Lipid Metabolism: Cholesterol/Eicosanoids Flashcards
What structures can be made from cholesterol?
- Cell membrane
- Regulators of skin differentiation (Cholesterol 3-O-Sulfate)
- Bile acid
- Vitamin D3
- Steroids precursor
What cellular functions are cholesterol important for?
- Intracellular transport
- Cell signaling and Nerve conduction
- Structure and functions of caveolae and clathrin coated pits w/ endocytosis
What is the desirable level of cholesterol to be low risk HD?
<200Mg/dL or <5.2 mM/L
Describe the general synthesis of mevalonate?
Three molecule Acetyl CoA Combine to form HMG CoA and then become reduced to form Mevalonate
What is HMG reductase, and what is it’s clinical significance?
- Enzyme which reduces HMG CoA to Mevalonate
- Statins block HMG Reductase
What important products can be made from mevalonate?
- Isoprenoids
- Cholesterol
How many steps are required for cholesterol synthesis? Where is it made?
- 37 Steps
- Mainly in liver; sometimes in intestine, reproductive tissue, and adrenal glands
What are the biochemical controls cholesterol synthesis when levels are high?
- High cholesterol inhibits HMG-CoA reductase
- High Cholesterol Activates AMP Activates kinase which I Activates HMG CoA
- High Cholesterol leads to proteosome degradation f HMG-CoA reductase
- Hormonal regulation via insulin activating protein phosphatase —> inactivation of HMG- CoA reductase
What are the genetic control for cholesterol synthesis when levels are low?
- SREBP bonds SRE of HMG-CoA Reductase gene and LDL gene to stimulate transcription
What are the genetic control fo cholesterol synthesis at high levels?
- In high levels, SREBP is bound to SCAP and INSIG-1 not allowing transcription
What are side effects of statins?
- Muscle weakness and pain
- Occasionally: myopathy
- Peripheral neuropathy
- Reduced cognition
What are possible replacements for statins?
- Co Q10
- Ubiquinone - Mt can be damaged if not enough
- Heme A - Prosthetc group for cytochrome C oxidase
- Squalene synthase inhibitors
- Zaragozic acid
What is Smith-Leslie Optiz Syndrome?
- Deficiency in DHCR7, an enzyme which converts 7-DHC to cholesterol
- 15-27% reduced levels
- Malformation and behavioral problems
What is Arcus Senilis?
- Results Form Cholesterol deposits in cornea
- indicates hypercholesterolemia
What is xanthelasma?
Cholesterol deposit underneath the skin
What are the most important chemicals in biles?
- Phosphatadylcholine
- Bile salts
What stimulates contraction of the gallbladder and release of bile?
CCK
What are the end chain compounds of Bile salts?
Either glycine or Taurine
How is bile conserved?
- Bile acids are transported back from intestinal epithelium through portal vein to liver
- Albumin in blood ties up bile acids and is picked up by liver
What is cholelithiasis?
- Less phospholipids and bile acids stored in gall bladder
- More cholesterol in bile causes precipitation of gallstones
What biochemical function is Dolichol used in?
Synthesis of N-linked glycoproteins
How many steps are involved in de novo synthesis of cholesterol?
37 Steps
How are prostaglandins synthesized de novo?
Free Arachidonic acid (released by Phospholipasee A-2) —> PGG2 (COX) —> PGH2 (Peroxidase)
What is the role of Cortisol signaled lipocortin?
Inhibits PLA-2
How does aspirin regulate synthesis of prostaglandins?
Inhibits COX
What is the role of prostacyclin (PGI2)?
Produced by vascular endothelial cells to inhibit platelet aggregation and stimulate vasodilation and block thrombogenesis
What is PGF(alpha2) produced in?
- Produced by most tissues
- In corpus lute up
- Contraction Of Smooth muscle
- Stimulates uterine contraction
What is the role of Thromboxane (TXA2)?
Thomboxanes A2 is produced in activated platelets. TX2 promotes adherence and aggregation of circulating platelets and contraction of vascular smooth muscle and promotes clot formation
Describe de novo synthesis of leukotrienes.
- Arachidonic acid is substate
AA —> (5-lipoxygenase) 5HPETE —> Leucotriene A4/B4/C4/D4
Where is LTB4 produced and released?
- Produced by polymorphonuclear leukocytes
- Increases chemotaxis
- release of lysosomal enzymes
- Causes adhesion of WBC
What are the effects of LTE4?
- Bronchocontriction
- Vasoconstriction
- Increased vascular permeability
- Contraction of smooth muscle
- Components of slow-enacting substances of anaphylaxis
What is the effect of Zyflo?
Inhibition of 5-lipoxygenase
What is the actions f Accolate (Zafirlukast)?
Leukotrienes receptor inhibitor
