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Year One: First Things First > Lipid Synthesis and Degradation > Flashcards

Lipid Synthesis and Degradation Flashcards

1
Q

Recall the types of lipids(6)

A

• fatty acids • glycolipids • glycerophospholipids • sphingolipids • triglycerides • cholesterol

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2
Q

Why is fat important?(5)

A
  • Fats are synthesised and stored when our calorific intake exceeds the immediate needs of the body
  • The energy content of fat per gram is over twice that of either carbohydrate or protein
  • Not all fats are stored as they are also the preferred energy source for cardiac muscle

A role in memebranes

precurssors of steroid hormones

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3
Q

How are faty acids stored?

A

stored by adipocytes

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4
Q

What are the requirements for FA synthesis?(3)

A
  • Acetyl-CoA
  • NADPH
  • ATP
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5
Q

Describe the transfer of ACetyl CoA to the cytosol(4)

A
  1. Acetyl CoA reacts with oxaloacetate to give citrate.
  2. Citrate is transported to the cytosol and Acetyl CoA is regenerated along with the oxaloacetate
  3. Oxaloacetate combines with NADH and coverts to malate and then to pyruvate forming NADH- additional NADPH is provided by the pentose phosphate pathway
  4. Pyruvate is then back inside mitochondria

This is done to transport acetyl Coa outside of mitochondrion as it can’t pass through the membrane

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6
Q

How is the NADPH required for Acetyl CoA transfer to the cytosol provided?(2)

A

• Citrate malate shuttle provides 40% NADPH needed for fatty acid synthesis 2

. 60% comes from the pentose phosphate pathway

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7
Q

Describe the process of fatty acid synthesis(6)

A
  1. Acetyl-CoA(C2) reacts with ATP and carbonate to produce malonyl CoA(C3) +ADP+ Pi.

Catalysed by acetyl-CoA carboxylase and is activated by citrate (positive feedback). Irreversible step. Inhibited by palmitic acid (negative feedback as end product). Requires the vitamin biotin.

  1. Malonyl-CoA(C3) binds to and is activated by Acyl carrier protein (ACP-).
  2. Malonyl-ACP(C3) reacts with Acetyl-CoA(C2), produced by another acetyl-CoA molecule which reacted with an ACP, in a condensation reaction to produce acetoacyl-ACP(C4). C02 is released.

5 . Acetoactyl-ACP undergoes a series of reactions to produce butyryl-ACP, which reacts with another malonyl-ACP in a condensation reaction, to produce a 6-carbon molecule.

  1. Process of elongation by 2 carbon molecules at a time.
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8
Q

How is glucagon involved in fatty acid synthesis?(2)

A

Glucagon stimulates phosphorylation

  1. Acetyl-CoA carboxylase is inhibited by phosphorylation
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9
Q

Describe fatty acid synthase(4)

A
  • The protein responsible for fatty acid synthesis is called fatty acid synthase
  • Intermediates are covalently linked to acyl carrier protein (ACP)
  • This enables the efficient and rapid movement of the growing fatty acid chain to be passed from one active site to the next.
  • The efficiency of the reaction is further enhanced as the enzyme exists as a dimer arranged head to tail so as the growing acid chain is passed from one dimer to another, the reaction be regulated.
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10
Q

What is the structure of cholesterol and how is transported, where is it synthesised?(4)

A
  • Rigid hydrophobic molecule virtually insoluble in water
  • Precursor of sterols, steroids, and bile salts
  • Transported in the circulation as cholesteryl esters
  • Cholesterol is synthesised mostly in the ER
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11
Q

Summarise the synthesis of cholesterol(5)

A
  • Over 30 steps are involved in the ER
  • Starts with the activation of acetate, acetyl-CoA
  • Major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate
  • Cholesterol inhibits HMGCoA reductase the enzyme involved in its own synthesis
  1. difficult to remove circulating cholesterol by diet alone as endogenous synthesis is increased.
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12
Q

What molecules stimulate/inhibit fatty acid degradation and when does it take place?(3)

A
  1. Stimulated by glucagon, adrenalin, and noradrenalin
  2. Takes place in fasting state when glucose levels are low and/or when demand for ATP is high
  3. Inhibited by insulin
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13
Q

Summarise the three steps in fatty acid degradation and their locations

A
  • Step 1 Mobilisation - adipocyte
  • Step 2 Activation – liver cytosol
  • Step 3 Degradation – liver mitochondria
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14
Q

Describe the mobilisation process of FA degradation(6)

A
  1. Adipocyte is activated by glucagon and adrenalin through 2 transmembrane domain receptors- G-coupled.
  2. Increase in cyclic AMP and activates protein kinase A
  3. Protein kinase a phosphorylates the triacylglycerol lipase
  4. Triacylglycerol lipases break down triglycerides into diacylglycerol,
  5. Following activity of lipases lead to fatty acids Glycerol absorbed by liver and undergoes glycolysis or gluconeogenesis (majority
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15
Q

how are fatty acids activated so they can cross the membrane?(5)

A
  1. Fatty acids are transported to the liver and activated by acyl-CoA synthase in the cytoplasm.
  2. Acyl-CoA is produced and is transported across the inner mitochondrial membrane bound to alcohol carnitine.
  3. Reacts with carnitine to produce CoA and acyl carnitine, which is transported across membrane through translocase.
  4. Acyl carnitine reacts with CoA to resynthesise Acyl CoA and carnitine in the mitochondria.
  5. Transport is inhibited by malonyl-CoA- the molecules that is formed during fatty acid synthesis
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16
Q

What can result from carnitine deficiency?

A

• muscle weakness or even death

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17
Q

Describe b-oxidation/ fatty acid oxidation(6)

A
  • Acyl-CoA degraded by sequential removal of two carbon units
  • As a result FADH2, NADH (used by cells to produce ATP) and acetyl-CoA are produced
  • Cyclic until fatty acid chain has been broken down
  • Odd chain length yield propionyl-CoA in the last round of oxidation
  • Propionyl-CoA is converted to oxaloacetate and used for gluconeogenesis
  • Odd numbered double bonds are removed by isomerase and even double bonds by reductase and isomerase
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18
Q

Compare FA synthesis and Degredation

A

Synthesis

Cytosol

  • Intermediates linked to acyl-carrier protein
  • Sequential addition 2C
  • Reductant NADPH
  • Fatty acid synthase enzyme complex

Degradation

Mitochondria

Intermediates linked to coenzyme A

  • Sequential removal 2C
  • Oxidants FAD and NAD
  • Carried out by individual enzymes
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19
Q

What happens to the Acetyl CoA produced by b-oxidation?

A

· funnelled to production of ketone bodies

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20
Q

What are some situtations that stimulate FA breakdown?(3)

A

Fasting, uncontrolled diabetes and prolonged exercise

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21
Q

Name the ketone bodies(3)

A

acetoacetate, 3-β-hydroxybutyrate and acetone

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22
Q

Describe the process of ketogenesis(4)

A
  1. Majority of acetyl-CoA from breakdown of fatty acids is converted to acetoacetyl-CoA
  2. Acetoacetyl-CoA is converted to HMG-CoA by HMG-CoA synthase
  3. Converted to acetoacetate which can be reduced further to ketone bodies (acetone) non- enzymatically. Acetyl CoA is lost
  4. Acetoacetate is then broken down into acetone and 3-b-hydroxybutyrate. NAD is made from NADH
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23
Q

What is the fate of ketone body- 3-bhydroxybutyrate?(4)

A

It is converted into acetoacetate using NAD+

  1. Acetoacetate is converted into acetetoacetyl CoA
  2. This is then broken down into 2 acetyl CoA
  3. Preferentially used by cardiac muscle and renal cortex Used by the brain during starvation
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24
Q

What is the fate of glycerol?(2)

A
  1. In the liver glycerol is used to synthesis glucose by gluconeogenesis
  2. In the muscle glycerol is used in glycolysis and oxidative phosphorylation to produce ATP
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25
Q

Describe the transport of lipids in three pathways

A

· The exogenous pathway transports lipid from the gut to the liver

· The endogenous pathway transports lipids synthesised by the liver to non-hepatic tissue including adipocytes

· Third pathway takes lipid from the circulation and from non-hepatic tissue back to the liver

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26
Q

Describe the proportion of lipids in circulation(4)

A

· Triglycerides (45%)

· Phospholipids (35%)

· Cholesterol esters Cholesterol (15%)

Free Fatty Acids (5%)

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27
Q

What is the role of fatty acids in metabolism?(4)

A
  1. particularly polyunsaturated FA are ligands for transcription factors involved in energy metabolism
  2. they play a role in the regulation of insulin metabolism
  3. They up regulate lipid oxidation in the liver and muscle and down regulate genes involved in lipogenesis in the liver and adipose tissue.
  4. increase expression of UCP-2 and 3 in mitochondria to increase thermogenesis
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28
Q

How do fatty acids enter cells?

A

By diffusion

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29
Q

How are free fatty acids formed?

A

From triglycerides in adipose tissue

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30
Q

How do FA circulate the around?

A

· Circulates bound to protein as Na+ salt particularly albumin as unbound FA would act as a detergent.

31
Q

Recall the five types of lipoproteins

A

– Chylomicrons

– Very low-density lipoproteins (VLDL)

– Intermediate density lipoprotein (IDL)

– Low density lipoproteins (LDL)

– High density lipoproteins (HDL)

32
Q

Describe the structure of lipoproteins(4)

A
  1. Apolipoproteins are some of the largest proteins found in the body.
  2. There are also other lipids eg phospholipids that form a single layer.
  3. Hydrophilic points toward the blood and hydrophobic points toward the hydrophobic core.
  4. The core consist of triglycerides and cholesterol esters.
33
Q

What are the functions of apoproteins?(4)

A
  1. structural
  2. to solubilise lipids
  3. act as enzymes or enzyme cofactors
  4. tissue targeting
34
Q

Which apoproteins act as enzymes or enzyme cofactors?(2)

A

APO C2 activates lipoprotein lipase (LPL, breaks down fat in the form of triglycerides, so a lipoprotein expressing this apoprotein will lose its triglycerides)

→ APO A1 activates Lecithin-Cholesterol AcylTransferase (LCAT, converts free cholesterol into cholesteryl esters)

35
Q

Which apoproteins are involved in tissue targetting?(2)

A
  • Apo B100 and Apo E bind to the LDL receptor
  • Apo E binds to the HDL receptor
36
Q

How do dietary lipids enter cells?

A

They enter the cell and reform as triglycerides

37
Q

What happens to triglycerides after they enter the cell?(4)

A
  1. These triglycerides along with other lipids form chylomicrons.
  2. These chylomicrons contain APOB48.
  3. The nascent chylomicrons will then be secreted by reverse pinocytosis into the lymphatic system.
  4. The lymphatic ducts allow it to be distributed to non-hepatic tissue before it passes to the liver
38
Q

Describe chylomicron synthesis(4)

A

→ formed in the cells that line the gut.

→In the lumen of the gut, triglycerides are broken down to fatty acids.

→the triglycerides and monoacylglycerols are brought into the mucosal cell and reformed into triacylglycerides.

→They then combine with other lipids and proteins in the cell to form chylomicrons.

39
Q

Describe the structure of chylomicrons(4)

A
  • Low density due to high TG
  • Km of lipoprotein lipase is greater in adipocytes than muscle, so will only be active when concentration of lipids in the circulation is very high (cell requirements fulfilled).

o vitamins A and Eo

Life time in the circulation of 1h (TG part of the chylomicrons last 5mins as a result of the work by LPL)

40
Q

Recall the different types of hyperlipidaemia(3)

A
  • Type 1: Deficiency in lipoprotein lipase or Apo C2 – characterised by high plasma triglyceride
  • Type 2: Characterised by high LDL – most are caused by a genetic defect in the synthesis, processing or function of the LDL receptor
  • Type 4: Most common form results in raised VLDL concentrations often due to obesity or alcohol abuse
41
Q

Describe the structure of VLDLs(2)

A
  • Triglycerides formed are packaged with FFA, phospholipids and cholesterol esters and Apo B100 to form nascent VLDL
  • Nascent VLDLs receive ApoE and ApoCII from HDL
42
Q

When and how does VLDL occur?

A

• Synthesised in the liver ER and golgi released with B100 then acquire Apo E and C from HDL

43
Q

What is the proportion of VLDLs removed by the liver and adrenal?(2)

A

• 60% 0f VLDL remnants are removed by the liver 40% removed by adrenal and gonadal tissue and the cholesterol is used for hormone

44
Q

How is formation of chylomicrons enhacned(4)

A

o dietary carbohydrate

o circulating FFA

o alcohol

o raised insulin and decreased glucagon

45
Q

What are the fate of VLDLs?(6)

A
  1. The ApoC2 interacts and activates the LPL. The TG will then be broken down into FA and glycerol. Enter the cell
  2. If the cell is adipocyte then the glycerol and fatty acids will be converted back into TG and stored
  3. If cell is muscle, then the free fatty acids will be converted into ATP and H2O is produced- beta oxidation
  4. The VLDL continues circulation. The loss of the TG creates the IDL(intermediate density lipoprotein).
  5. Some of the IDL will be passed onto the liver- 60% through the removal of interaction with ApoE and its receptor.
  6. Some will interact with HDL and the HDL will take back ApoE and the ApoC2 for future donation. Resultant lipoprotein is LDL which contains ApoB100
46
Q

What are LDLs?(4)

A
  • Are the major carrier of cholesterol
  • Metabolised slowly - 3 days- oxidation
  • Carry cholesterol to the periphery and regulate de novo synthesis of cholesterol by that tissue
  • Contain 1 ApoB100 which can bind to a specific receptor on hepatocytes
47
Q

What are the three ways HDLs can be created?

A
  1. As nascent particles by the liver and intestine
  2. Budding of apolipoproteins from chylomicrons
  3. From free ApoAI
48
Q

how do HDLs remove cholesterol from circulation?(3)

A

→they contain an enzyme called Lecithin-Cholesterol AcylTransferase (LCAT)

→ LCAT modifies free cholesterol and then retains it within the HDL.

→This prevents the cholesterol from diffusing out of the HDL.

49
Q

How are LDLs removed from circulation?(3)

A
  1. LDL receptors on cells are in pit-like structures and LDL binds to the receptor in the pit and endocytosis occurs.
  2. LDL and receptor dissociate, and receptor is sequestered into vesicles which remain in cytosol and, ultimately, returned to cell membrane.
  3. Endosome containing LDL fuse with lysosome containing hydrolytic enzyme which breaks down proteins into constituent amino acids and used to create new proteins.
50
Q

What happens to the cholesterol delivered to lysosomes?

A
  1. Cholesterol is de-esterified

The cholesterol esters are converted to cholesterol
→which diffuse out into the cytoplasm
→where they are immediately esterified
→(since free cholesterol is not desirable within a cell, unless associated with a membrane).

→The triglycerides will be broken down to give fatty acids, which can be further metabolised, and amino acids will also be broken down.

Process is regulated by concentration of cholesterol within the cell. Cholesterol regulates its own uptake and synthesis.

51
Q

What process occurs when intracellular cholesterol is low/high?

A
  1. Increased intracellular cholesterol inhibits HMG-CoA reductase activity, reducing endogenous synthesis of cholesterol 2. Decreased intracellular cholesterol increases LDL receptor expression, allowing for increased uptake of LDL by cell.
52
Q

How does statin regulate cholesterol levels?(2)

A

Statins inhibit HMGCoA reductase and therefore decrease cholesterol synthesis within cells

  1. this will result in an increase in the synthesis and expression of the LDL receptor at the cell surface and so increase LDL-cholesterol uptake
53
Q

Describe scavenger receptors(3)

A
  1. Unregulated and found on endothelial cells, vascular smooth muscle cells and macrophages.
  2. Very high blood cholesterol causes macrophages in vessel wall to take up cholesterol, forming a foam cell
  3. Low affinity for lipoproteins so active when circulating concentration of LDLs is high or oxidised
54
Q

How are lipoproteins regulated?(3)

A
  • Hormonal regulation- insulin, cortisol, thyroid hormones.
  • Nutritional status- decreased synthesis during fasting/increased by dietary fats(unsaturated).
  1. LDL expression- oestrogen
55
Q

What is Familial Hypercholesterolemia (FH)?(4)

A
  1. Single substitution
  2. Develop blocked arteries (atherosclerosis)
  3. Die young from heart attacks
  4. De novo synthesis is not regulated by LDL
56
Q

How does diabetes arise as result of lipid transport diabetes mellitus?(2)

A
  • increased FFA mobilisation
  • decreased Chylomicron and VLDL utilisation
57
Q

how does insulin regulate fat metabolism?

A

→increases glycolysis in the liver
→increases fatty acid synthesis in the liver
→ increases TG in adipose tissue
→ decreases β-oxidation

58
Q

how do glucagon and adrenaline regulate fat metabolism?

A

→increase TG mobilization

59
Q

Why are FFA transported into the Inner Mitochondrial Matrix?

A

The enzymes that break down fatty acids are present in the Inner Mitochondrial Matrix.

60
Q

What inhibits fatty acid transport into the Inner Mitochondrial Matrix and how?

A

→The transport is also inhibited by malonyl-CoA, which is a step in the synthesis of fatty acids.

→ if it builds up, we will be moving towards synthesis, meaning this degradation transport process is inhibited.

61
Q

How are the intermediates linked in Fatty Acid Synthesis?

A

→the intermediates in this reaction are covalently linked to ACP.

62
Q

How does Palmitate get generated from Fatty Acid Synthesis?

A

→Each cycle leads to the sequential addition of 2 carbons.
→So 6 cycles needed to generate 16C Palmitate Fatty Acid.

63
Q

how many ATP molecules are produced from the oxidation of palmitate?

A

106 ATP

64
Q

why does fatty acid oxidation occur in the liver?

A

→In the liver, the main production of fatty acid oxidation is for generation of Acetyl-CoA which can be fed into citric acid cycle to generate energy,

→ACoA tends to be converted to ketone bodies.

65
Q

what does fatty acid oxidation produce?

A

→This produces FADH2, NADH and Acetyl-CoA. The FADH2 and NADH form ATP.

→The Acetyl-CoA ( from β-oxidation) will enter the citric acid cycle, but only in the presence of glycolysis.

66
Q

what happens to the glycerol mobilized in Fatty Acid Mobilisation?

A

→absorbed by the liver.

→1) Glycerol is phosphorylated to Glycerol-3-Phosphate.

→2) Glycerol-3-Phosphate is oxidised by Dihydroxyacetone Phosphate.

→3) Dihydroxyacetone Phosphate is isomerised to Glyceraldehyde-3-Phosphate (GAP).

→The majority of GAP goes towards GLUCONEOGENESIS, and a bit of it goes towards GLYCOLYSIS.

67
Q

what are the apoproteins involved in the composition of the different lipoproteins?

A

→CHYLOMICRONS: B48, APO C2, C3 and E

→VLDL: B100, APO C1, C2, C3 and E

→ LDL: B100

→ IDL: B100, APO E

→HDL: APO A1, A2, C1, C3, D and E

68
Q

how and why are chylomicrons delivered directly to the lymph system?

A

→Chylomicrons are secreted into the lymphatics which carries them via the thoracic duct to the superior vena cava.

→By this pathway, dietary fats avoid the direct delivery to the liver and instead are made available to the extrahepatic tissue.

69
Q

where are digested proteins and carbohydrates delivered?

A

digested proteins and carbohydrates are released into the portal vein and delivered directly to the liver.

70
Q

how does a nascent chylomicron become a mature chylomicron (in terms of apoproteins)?

A

→when first formed, the only apoprotein chylomicrons consist of are the ApoB48.

→as it circulates, it interacts with HDL and the HDL donates certain apoproteins to the nascent chylomicron, primarily Apo C2 and Apo E.

→this forms a mature chylomicron.

→this donation occurs in the SER.

71
Q

what are chylomicrons for and how are they removed?

A

→they’re important for transporting exogenous (dietary) lipids from gut around the circulation

→ they reflect meal composition (if a fatty meal is ingested, there will be many chylomicrons of that composition)

→ their remnants are removed by the liver, with the help of Apo E

72
Q

how does lipoprotein lipase work?

A

Lipoprotein Lipases levels vary with the tissue, found in cells that utilise a lot of fats.

73
Q

how does HDL pick up cholesterol?(3)

A

→the process by which it picks up cholesterol is known as Reverse Cholesterol Transport.

→this occurs in the plasma and on endothelial cells.

→ to signal this, they express the ABCA1 transporter, which moves cholesterol from the extracellular surface of the membrane and interacts with the Apo A1 on the HDLs to transport the cholesterol away.

Year One: First Things First (27 decks)

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