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BIOM30001 > lecture 7: lipid control in health and disease > Flashcards

lecture 7: lipid control in health and disease Flashcards

To be able to describe and understand: - the general features and roles of the different classes of lipoprotein - lipid transport - the factors that affect blood levels of cholesteryl esters and trialglycerols -hypercholesterolaemia and hypertriglyceridaemia and some of the causes - a current model of how atherosclerosis develops

1
Q

What are classes of plasma lipoproteins?

A
  • with one exception, the lipoprotein classes were named according to where they band in an equilbrium density gradient centrifugation
  • increasing density – more protein and less lipid
  • lipoprotein = lipids + proteins
  • spherical particles
  • complexes incorportaed into spheres
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2
Q

What is the structure and composition of e.g. LDL?

A
  • all look like little spheres
  • not absolutely uniform in size
  • 4 classes:
    • chylomicrons (very big particles)
    • VLDL
    • LDL
    • HDL
  • top to bottom get smaller
  • lipoproteins exist due to the inability of oil and water to mix
  • lipids will not happily move through an aqueous environment
  • these particles have a polar outer surface that is happy to exist in an aqueous environment while the inside is non-polar
  • the only thing that brings lipids together into a class is that they are non-polar
  • outer shell is a layer of phospholipid
    • phospho part is polar and on the outside
    • non polar ends are aimed in towards the centre of the sphere
  • also on the outside is free (unesterified) cholesterol embedded in the membrane
  • cholesterol is almost entirely nonpolar except for this tiny little bit of polar character which enables it to participate in the outer membrane
  • the inside is a very non polar environment
    • triacylglycerols (TAGs) (same thing as triglycerides)
    • cholesteryl esters (polar bit is lost through esterisation with a fatty acyl chain)
  • one protein: ApoB-100
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3
Q

What is the relationship between blood lipids and risk of heart disease?

A
  • there is a positive correlation between blood cholesterol levels and the risk of heart disease (heart attack)
  • there is an inverse correlation between HDL cholesterol level and risk of heart disease
  • a strong positive correlation exists between the ratio of total cholesterol/HDL cholesterol and risk of heart disease – ↑ ratio, ↑ risk
  • risk increases signficantly as total cholesterol levels rise above ~5mM
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4
Q

What is the structure and composition of chylomicrons?

A
  • chylomicrons are formed in the intestinal mucosa
  • they carry TAGs from the diet to tissues via the lymphatics and blood
  • virtually no cholesterol ester inside
  • outer layer is still phosopholipid and unesterified cholesterol
  • 3 major apolipoproteins
    • B-48
    • C-II
    • C-III
  • these differences are why these particles function differently – recognised by different tissues
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5
Q

What are properties of lipoproteins (Lp)?

A

Lp - density (g/mL) - prot - PLs - Chol - CEs - TAGs

  • CM - less than 1.006 - 2 - 9 - 1 - 3 - 85
  • VLDL - 0.95 - 1.006 - 10 - 18 - 7 - 12 - 50
  • LDL - 1.006 - 1.063 - 23 - 20 - 8 - 87 - 10
  • HDL - 1.063 - 1.210 - 55 - 24 - 2 - 15 - 4
  • key differences include the increase in the amout of protein (% composition, g/100g)
  • the more dense have a lot more protein
  • CM and VLDL are far and away responsible for transporting TAGs
  • Cholesterol + cholesteryl esters = total blood cholesterol
  • most of the cholesterol that is being transported has been converted to esters and is being transported inside these particles
  • LDL is the main transporter of cholesterol in the blood (~45% of LDL is cholesterols)
  • HDL has a very low level of TAGs
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6
Q

What are the three pathways of lipid transport?

A
  • exogenous pathway
  • endogenous pathway
  • reverse cholesterol transport
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7
Q

What is exogenous lipid transport?

A
  • dietary fats are broken down to free fatty acids and mono- and diacylglycerols by intestinal lipases
  • breakdown products are taken up by the mucosa and reformed into TAGs, incorporated into chylomicrons
  • more hydrolysis of TAGs by lipoprotein lipase attached to the endothelium of capillaries and re-esterification of free fatty acids
  • CMs depleted of most TAGs are called ‘chylomicron (CM) remnants’
  • CM remnants are carried in blood back to the liver for uptake by receptor-mediated endocytosis
  • END of exogenous lipid transport
    1. bile salts emulsify dietary fats in the small intestine, forming mixed micelles
    1. intestinal lipases degrade TAGs
    1. fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into TAGs
    1. TAGs are incorporated, with cholesterol and apolipoproteins, into chylomicrons
    1. chylomicrons move through the lymphatic system and bloodstream to tissues
    1. lipoprotein lipase, activated by apoC-II in the capillary, converts TAGs to fatty acids and glycerol
    1. fatty acids enter cells
    1. fatty acids are oxidsed as fuel or reesterified for storage
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8
Q

What is endogenous lipid transport?

A
  • VLDL is produced in the liver
    • mainly a transporter of TAGs
  • enters the circulation
  • delivers lipid/fatty acids from broken down TAGs to:
    • adrenal glands, gonads
    • muscle
    • adipose
  • as this process occurs VLDL shrinks gives off its surface and becomes LDL
  • passes through IDL
  • LDL is taken up by other tissues or returned to the liver
  • all starts in the liver with ApoB-100 and various other proteins e.g. microsomal transfer protein etc
  • produce VLDL
  • apoB acts like a scaffold
  • VLDL released into circulation where it picks up additional lipoproteins (Apos E, CII) - not on the first produced particle
  • travels into capillaries etc → adipose tissue and muscle
  • lipoprotein lipase enzyme hydrolyses TAGs to mainly monoacylglycerol + 2 free fatty acids (other enzymes take off third fatty acid)
  • once that’s happened - the particle shrinks, sheds ApoCII → IDL (more ApoCII comes off after this step too)
  • apoCII is the activator protein of lipoprotein lipase
  • further acted on by hepatic lipase to make it even smaller → LDL
  • LDL is like a metabolic end product of VLDL
  • by the time we get to LDL activation of lipoprotein lipase is lost because apoCII is lost
  • LDL has only one apolipoprotein - ApoB-100
  • about 50% of IDL is converted to LDL
  • about 70% of LDL goes back to the liver
  • about 30% taken up by extra hepatic tissues
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9
Q

What is the synthesis of VLDL and conversion to LDL?

A
  • VLDL is assembled in the endoplasmic reticulum (ER) of hepatocytes on a scaffold of ApoB-100 (4,536 amino acids residue)
  • ApoB-100 has several binding sites for microsomal transfer protein (MTP) necessary for assembly of VLDL
  • ApoE and ApoCII mainly become associated with VLDL in the circulation
  • TAGs in VLDL are broken down by lipoprotein lipase (LPL) and the free fatty acids are taken up by skeletal muscle (for storage)
  • loss of TAG from core via lipolysis converts VLDL to IDL (intermediate density lipoproteins, also called VLDL remnants). Surface apoCII is released into the blood leaving ApoB-100 and ApoE
  • ~50% of IDL is taken up by the liver via the LDL receptor (LDLR) that recognises ApoE on IDL
  • ~50% of IDL is converted to LDL via extra lipolysis. ApoE is shed leaving only APoB-100 on LDL
  • ~70% of LDL is removed from blood by the liver cia the LDLR
  • end of endogenous lipid transport
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10
Q

What is reverse cholesterol transport (RCT)?

A
  • the process where excess cholesterol is picked up from tissues and returned to the liver for disposal
  • RCT is a possible explanation for the inverse relationship between HDL levels and atherosclerosis, i.e. high HDL-chplesterol, low risk of atherosclerosis
    • atherosclerosis is the build up of lipid and growth of smooth muscle cells (SMCs)
    • plaque or ‘atheroma’ contains fatty material (mainly cholesterol), SMCs and connective tissue
    • cholesterol is a molecule that doesn’t have any natural enemies - needs to be eliminated in foeces, but even this is hard
  • HDL produced in the blood picks up excess free cholesterol from artery walls, converts them to cholesteryl esters (CEs) and delivers them to the liver for disposal as bile
  • e.g. takes it up from macrophages/foam cells and delivers it to the liver by a receptor called SR-BI
  • HDL starts as a disc of ApoA-1 and phospholipid
  • it is made in liver and intestine
  • the disc → a sphere when free cholesterol is esterified to CE by the enzyme LCAT (HDL3) (lecithin cholesterol acyl transferase)
  • the sphere grows as more free cholesterol is picked up and esterified (HDL2)
  • HDL2 exchanges cholesteryl ester for TAG from LDL and VLDL under the action of protein CETP (cholesteryl ester transfer protein)
  • HDL finally interacts with membrane protein SR-B1 on the liver and transfers its cargo of CE to the liver
  • LDL delivers the CE from HDL via uptake by the LDL receptor
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11
Q

What does HDL start as?

A
  • a disc of ApoA-1 and phospholipid
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12
Q

Where is HDL made?

A
  • it is made in liver and intestine
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13
Q

What are factors that affect blood cholesterol?

A
  • can change
    • diet: foods high in saturated fat and C are associated with high blood C
    • exercise: can decrease LDL-C and increase HDL-C
    • weight: overweight is associated with high blood C. weight loss can decrease LDL-C and increase HDL-C
    • smoking: there appears to be a correlation with smoking intensity and increased total C, LDL-C, and triglycerides, and decreased HDL-C
  • cannot change
    • genes: familial hypercholesterolaemia caused by mutations in the gene expressing the LDL receptor or that cause decreased LDL clearance. ApoB and Apo E mutations can increase blood C
    • age: blood C rises with age
    • sex: usually women have lower C than men before age about 55 years, then they catch up
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14
Q

What are factors that increase blood TGs (TAGs)?

A
  • acquired or secondary causes
    • insulin resistance –
      • diabetes: ++ TG production, – TG clearance
      • obesity: ++ TG production, +/– TG clearance
    • excess alcohol: ++ TG production, +/– clearance
    • hypothyroidism: + TG production, – TG clearance
    • medications:
      • beta blockers: + production, – clearance
      • immunosuppressants: ++ production, + clearance
      • protease inhibitors: – production, – clearance
      • oestrogen replacement: + production, + clearance
  • primary
    • genes (all rare causes)
      • mutations in ApoB-100 can cause increased VLDL production
      • mutations in lipoprotein lipase (LPL) or its activatory ApoC-II (found on VLDL and chylomicrons) lead to decreased lipase activity and increased TG
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15
Q

What are dyslipidaemias?

A
  • disorders of Lp metabolism
  • hypercholesterolaemia: ↑ total cholesterol (i.e. free and esterified) in blood
  • ↑ blood levels of cholesterol associated with LDL particles and ↑ small, dense LDL particles – which are ‘atherogenic’
  • hypertriglyceridaemia: ↑ blood levels of triglycerides, or ‘TGs’, also called ‘triacylglycerols’ abbreviated to ‘TAGs’
  • ↓ HDL-cholesterol (i.e. free and esterified cholesterol associated with the HDL class of lipoproteins)
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16
Q

What is the relationship between dyslipidaemia and the metabolic syndrome?

A
  • alterations to blood lipids in both LDL and HDL particles, elevated TGs
  • LDL-cholesterol levels are often normal
  • The LDL particles themselves have an abnormal structure that makes them atherogenic:
    • small, dense, triglyceride-rich
    • oxidised
    • glycated (particularly of the ApoB-100)
  • atherogenic LDL particles remain in the circulation for longer → accumulation of cholesterol in the arterial wall
17
Q

What is the role of HDL in metabolic syndrome and T2DM?

A
  • blood levels of HDL are lower due to increased catabolism
  • one cause of increased HDL catabolism is hyper-triglyceridaemia
  • the action of CETP on HDL and VLDL → TG-rich HDL, a good substrate for hepatic lipase
  • increased glycated HDL could interfere with cholesterol efflux from cells and reverse cholesterol transport (RCT)
  • note that the decreased HDL does not only affect RCT
  • decreased HDL is associated with a loss of its other beneficial properties
  • HDL is:
    • anti-oxidative
    • anti-inflammatory
    • anti-thrombic
    • endothelium-dependent vasorelaxant
18
Q

How does atherosclerosis develop?

A
  • some blood vessels express adhesion molecules which encourages the adhesion and migration of monocytes
  • monocytes can move into the intima, not normally present here
  • LDL can also enter blood vessels between endothelial cells into the intima
  • oxidation → oxLDL
  • oxLDL can be taken up by non-regulated transport steps
  • scavenger receptors
  • stuff the macrophage with lipid
  • damage to endothelium (e.g. by Ox-LDL, infection, etc)
  • uptake of LDL and increased production of Ox-LDL by oxidants from endothelial and smooth muscle cells and macrophages
  • Ox-LDL → increased expression of:
    • adhesion molecules e.g. P-selectin
    • chemotactic factors e.g. monocyte chemattractant protein-1 (MCP-1) and macrophage colony stimulating factor (MCSF)
  • → tethering, activation and attachment of monocytes and T lymphocytes to endothelial cells
  • migration of monocytes to the subendothelial space
  • uptake of LDL and differentiation of monocytes → macrophages → increased ROS causing conversion of ox-LDL → highly ox-LDL
  • highly ox-LDL is taken up by macrophages in an unregulated way → formation of foam cells
  • foam cells plus leukocytes → formation of fatty streak on the blood vessel
  • foam cells secrete growth factors that cause smooth muscle cells to migrate into the intimal space (and so on..)
  • the fatty streak is eventually converted to a fibrous plaque with a fibrous cap and lipid-rich core
  • if the fibrous cap is thin, the plaque is unstable
  • it can rupture leading to the formation and release of thrombi that can block vessels

BIOM30001 (35 decks)

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