Lipids and Atherosclerosis

Question 1

Fatty Acid Synthesis

Answer 1

• 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

Question 2

Lipid Metabolism

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

Answer 2

• 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

Question 3

Three Main Lipids

Answer 3

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

Question 4

Lipoproteins

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

Answer 4

• 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)

Question 5

Lipoprotein Structure

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

Answer 5

• 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)

Question 6

Lipoprotein Functions

Answer 6

• 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

Question 7

3 Lipoprotein Metabolism Pathways

Answer 7

• 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

Question 8

Exogenous Lipid Metabolism

• Where absorbed cholesterol goes
• Where intestinal cholesterol comes from

Answer 8

• 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

Question 9

Chylomicrons

• General
• Synthesis
• Functions
• Surface lipoprotein

Answer 9

• 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

Question 10

Chylomicron Metabolism

Answer 10

• 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

Question 11

Endogenous Lipid Metabolism

• Liver & cholesterol
• VLDL remnants

Answer 11

• 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

Question 12

VLDL

• General
• Biogenesis
• Function
• Metabolism
• Remnant uptake

Answer 12

• 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

Question 13

LDL

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

Answer 13

• 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

Question 14

Answer 14

Tendon Xanthoma

Question 15

Answer 15

Corneal Arcus

Question 16

HDL

• General
• Synthesis
• Functions

Answer 16

• 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

Question 17

3 Structural Components of Arterial Walls

• Adventitia
• Media
• Intima

Answer 17

• 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

Question 18

During early atherosclerosis, compromised endothelium integrity –>

Answer 18

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

Question 19

Plaque Formation: The Fatty Streak

Answer 19

• 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

Question 20

Answer 20

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

Question 21

Plaque Formation: The Fibrous Cap & Lipid Core

Answer 21

• 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

Question 22

Plaque Formation: Oxidized LDLs & Macrophages

Answer 22

• 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

Question 23

Plaque Rupture

Answer 23

• 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

Question 24

Answer 24

Ruptured plaque –> complete luminal occlusion

Question 25

Coronary Artery Disease Timeline

Answer 25

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