Lipoproteins Flashcards
Describe the factors that affect HMG-CoA reductase and mevalonate production.
Insulin (only present in high glucose situation), promotes Phophatases which cleave the phosphate turning the enzyme on.
Glucagon/epinephrine (secreted in situations of low glucose) promote AMPkinase to phosphorylate HMGR to preserve acetyl coA for Krebs.
SREBP on the other hand monitors cholesterol levels and is found in the ENDOPLASMIC reticulum of HEPATOCYTES. If cholesterol is LOW, SREBP2 will be transported in vesicles to the Golgi. There proteases cleave the terminal segment of SREBP2, so it can move into the nucleus and enhance:
LDL receptor production and HMG-R enzymes
Statins are homonlogues of HMG-coA and compete for binding on the reductase anddecreasing intrahepatic synthesis. (low cholesterol increases number of LDL receptors thereby taking LDL out of circulation.
What are the NPC1L1 and ABCG5/G8 channels?
They are found in the intestines and regulate cholesterol absorption and secretion.
NPC1L1: brings cholesterol across the brush border.
ABCG5/G8: brings cholesterol out into the lumen for excretion.
What is ABCA1 transporter?
So HDL begins forming in the liver and instestine by loading phophatidylcholine, cholesterol and cholesteryl esters onto apoA-1.
Then ABCA1 transporter will enrich discoidal HDL with phosphatydylcholine and cholesterol out of the plasma membrane to generate nascent HDL.
Tangier disease is the absence of ABCA1. Therefore HDL cannot mature and cholesterol cannot efflux from peripheral tissues. apoA-1 is rapidly cleared.
(discoloration of tonsils), really low HDL, really low apoA-1 because ABCA1 lipidates apoA-1).
What are treatments for dyslipidemia?
- statins
- Ezetimibe: is a competitive inhibitor of cholesterol uptake by NPC1L-1 protein which absorbs cholesterol cross the brush border
- Bile Acid Binding Resins (cholestryamine), increases shunting of cholesterol and bile acids to feces
- Nicotinic acid (vitamin B3), lowers plasma TAGS, increases HDL, lowers plasma LDL.
- monoclonal antibody that targets PCSK9
- Fibrate drugs activate PPARalpha TFs which lead to increase LPL activity.
How does ezetimibe inhibit absorption of dietary cholesterol
It outcompetes cholesterol for Niemann-Pick C1-like 1 protein. This lack of absorption increases LDL receptor expression in liver and thereby decreases LDL in circulation.
What occurs in Tangier Disease
There is absence of ABCA1 which prevents HDL maturation because apoA-1 is rapidly cleared.
ABCA1- enriches discoidal HDL to make nascent HDL.
Profoundly low HDL.
Therefore cholesterol can’t be cleared and accumulates throughout the body, especially tonsils.
*tangerine, orange tonsils due to cholesterol deposits
What is going on in “fish eye disease”?
LCAT deficiency - converts cholesterol to cholesterol esters to be stored in HDL. Critical for maturation of HDL. Therefore profoundly decreased HDL particles.
nascent HDL > HDL3 > HDL2 (CE rich)
Describe the most common genetic disorder of HDL, familial hypoalphalipoproteinemia
That is an Apo A-1 deficiency.
Apo A-1 activates LCAT. There will be profoundly low HDL with complete absence of ApoA-1. Yet normal LDL and TAGs.
Non esterified cholesterol will be deposited in excess, example is mild corneal opacification but not as bad as LCAT deficiency. FIsh eye.
Describe what happens in Familial hypercholesterolemia
It boils down to defects in the synthesis, processing or function of LDL receptors.
There is elevated LDL with normal VLDL.
Greatly increases risk of Coronary Artery Disease.
People with only hypercholesterolemia and no high Tags have TENDON xanthomas as well as xenthalasma (yellow deposits under skin of eyelids). THose with both have tuberus xanthamas at the joints.
Describe hypertriglyceridemia and treatments for it.
Treatments (get those tags out of blood):
- statin to decrease VLDL synthesis.
- fish oil, omega 3 stimulates LPL activity, giving up tags to periphery
- Fibrates do the same thing as omega-3
- Niacin decreases cholesterol and TAGs. It inhibits lipolysis.
Describe familial dysbetalipoproteinemia.
There are way too much apo B proteins in the blood.
This is caused by an apoE deficiency.
IDL should be absorbed so there is accumulation of IDL and VLDL. Low levels of LDL.
Also accumulation of chylomicron remnants
Describe familial hyperchylomicronemia (a kind of hypertriglyceridemias)
Due to a lipoprotein lipase deficiency or C-II deficiency.
So you have trouble clearing chylomicrons. High TAGs in blood.
Could also have abnormally high VLDL.
There is a pathologic presence of chylomicrons even after a 12-14 hour period of fasting
ERUPTIVE Xanthomata is a symptom and increased risk of pancreatitis. Milky shit.
