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MEH > Lipids > Flashcards

Lipids Flashcards

1
Q

How can lipids be classified?

A

Fatty Acid Derivatives:

  • fatty acids
  • triacyclglycerols (fuel storage and insulation)
  • phospholipids (components of membranes and plasma lipoproteins)
  • Eicosanoid ( local mediators)

Hydroxy-methyl-glutaric acid derivatives (C6 compound):

  • ketone bodies (C4, water soluble fuel molecules)
  • cholesterol (C27, membranes and steroid hormone synthesis)
  • cholesterol esters (cholesterol storage)
  • bile acids and salts (C24, lipid digestion)

Vitamins:

  • A
  • D
  • E
  • K

All fat-soluble

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2
Q

How are dietary triacylglycerols processed by the body?

A
  • hydrolysed by pancreatic lipase in the small intestine to release glycerol and fatty acids. (bile salts and cofactor protein colipase required)
  • recombination of fatty acids and glycerol into TAG’s in small intestine
  • In intestinal epithelial cell, TAG’s synthesised into chylomicrons
  • chylomicrons travel via lymphatic system
  • can be released into blood where they can enter tissues for fatty acid oxidation or into adipocytes for storage
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3
Q

How are triacylglycerols stored?

A
  • In adipocytes
  • TAGs are hydrophobic and therefore stored in an anhydrous form in adipose tissue

utilised in prolonged exercise, starvation, during pregnancy.

mobilisation under hormonal control

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4
Q

List the three ketone bodies

A
  • Acetoacetate
  • Acetone
  • b-Hydroxybutyrate
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5
Q

Describe the synthesis of ketone bodies

A
  • synthesised by liver mitochondria from acetyl-coA
  • Acetoacetate formed from acetyl-coA via HMG-CoA lyase
  • Acetone formed from Acetoacetate by spontaneous decarboxylation
  • b-hydroxybutyrate formed from acetoacetate

When the insulin/glucagon ratio is high, i.e. fed state:

  • HMG-CoA lyase is inhibited
  • HMG-CoA reductase stimulated and cholesterol synthesised
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6
Q

Describe the clinical relevance of ketone body concentration in the blood

A

Normal plasma ketone body concentration is under 1 mM
Starvation 2-10 mM (physiological ketosis)
Untreated Type 1 diabetes > 10mM (pathological ketosis)

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7
Q

Explain the process of beta oxidation of fatty acids

A
  • sequence of reactions that oxidises the fatty acid and removes the C2 unit (acetate) until only two carbons remain.
  • requires mitochondrial NAD+, FAD, oxygen (required for stage 4 (oxidative phosphorylation/ET) of catabolism to re-oxidise the NADH and FAD2H formed)
  • no direct synthesis of ATP by the pathway.
  • all the intermediates linked to coenzyme A
  • C-atoms of the fatty acid are converted to acetyl~CoA
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8
Q

Explain the process of lipogenesis

A
  • occurs mainly in liver
    1) glucose converted into pyruvate in cytoplasm
    2) pyruvate enters mitochondria and forms acetyl-CoA and Oxaloacetate
    3) They condense to form citrate
    4) Citrate moves into cytoplasm and cleaved back to Acetyl-CoA and Oxaloacetate
    5) Acetyl-CoA carboxylase produces Malonyl-Coa from acetyl-CoA
    6) Fatty acid synthase complex builds fatty acids by sequential addition of 2 carbon units provided by malonyl-CoA
  • NADPH from pentose phosphate pathway provides reducing power for building up the fatty acids
  • ATP regulated.
  • Key regulator is Acetyl-CoA carboxylase; insulin stimulates and glucagon inhibits (covalent dephospho rylation)
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9
Q

What is the structure of phospholipids?

A
  • Polar head (hydrophilic)
  • linked to a phosphate
  • which is linked to glycerol
  • with two fatty acid tails (hydrophobic)
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10
Q

Describe the structure of lipoproteins

A
  • Phospholipid monolayer with small amount of cholesterol
  • Peripheral apolioproteins (e.g apoC, apoE)
  • Integral apolioproteins (e.g apoA, apoB)
  • Cargo consisting of triacylglycerol, cholesterol esters, fat soluble vitamins
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11
Q

What are apolioproteins?

A
  • Each class of lipoprotein particle has a particular complement of associated proteins (apolioproteins)
  • Six major classes (A, B, C, D, E and H)
  • apoB (VLDL, IDL and LDL) and apoAI (HDL) important
  • peripheral; c and e
  • integral; a and b

They have two roles:

Structural- Packaging water insoluble lipid

Functional- cofactor for enzymes, ligands for cell surface receptors

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12
Q

What are the classes of lipoprotein?

A

From least to most dense:

  • chylomicrons
  • VLDL’s
  • IDL’s
  • LDL’s
  • HDL’s
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13
Q

What are hyperlipoproteinaemias?

A

Raised plasma level of one or more lipoprotein classes. Caused by either:

1) overproduction
2) underremoval

6 main classes

Defects in:

Enzymes
Receptors
Apoproteins

see notes

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14
Q

What is an adipocyte?

A
  • Large lipid droplet (mainly TAG and cholesterol ester)
  • Cytoplasm and organelles pushed to edge
  • Typical adipocyte is around 0.1mm in diameter however cells expand as more fat added
  • Average adult has around 30 billion fat cells weighing 15kg
  • Can increase in size about fourfold on weight gain before dividing and increasing total number of fat cells
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15
Q

Discuss the importance of cholesterol in the body

A
  • Some cholesterol obtained from diet but most is synthesised in liver
  • Essential component of mebranes (Modulates fluidity)
  • Precursor of steroid hormones: cortisol, aldosterone, testosterone, oestrogen

-Precursor of bile acids
Transported around body as cholesterol ester

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16
Q

Describe chylomicron metabolism

A
  • Chylomicrons loaded in small intestine and apoB-48 added before entering the lymphatic system
  • Travels to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood
  • apoC binds to lipoprotein lipase (LPL) on adipocytes and muscle. Released fatty acids enter cells depleting chylomicron of its fat content.
  • When triglyceride reduced to around 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
  • Chylomicron remnants return to liver. LDL receptor on hepatocytes binds remnant (via receptor mediated endocytosis). Lysosomes release remaining contents for use in metabolism
17
Q

Describe VLDL metabolism

A
  • VLDL made in liver for purpose of transporting triacylglycerols (TAG’s) to other tissues
  • Apolioprotein apoB100 added during formation and apoC and apoE added from HDL particles in blood
  • VLDL binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose and starts to become depleted of triaglycerol
  • In muscle the released fatty acids are taken up and used for energy production
  • In adipose the fatty acids are used for re-synthesis of triacyclglycerol and stored as fat
18
Q

Describe IDL metabolism

A
  • As triacylglycerol content of VLDL particles drops some, VLDL particles dissociates from the LPL enzyme complex and return to liver
  • If VLDL content depletes to around 30%, the particle becomes a short lived IDL particle
  • IDL particles can also be taken up by liver or rebind to LPL enzyme to further deplete in TAG content
  • Upon depletion to around 10%, IDL loses apoC and apoE and becomes an LDL particle (high cholesterol content)
19
Q

What are the functions of LDL’s?

A

-Primary function of LDL is to provide cholesterol from liver to peripheral tissues.

20
Q

Describe how LDL’s enter cells

A

-Receptor mediated endocytosis
-Cells requiring cholesterol express LDL receptors on plasma membrane
-apoB-100 on LDL acts as a ligand for these receptors
Receptor/LDL complex taken into cell by endocytosis into endosomes
-Fuse with lysosomes for digestion to release cholesterol and fatty acids
-LDL-Receptor expression controlled by cholesterol concentration in cell

21
Q

Describe the synthesis of HDL’s

A
  • Nascent HDL synthesised by liver and intestine (low triaglyceride levels)
  • HDL particles can also “bud off” from chylomicrons and VLDL as they are digested by LPL
  • Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL.
22
Q

Describe HDL’s functions

A
  • Reverse Cholesterol Transport from cholesterol-laden cells and return it to liver
  • reduces likelihood of foam cell and atherosclerotic plaque formation
  • ABCA1 protein within cell facilitates transfer of cholesterol to HDL. Cholesterol then converted to cholesterol ester by LCAT.
  • HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
23
Q

What are the clinical signs of hypercholesterolaemia?

A

Xanthelasma- Yellow patches on eyelids

Tendon Xanthoma- Nodules on tendon

Corneal Arcus- Obvious white circles around eye. Common in older people but a sign of hypercholesterolaemia in the young.

24
Q

Describe how raised levels of LDL’s can cause atherosclerosis

A

1) Oxidised LDL’s recognised and engulfed by macrophages
2) Lipid laden macrophages called foam cells accumulate in intima of blood vessel walls to form a fatty streak
3) Fatty streaks can evolve into atherosclerotic plaque which grows and encroaches on lumen of artery (angina)
4) Rupture triggers acute thrombosis by activating platelets and clotting cascade

25
Q

What is the mechanism of action of statins?

A

by inhibiting HMG-CoA reductase e.g. Atorvastin

-HMG-CoA required to form mevalonate, a key intermediate in forming cholesterol

26
Q

Describe the process of lipolysis

A

-Occurs in adipose tissue.

  • Triacylglycerol acted on by lipases to release glycerol and free fatty acids into the blood.
  • The glycerol travels to liver to be used as a carbon source for gluconeogenesis. The free fatty acids are complexed with albumin, travel to muscle and other tissues for beta oxidation.
27
Q

How are hyperlipoproteinaemias treated?

A

First approach:

Diet: reduce cholesterol and saturated lipids in diet. Increase fibre intake

Lifestyle: increase exercise, stop smoking to reduce cardiovascular risk

If no response:

  • Statins: Reduce cholesterol synthesis
  • Bile salt Sequestrants: Bind bile salts in GI tract. Forces liver to produce more bile acids utilising more cholesterol
28
Q

Explain the use of the the carnitine transport system in transporting fatty acids into the mitochondrial matrix

A

1) Fatty acid is activated by linking to coenzyme A (via high energy bond by the action of fatty acyl CoA synthase, from via B5) outside the mitochondrion, in cytoplasm.
2) Fatty Acyl-CoA binds to carnitine shuttle to form Acyl Carnitine. CAT1 catalyses this binding
3) Acyl-Carnitine moves into matrix. Here, reverse reaction occurs and Carnitine and Fatty Acyl-CoA released from Acyl Carnitine. CAT2 catalyses this reaction

CAT1 and CAT2 are Carnitine Acyltransferases

Malonyl-CoA regulates CAT1 via allosteric regulation

29
Q

How are lipids transported in the blood?

A
  • hydrophobic molecules, problem for transport in the blood.
  • transported in the blood bound to carriers:
  • 2% of lipids (mostly fatty acids) are carried bound to albumin but this has a limited capacity ( around 3mmol/L)
  • 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins and triglycerides
30
Q

What is LCAT?

A

Lecithin cholesterol acyltransferase catalyzes the formation of cholesterol esters in lipoproteins (esterifies with fatty acid)

31
Q

Describe the maturation of HDL particles

A
  • Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels
  • Hollow core progressively fills and particle takes on more globular shape
  • Transfer of lipids to HDL does not require enzyme activity
32
Q

How are mature HDL’s taken up by the liver?

A
  • Mature HDL taken up by liver via specific receptors
  • Cells requiring additional cholesterol (e.g. for steroid hormone synthesis) can also utilise scavenger receptor (SR-B1) to obtain cholesterol from HDL
33
Q

Describe the effect of different hormones on the lipase involved in lipolysis

A

The lipases are hormone sensitive:

  • Glucagon and Adrenaline leads to phosphorylation and activation of the lipase
  • Insulin leads to dephosphorylation and inhibition of the lipase
34
Q

Why aren’t LDL’s efficiently cleared by the liver?

A

-Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (liver LDL receptor has a high affinity for apoE)

35
Q

How is glycerol metabolised once it is in the liver?

A

Glycerol kinase (ATP to ADP) converts glycerol to glycerol phosphate.

Glycerol phosphate can be used in TAG synthesis or go into glycolysis (via conversion into DHAP).

36
Q

Why is the synthesis of ketones important in the body?

A

Spares glucose in early-late starvation (brain needs circulating glucose). In late starvation, muscle breaks down so amino acids are released and gluconeogenesis can occur in the liver.

Other tissues can mobilises fatty acids.

MEH (19 decks)

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