L7 - Lipids and Cardiac Disease Flashcards
Effects of Intermittent Fasting on Health and Aging?
Intermittent fasting improves multiple
indicators of cardiovascular health, including
blood pressure; resting heart rate; lipids; etc.
Global Burden of Cardiovascular Disease?
1) Aging and population growth have resulted in a global increase in
cardiovascular deaths
2) 17.3 million deaths globally from Cardiovascular disease in 2013
• 40.8% increase from 1990
• Coronary Heart Disease was the largest contributor to cardiovascular death (8.1 million)
Lipids’ roles?
- Hormones or hormone precursors
- Aids in digestion
- Source of metabolic fuel and energy storage
- Structural component of the cell membrane
- Insulators (aid in nerve conduction or prevent heat loss)
Cholesterol?
1) All cells and body fluids contain some cholesterol
2) Starting point of different metabolic pathways
• Vitamin D synthesis
• Steroid hormone synthesis (e.g. progesterone, aldosterone, etc.)
• Bile acid synthesis
(Bile acids – acids that are synthesized by the liver from cholesterol to aid in the absorption and digestion of fats)
3) Except for the liver and few endocrine tissues (e.g adrenal gland), most cells cannot further
catabolize/modify cholesterol
Lipid Fundamentals?
1) Major circulating lipids are cholesterol and triglyceride
2) 70% of cholesterol is esterified
• ∴ Lipids are not water soluble -> once synthesized by liver or intestine, packaged into lipoproteins for transport and circulation
3) What are Lipoproteins? Macromolecular complexes
with an outer shell and inner core
• Outer shell: molecules that solubilize the Lipoprotein
(phospholipids, cholesterol, and apolipoproteins)
• Hydroxyl group of cholesterol and phosphate groups of phospholipids are oriented toward the outside
• Amphipathic
Apoproteins (Apolipoproteins)?
• Proteins that contribute structurally to the formation
of lipoproteins
• Assist in the solubilization of lipoprotein (amphipathic)
• Ligands for cell-surface receptors and enzymes
attached to endothelial and cell surfaces
What are the types of Lipoproteins?
1) Categorized based on hydrated densities determined from ultracentrifugation:
• Chylomicrons
• VLDL
• IDL
• LDL
• HDL (HDL2, HDL3)
• Lipoprotein (a) - abbreviated as Lp (a)
2) Different physical and chemical properties due to variation in lipid and apoprotein composition
Chylomicron – the overnight standing test?
1) Normal fasting plasma does not contain chylomicrons or remnant chylomicrons
2) When plasma contains chylomicrons, the chylomicrons will float to the top and form a creamy layer overnight at 4°C
• low density (<0.95 g/mL)
• Possible causes: mutations in LPL or apo-CII
Lipoprotein Metabolism - Exogenous Pathway: Function?
Absorption of dietary
lipids and as energy carriers (i.e. delivery of
triglycerides to liver and peripheral tissues)
Endogenous Pathway of Lipoprotein Metabolism?
1) Triglycerides consumed in the diet -> bile acids
help solubilize the triglyceride -> pancreatic lipase helps to break it down to monoglycerides + free glycerol
2) Intestinal epithelial cells resynthesize triglycerides
(from monoglycerides, glycerol and free fatty acids)
and package into chylomicron along with apo B-48
3) Intestinally derived chylomicrons enter the blood stream
4) As Triglycerides are cleaved from chylomicrons they are reduced in size and is now referred to as chylomicron remnant
5) Apo C-II activates LPL -> cleaves triglyceride on chylomicrons -> taken up by muscle and adipose tissue
• LPL = Lipoprotein Lipase (degrades circulating triglycerides in blood stream)
6) Remnants reach liver for further catabolism
7) The liver produces endogenous lipoproteins for delivery of lipids to peripheral cells
8) Liver can synthesize triglycerides from carbohydrates and fatty acids especially when chylomicron remnant uptake is insufficient
9) Endogenously made triglycerides and cholesterol are packaged along with apo B-100 into VLDL
10) VLDL sheds apo C-II and triglycerides -> IDL -> additional triglyceride removed + apo E -> LDL
Liver connects the Exogenous and endogenous pathway?
1) Lipolysis = cleavage of triglycerides via lipoprotein lipase
2) LCAT- lecithin:cholesterol acyltransferase;
• Converts cholesterol in extrahepatic tissue to CE
3) CETP - cholesteryl ester transfer protein
• Transports Cholesterol Ester from HDL to LDL of the endogenous pathway
LDL- Cholesterol?
- Liver normally removes 2/3 of LDL via interaction through hepatic LDL - Receptor
- When LDL concentration rise, LDL deposited into sub- endothelial, subintimal space
What happens in Familial hypercholesterolemia?
Accelerated deposition of cholesterol in the walls of
arteries.
Familial Hypercholesterolemia (FH)
- Results from mutations in the LDL-Receptor
- Heterozygous FH is the most common monogenic disorder (in 1/250 individuals)
- Decreased LDL-Receptor functions impair the LDL clearance
- [LDL] is increased
- [VLDL] may also be increased
- Initial screening involves Lab measurement of LDL
Lp(a) – another atherogenic LDL?
1) A modified form of LDL with apoprotein(a)
covalently bound to apo B
• disulfide bond between apoB-100 of the LDL moiety
and one of the kringle domains in apo(a)
2) Kringle Domains: Repeating subunits on apo(a)
3) Variation in size as a result of varying number of kringle domains
• Variation = genetic contribution
• Genetic risk factor for MI & aortic valve stenosis
• ∴Prothrombotic – promotes the formation of thrombus
– a blood clot inside the blood vessel