Lectures 25/26: Lipid Metabolism Flashcards Preview

Biochemistry 2300 > Lectures 25/26: Lipid Metabolism > Flashcards

Flashcards in Lectures 25/26: Lipid Metabolism Deck (64):
1

Atherosclerosis

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

2

Lipoprotein particles

Water-insoluble fat is packaged into soluble lipoproteins

3

Amphipathic

Phospholipid, cholesterol, apolipoproteins

4

Hydrophobic

Triacylglycerols
Cholesteryl esters

5

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

6

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

7

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

8

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

9

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

10

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

11

Glycerol kinase

In liver
Phosphorylates glycerol to glycerol-3-phosphate

12

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

13

Acyl CoA synthetase

Source for fatty acyl-CoA

14

Glycerol-3-phosphate

Precursor for TG and glycerophospholipids
Derived form glycolysis, or DHAP reduced during glycerneogenesis, or synthesized form glycerol

15

Mitochondrial dehydrogenase

Reduces DHAP to glycerol-3-phosphate

16

Fatty acid activation

Binding of fatty acids to CoA
Fatty acid + Co-ASH + ATP = Fatty acyl-CoA + AMP + ppi

17

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

18

Adipocyte

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

19

Hydrolysis of triacylglycerols in adipose tissue

When body requires energy
Fatty acids and glycerol are secreted into the bloodstream

20

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

21

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

22

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

23

Glycerol-3-phosphate

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

24

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

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