inhibits carnitine palmitoyltransferase: import of fatty acids into mitochondria for oxidation
41
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
42
Acyl carrier protein
Fatty acid synthase | Binds and activates acyl groups similar to CoA
43
Step 3 of fatty acid synthesis: elongation
Intermediates attach to carrier protein | Two carbons at a time
44
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
45
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
46
delta4-desaturase
Double bond at 4 carbons from carboxyl group
47
delta5-desaturase
Double bond at 5 carbons from carboxygroup
48
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
49
Inhibition of fatty acid metabolism
From malonyl-CoA: to carinitine | From fatty acid: to acetyl-CoA carboxylase
50
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
51
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
52
Cholesterol synthesis
Synthesized from acetyl CoA Requires NADPH and ATP Dietary uptake and endogenous synthesis are balanced
53
HMG CoA reductaste
Target of cholesterol-lowering drugs, statins | Convers HMG CoA to mevalonate
54
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
55
Endocytosis of lipoproteins
Mediated by specific receptors that recognize the apolipoprotein
56
LDL receptor
Located in all cells Recognize ApoB, ApoE of LDL and VLDL remnants Without protein part, lipoproteins are not taken up
57
Efflux of cholesterol
Can be transferred to HDL to reduce cellular cholesterol content Mediated by transmembrane protein ABCA1
58
Cardiovascular Risk
Positive correlation with serum LDL, LDL/HDL ratio and serum cholesterol with cardiovascular risk Negative correlation with serum HDL
59
Nile red
Stains fat lesions red | High fat, high cholesterol diet leads to increase lesion area and occlusion of arterial lumen
60
Chronic endothelial injury
``` Hyperlipidemia Hypertension Hyperinsulinemia Skiing Hemodynamic factors Toxins Viruses Immune reactions ```
61
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
62
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
63
Plaque rupture
``` Cell death: formation of necrotic core Calcium deposition Cholesterol crystal formation Plaque instability Plaque rupture ```
64
Lecithin-acyl CoA transferase (LCAT)
Activated by ApoA1 Esterifies cholesterol to cholesterol ester Cholesterol ester forms hydrophobic core