Lipids and Atherosclerosis Flashcards
1
Q
Fatty Acid Synthesis
A
- 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
Q
Lipid Metabolism
- Lipids
- Most important simple lipids
- Most important complex lipids
A
- 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
Q
Three Main Lipids
A
- Triacylglycerol
- Main constituent of dietary fats used for energy storage
- Phospholipids
- Major structural component in membranes
- Cholesterol & cholesteryl esters
- Cell membrane components
4
Q
Lipoproteins
- Plasma lipoproteins
- Plasma lipoprotein characteristics
- Lipids in core
- Lipids on surface
A
- 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
Q
Lipoprotein Structure
- General
- Potentially atherogenic lipoproteins contain…
- Potentially protective lipoproteins (HDL) contain…
A
- 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
Q
Lipoprotein Functions
A
- 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
Q
3 Lipoprotein Metabolism Pathways
A
- 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
Q
Exogenous Lipid Metabolism
- Where absorbed cholesterol goes
- Where intestinal cholesterol comes from
A
- 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
Q
Chylomicrons
- General
- Synthesis
- Functions
- Surface lipoprotein
A
- 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
Q
Chylomicron Metabolism
A
- 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
Q
Endogenous Lipid Metabolism
- Liver & cholesterol
- VLDL remnants
A
- 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
Q
VLDL
- General
- Biogenesis
- Function
- Metabolism
- Remnant uptake
A
- 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
Q
LDL
- General
- Synthesis
- Function
- Metabolism
- Uptake by tissues
A
- 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
Q

A
Tendon Xanthoma
15
Q

A
Corneal Arcus
16
Q
HDL
- General
- Synthesis
- Functions
A
- 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
Q
3 Structural Components of Arterial Walls
- Adventitia
- Media
- Intima
A
- 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
Q
During early atherosclerosis, compromised endothelium integrity –>
A
- 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
Q
Plaque Formation: The Fatty Streak
A
- 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
Q

A
Non-obstructive fatty streaks beneath the endothelial surface of an epicardial coronary artery
21
Q
Plaque Formation: The Fibrous Cap & Lipid Core
A
- 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
Q
Plaque Formation: Oxidized LDLs & Macrophages
A
- 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
Q
Plaque Rupture
A
- 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
Q

A
Ruptured plaque –> complete luminal occlusion
25
Q
Coronary Artery Disease Timeline
A
- Atherosclerosis development is gradual
- Depends on the number of atherogenic (apoB containing) lipoproteins being exposed to a vulnerable endothelium over time
