Lipids and Atherosclerosis Flashcards Preview

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Flashcards in Lipids and Atherosclerosis Deck (25):
1

Fatty Acid Synthesis

  • FAs are synthesized in various tissues through a lipogenic pathway
    • Tissues: liver, intestine, & adipose cells from glucose
    • Pathway: regulated by the hormones insulin, glucagon, & somatostatin
  • Availability of initial substrates & products of this pathway influence lipogenesis

2

Lipid Metabolism

  • Lipids
  • Most important simple lipids
  • Most important complex lipids

  • Lipids
    • Structural & bioregulatory components o fhuman cells & plasma lipoproteins
    • Simple or complex
      • Complex: derived from simple by covalent association
  • Most important simple lipids
    • ​Fatty acids
    • Sphingosine
    • Cholesterol
  • Most important complex lipids
    • ​Cholesteryl esters
    • Triacylglycerol (TG)
    • Phosphatidylcholine (lecithin)
    • Phosphatidylethanolamine (cephalin)
    • Sphingomyelin

3

Three Main Lipids

  • Triacylglycerol
    • Main constituent of dietary fats used for energy storage
  • Phospholipids
    • Major structural component in membranes
  • Cholesterol & cholesteryl esters
    • Cell membrane components

4

Lipoproteins

  • Plasma lipoproteins
  • Plasma lipoprotein characteristics
  • Lipids in core
  • Lipids on surface

  • Plasma lipoproteins
    • Complexes of lipids & proteins
    • Classified according to their densities & electrophoretic mobilities
  • Plasma lipoprotein characteristics
    • Inner droplet of neutral (water-insoluble) core lipids
    • Solubilizing surface layer
    • Specific proteisn (apolipoproteins) attached to the outer layer through their specific lipophilic domains
  • Lipids in core
    • Hydrophobic: triacylglycerol (TG), cholesteryl esters (CE)
  • Lipids on surface
    • Hydrophilic: phospholipids (PL), unesterified cholesterol (UC)

5

Lipoprotein Structure

  • General
  • Potentially atherogenic lipoproteins contain...
  • Potentially protective lipoproteins (HDL) contain...

  • General
    • Water soluble carriers of hydrophobic elements (ex. cholesterol, triglyceride) through the circulatory system
  • Potentially atherogenic lipoproteins contain...
    • Apolipoprotein B on their surface (B = bad)
  • Potentially protective lipoproteins (HDL) contain...
    • Apolipoprotein A (A = want to get an A)

6

Lipoprotein Functions

  • Transport lipid-soluble (water-insoluble) compounds b/n tissues
  • Substrates for energy metabolism (TG)
  • Essential componetns for cells (PL, UC)
  • Precursors for hormones, eicosanoids, & bile acids
    • Ex. eicosanoids: thromboxane & prostacyclin
  • Lipid soluble vitamins

7

3 Lipoprotein Metabolism Pathways

  • Exogenous / chylomicron pathway
    • Dietary fat
    • Characterized by chylomicron mobilization
  • Endogenous pathway
    • Lipids synthesized by the liver
  • HDL metabolism
    • Apolipoprotein transfer
    • Cholesteryl ester transfer
    • Reverse cholesterol transport

8

Exogenous Lipid Metabolism

  • Where absorbed cholesterol goes
  • Where intestinal cholesterol comes from

  • Where absorbed cholesterol goes
    • Most --> liver via intestinally derived Apo B (48) containing lipoproteins
    • Some --> extrahepatic tissues & plaques
    • Free --> absorbed via the NPC1L1 transporter mechanism
    • Remaining --> eliminated from body
      • B/c some biliary cholesterol is reabsorbed & returned to the liver, elimination is incomplete
  • Where intestinal cholesterol comes from
    • Partially from diet
    • Mostly from liver via the biliary system

9

Chylomicrons

  • General
  • Synthesis
  • Functions
  • Surface lipoprotein

  • General
    • Largest lipoproteins
    • Contain >90% triglycerides
  • Synthesis
    • Synthesized by the intestine
  • Functions
    • Transport dietary fat to peripheral tissues for metabolism & storage
  • Surface lipoprotein
    • Apolipoprotein B (48)
    • A = good
    • B = bad
    • 8 = what you ate

10

Chylomicron Metabolism

  • Long chain FAs are re-esterified into triglycerides in the gut
    • They're transfered to apoB48 containing chlyomicrons
    • These chylomicrons are synthesized in the gut & secreted into the blood via the lymphatic system
  • apoC-II activates lipoprotein lipase
    • Catalyzes the hydrolysis of the triacylglycerols
  • Chylomicron remnant either...
    • Is taken back up by the liver via the apoB48 / remnant receptors in the liver
    • Can infilitrate hte endothelium & contribute to atherosclerotic plaque formation

11

Endogenous Lipid Metabolism

  • Liver & cholesterol
  • VLDL remnants

  • Liver endogenously synthesizes cholesterol
    • Liver secretes cholesterol into the circulation via hepatically derived apoB100 lipoproteins
    • Liver excretes cholesterol into the intestine as free cholesterol or bile acids via the biliary system
  • VLDL remnants (IDL & LDL) are apoB100 containing lipoproteins that can penetrate the arterial endothelium
    • LDL is taken up by the lvier by the LDL receptor

12

VLDL

  • General
  • Biogenesis
  • Function
  • Metabolism
  • Remnant uptake

  • General
    • Contain 60-70% triglycerides
  • Biogenesis
    • Nascent VLDL particles are assembled in the liver where apoB100 & triglycerides are synthesized
  • Function
    • Transport endogenously synthesized triglycerides to peripheral tissues
  • Metabolism
    • apoC-II, apoC-III, apoE, & cholesteryl ester are acquired from HDL in circulation
    • apoC-II activates lipoprotein lipase
      • Catalyzes the hydrolysis of triglycerides
      • FAs, complexed w/ albumin, are transported to muscle for enegy, to adipose tissue for storage, & to liver for further metabolism
    • Apolipoproteins are transferred back to the HDL
    • Triglyceride poor (cholesterol ester rich) VLDL remants (intermediate density lipoprotein, IDL) is further processed
      • Can contribute to the subendothelial atherosclerotic plaque
  • Remnant uptake
    • VLDL remnant particle (IDL) can be taken up by hepatic apoE / remnatn receptors or can undergo further hydrolysis by hepatic triglyceride lipase to form LDL

13

LDL

  • General
  • Synthesis
  • Function
  • Metabolism
  • Uptake by tissues

  • General
    • Major cholesterol carrying lipoprotein
    • 2/3 to 3/4 of serum cholesterol is carried by LDL
    • 50% of mass is cholesterol
  • Synthesis
    • Produced as a product of VLDL metabolism
  • Function
    • Delivers cholesterol to peripheral tissues for biosynthesis & steroid hormone production
  • Metabolism
    • LDL is removed by apoB100 receptors which are mainly expressed in the liver
  • Uptake by tissues
    • Defects in the LDL receptor --> familial hypercholesterolemia
    • Increased nonreceptor mediated uptake of LDL in the liver & non-hepatic tissues

14

Tendon Xanthoma

15

Corneal Arcus

16

HDL

  • General
  • Synthesis
  • Functions

  • General
    • Smallest of the lipoproteins
    • Rich in cholesteryl esters
  • Synthesis
    • Synthesized by the intestine & liver as a nascent cholesterol-poor lipoprotein
  • Functions
    • Accumulates cholesterol & cholesteryl esters through interactions w/ peripheral cells & other lipoproteins
    • Participates in reverse cholesterol transport, removal of excess cholesterol from peripheral cells, & delivery to the liver for metabolism
  • Maturation
    • HDL is secreted in a discoidal form from the liver & gut
    • As HDl acquired cholesterol from tissues in circulation, it matures into a spherical form though the action of lecithin : cholesterol acyl transferase

17

3 Structural Components of Arterial Walls

  • Adventitia
  • Media
  • Intima

  • Adventitia
    • Carries blood & nerve supply to the artery
  • Media
    • Comprised of somoth muscle
    • Controls vascular tone
  • Intima
    • Basement membrane covered by endothelium
    • Regulates homeostasis, thrombosis, vascular tone, & permeability
    • Site of atherosclerosis

18

During early atherosclerosis, compromised endothelium integrity -->

  • Increased permeability
    • Facilitates penetration of the intima by atherogenic lipoproteins
  • Increased adhesion
    • Facilitates migration of monocytes into the subendothelium
  • Diminished vasodilation
    • Compromises hemodynamic control

19

Plaque Formation: The Fatty Streak

  • Monocytes penetrate the intima
    • Transformed into macrophages & then into cholesterol-rich foam cells
  • Activated macrophages scavenge & ingest oxidized LDL in the subendothelial space
  • Progressive accumulation of intracellular & extracellular lipids --> fatty streak

20

Non-obstructive fatty streaks beneath the endothelial surface of an epicardial coronary artery

21

Plaque Formation: The Fibrous Cap & Lipid Core

  • Growing fatty streak forms the lipid core
    • Becomes isolated by the progressive formation of a fibrous cap
  • Fibrous cap
    • Contains collagen, proteoglycans, & activated smooth muscle
    • Sturdier cap --> less likely plaque rupture
  • Further lipid accumulation in the lipid core -->
    • Cell death (apoptosis
    • Potential destablizaiton of the plaque

22

Plaque Formation: Oxidized LDLs & Macrophages

  • Oxidized LDLs contain large amounts of cholesterol ester (CE)
  • When macrophages are full of CE, they secrete cytokines (Il-6, CRP, TNFa)
  • These cytokines induce vascular inflammation, cell recruitment, & weakening fibrous cap
  • The macrophages in atherosclerotic lesions secrete metalloproteases & collagenases that eventually weaken the fibrous cap

23

Plaque Rupture

  • Plaqure rupture exposes the thrombogenic lipid "gruel" to the blood
    • --> partial thrombotic occlusion of the vessel
    • --> unstable angina
  • Sudden total thrombotic occlusion of the vessel --> acute myocardial infarction

24

Ruptured plaque --> complete luminal occlusion

25

Coronary Artery Disease Timeline

  • Atherosclerosis development is gradual
  • Depends on the number of atherogenic (apoB containing) lipoproteins being exposed to a vulnerable endothelium over time