CB Quiz 2 Flashcards
What enzyme is mainly responsible for Cholesterol Synthesis
Acetyl Coenzyme A (Acetyl CoA)
What is the main source of transport for Cholesterol?
How is it taken up in cells?
LDLs
Specific surface receptors
Describe the Structure of Cholesterol
Made up of a steroid nucleus with a condensed 4 ring structure
Attached to a hydrocarbon chain
Low H2O solubility
Explain the full Process of Cholesterol Synthesis
Cholesterol is synthesized from Acetyl CoA enzyme in 3 stages
- Synthesis of Isopentenyl Pyrophosphate from Mevalonate (in 3 consecutive reactions requiring ATP)
- Condensation of six molecules of Isopentenyl Pyrophosphate to form Squalene (C5 -> C10 -> C15 - C30)
- Squalene cyclizes and the tetracyclic product is converted to cholesterol (first changes to Squalene 2,3-epoxide, which undergoes cyclization to form Lanosterol which is then converted to Cholesterol by multiple reactions)
=> Mevalonate -> Isopentenyl -> Squalene ->Squalene 2,3-epoxide -> Lanosterol -> Cholesterol
What’re the 2 main ways cholesterol can be obtained
Diet (Exogenous)
Synthesized in the body (Endogenous)
Endogenous
Synthesized in the body
Exogenous
Obtained in diet
What are the major sites of cholesterol synthesis? Can it, generally speaking, be produced in any cell?
All nucleated cells are capable of synthesis but the major sites are the Liver, Intestine, Reproductive Tissue, and Adrenal Glands.
So no, not every cell… every nucleated cell lmao
Statins
Class of drugs that inhibit cholesterol Synthesis
Brownie points: Inhibits HMG CoA Reductase
LEARNING OUTCOME: Describe the Physiological Regulation of Cholesterol in the body
The rate of cholesterol formation in the body is highly responsive to cellular levels of cholesterol. This is controlled by the negative feedback mechanism mediated primarily by changes in its amount in the body and the activity of
3-Hydroxy-3-Methylglutaryl CoA Reductase (HMG CoA Reductase) which is inhibited by Statins.
Control of HMG CoA Reductase:
• Rate of Synthesis of Reductase mRNA is controlled by the sterol regulatory element binding protein (SREBP). When cholesterol levels are low, this transcription factor induces transcription of HMG CoA Reductase.
• Rate of Translation of Reductase mRNA is inhibited by Nonsterol Metabolites derived from Mevalonate and dietary cholesterol.
• Degredation of the Reductase due to increased levels of cholesterol.
• Phosphorylation decreases the activity of the Reductase in response to low levels of ATP
LEARNING OUTCOME: Describe the Pharmacological Regulation of Cholesterol
Pharmacological Regulation of Cholesterol:
1. Statins: Inhibition of in vivo synthesis of cholesterol in the liver (by inhibiting HMGCoA Reductase)
2. Cholestyramine/Colestipol: Reduces Bile Acids in the intestine which reduces absorption of Exogenous cholesterol and increases the metabolism of Endogenous cholesterol into bile acids
3. PCSK9 Inhibitors: Reduces circulating LDL. PCSK9 enhances the number of LDL receptors across tissues (given to patients intolerant of Statin)
These methods proved to decrease cardiovascular-related mortality among patients with high LDL presence in their blood.
Describe the role of the drug Colestipole
Reduces Bile Acids in the Intestines which reduces absorption of Exogenous cholesterol and increases the metabolism of Endogenous Cholesterol into bile acids
What is the Role of PCSK9?
PCSK9 enhances the number of LDL Receptors across tissues
When are PCDK9 inhibitors prescribed?
When the patient is intolerant of Statin
What are the main derivatives of Cholesterol?
Bile Acids
Bile Salts
Steroid Hormones
Vitamin D
What is the significance of Bile Salts and Bile Acids in terms of cholesterol regulation.
Their production eliminates cholesterol from the body by converting it into Bile
Where is Bile synthesized
Liver
Where is bile stored and secreted? Where is it secreted to?
Stored in the gall-bladder
Secreted through the bile duct
Secreted into the small intestine (Duodenum)
What is the primary function of Bile Acids
Bile acids are amphipathic molecules which allows them to emulsify triglycerides in the small itnestine
How are Bile Salts produced?
What is their main function?
What happens when bile salts are exposed to the Bacterial Flora of the intestine
Produced in the liver, bile salts are made through conjugating bile acids with either Glycine or Taurine.
The main function of Bile Salt is being a detergent
When Bile Salts are exposed to Bacterial Flora of the intestine:
- Aids in the regeneration of Bile Acids (from the removal of glycine or Taurine) and production of Secondary Bile Salts (removal of OH group)
What is Cholelithiases?
How is it treated?
Occurs due to lack of bole salts being secreted to handle the amount of cholesterol present. It is caused by either:
malabsorption of bile acids
Biliary tract obstruction
Lack of Melatonin
This condition results in cholesterol precipitates in the Gall-Bladder
Cholecystectomy is the removal of the gall bladder (Treatment)
What are the steroid hormones that are derived from Cholesterol?
Progesterone Androgens Estrogens Glucocorticoids Mineralocorticoids
Progesterone
Prepares the lining of the uterus for implantation of an ovum and maintenance of pregnancy
Androgens
Responsible of the development of male characteristics
Estrogens
Responsible for the development of female secondary characteristics as well as participation in the ovarian cycle
Glucocorticoids
Promote Gluconeogenesis and breakdown of glycogen, Enhances segregation of Fat and protein, and inhibits inflammatory response
Gluconeogenesis
Production of glucose and eventually glycogen
Mineralocorticoids
Aldosterone:
Or Anti-diuretic hormone
Acts on distal tubules of the kidney to increase reabsorption of Na+ along with the excretion of K+ and H+
How is Vitamin D synthesized?
Cholesterol is photolysed bu UV light to pre-vitamin D3 which spontaneously isomerizes into Vitamin D3 which is converted to Calcitol, the active hormone which produced Vitamin D
What are the functions of Vitamin D
Vitamin D binds to intracellular receptors and selectively stimulates gene transcription.
Also Regulates plasma levels of Calcium and Phosphorus
What are the diseases associated with vitamin D
Vitamin D deficiency in children causes Rickets which is characterized by inadequate calcification of cartilage and bone.
Vitamin D deficiency in Adults leads to the softening and weakening of bones which is called Osteomalacia.
What is the primary function of blood flow?
Delivery of O2, nutrients, and water as well as the removal of metabolic waste from tissues and cells
What is Ohm’s law in relation to blood flow?
(DeltaP) = Flow (Q) x Resistance (R) or DeltaP = QR
Darcy’s Law
Darcy’s Law: Q = DeltaP/R => Flow varies proportionately with pressure gradient and inversely proportionately with resistance
How do we measure Cardiac Output CO?
CO = HR x SV
Heart rate x stroke volume
AND
CO = MAP/TPR where CO is the cardiac output, MAP is the mean arterial pressure, and TPR is the total peripheral resistance. Therefore, a circulation with low resistance does not require a high pressure to maintain flow
Equation for Vascular Resistance
Vascular Resistance: R = nL/r^4. R is resistance, n is viscosity, L is length, r is the vessel radius
When is pressure in the heart generated
During systole
What is the relation between CO and Systolic Pressure
As CO increases, Systolic pressure increases
What is the vascular tree and how does pressure vary between them?
• Pressure drops across the vascular tree (Aorta > Capillaries > Great Veins
What is the relation between changes in vessel diameter and resistance
small changes in vessel diameter have large effects on resistance and hence flow R = 1/r^4
As the radius increases, resistance decreases dramatically
What is the relation between Flow Q and vessel radius
Flow (Q) is proportional to the 4th power of the radius
What is the relation between viscosity n and Flow Q as well as resistance R
Viscosity is proportional to resistance and inversely proportional to flow as resistance is inversely related to flow.
WhaWhat are the Factors affecting viscosity?
- Concentration and type of plasma protein
- Hematocrit (The proportion of blood volume occupied by red cells). Anemia would decrease and Polycythemia would increase viscosity
What is Axial Accumulation and it’s effects on hematocrit levels in capillaries?
• Capillaries and smaller vessels tend to have slightly lower hematocrit due to Axial Accumulation (Red cells are in the center of the flow so branches get relatively more plasma to red cell
What tends to affect flow more?
Viscosity or Radius and why?
• Radius has much more effect on flow than viscosity (r^4)
What is Laminar Flow and its association with Shear Stress in blood vessels
- Laminar Flow: Viscosity of blood causes Laminar Flow. At the sides of the vessel, the flow is lowest as blood pulls on the vessel wall. This is Shear Stress => increasing flow increases shear => Slowest flow is this outer later which slows the flow in the next layer => the highest velocity is at the center. Note that Laminar Flow is silent.
- Small arteries have a large area to volume ratio => most blood is near the wall => increased viscosity slows flow. In larger arteries, there are more layers and so there is increased velocity
Describe the Relationship between Cross Sectional Area and Flow Velocity
• Cross Sectional Area & Flow: In a closed system, the volume of blood flowing should be constant => Cardiac Output = Venous Return. Flow (Q) = Area (A) x Flow Velocity (V). Since size varies through circulation, but flow is constant, flow velocity varies with size. With a large area, the flow velocity in capillaries is much slower than in both veins and arteries
What is Non-Laminar Flow and under normal conditions, where can we find this flow.
• Non-Laminar Flow: At high velocities (or at large diameters), flow can become turbulent. Under normal conditions, non-laminar flow tends to occur in the ascending aorta and around branch points (narrowed points where velocity increases). Unlike laminar flow, turbulent flow is not silent
What is Transmural Pressure?
Transmural Pressure: Pressure that either distends (swells) or collapses blood vessels. It is the difference in pressure across the wall where PTM = Pi - Po. Pi is pressure inside and Po is the pressure outside. If Po > Pi, then the vessel will collapse
What is the Law of LaPlace and answer the following questions:
How does wall tension increase
How does this law apply in Capillaries and small vessels
How does this law apply in large arteries
How does this law apply in large Veins
The Law of LaPlace: The Transmural Pressure (PTM) is related to the wall tension and the radius where PTM = T/R where T is tension and r is radius or T = PTM x R => wall tension increases with radius and PTM. Wall tension can be thought of as how thick the vessel wall needs to be. For small vessels such as capillaries, they have a small radius and hence less wall tension is required to balance out the dissenting pressure => Thin walls. For vessels with a larger radius, more wall tension is required to balance the distending pressure and hence why a Dilated Aneurysm (Dilated Aorta) is more likely to rupture. Arteries are more likely to rupture when compared to veins due to the decreased pressure in veins
Dilated Aneurysm
Dilated Aorta or other Large arteries.
What is Distensibility and Compliance?
How does this differentiate Arteries and Veins
Distensibility is the ability of a vessel to change in volume compared to pressure.
Distensibility and Compliance: Veins are much more distensible than arteries due to their ability to expand and swell. Compliance is the change in volume for a given change in pressure where DeltaV = C x DeltaP. Since veins have a larger volume as well as a greater Distensibility, they have a lot more compliance which allows them to be a reservoir for blood
Describe the Structure of Arteries and Arterioles
Arteries and Arterioles:
Arteries have a thick layer of Smooth Muscle which allows them to withstand high pressures.
Elastin Fibers provide elasticity. As blood is ejected, the aorta expands and the rebound in diastole propels the blood onward.
Collagen Fibers provide strength
What is the relation between the abundance of Collagen and Elastin in arteries and arterioles and their size
Collagen and Elastin Fibers decrease in abundance as arteries and arterioles get smaller
What is the relationship between Age and Blood Pressure
As we get older, vessels get stiffer and less compliant which is one of the factors pertaining to high blood pressure in older patients
What are Arterial Pulses and how do they differ across different arterial sizes
Compliance of large arteries evens out flow so that it occurs through the whole cardiac cycle. In large arteries, flow is pulsatile but in smaller ones like arterioles and capillaries compliance has reduced the pulsations and flow is mainly continuous. The Pressure Pulse Wave (PPW) is created by systolic ejections and travels much faster than blood. An increased PPW is a Parker of increased arterial stiffness and cardiovascular morbidity
