Lipids and Lipoproteins Flashcards
What is the building block of all isoprenoids
IPP
Cholesterol is precursor for what important compounds
Bile acids/salts
Vitamin D
Steroid hormones
Atherosclerosis
Cells are unable to degrade the steroid nucleus of cholesterol
It must be used biochemically or excreted by liver
Excess cholesterol leads to atherosclerosis
What is rate limiting step in cholesterol synthesis
HMG Coa–>Mevalonate by HMG CoA reductase
What molecules give positive feedback on HMG CoA reductase in cholesterol synthesis
Insulin, thyroxine
What molecules are inhibitors of HMG CoA reductase
Direct: Sterols, statins, bile acids/FFA
Indirect:
-High AMP, phosphorylates HMG CoA reductase to inactivate it
-Glucagon phosphorylates HMG CoA
Translational control- Reduced by tocotrienol (member of vitamin E family) and oxylanosterol
What molecules inhibit the final step of cholesterol synthesis
Azoles (i.e. miconazole)
KCN, Tamoxifen, triparanol, morpholine, AY-9944
Statins and SREBP
Statins cause an increase in sterol regulatory element binding protein SREBP which leads to transcription of LDL receptor and subsequent enhanced clearance of cholesterol
Myotoxic side effects of statins
Statins cause depletion of muscle levels of ubiquinone and resultant impairment of mitochondrial function. Squalestatins will inhibit enzyme that causes the drop in ubiquinone
Fate of cholesterol for CPR purposes
It is esterified to cholesterol esters by Acyl CoA cholesterol acyltransferase (ACAT)
Packaged into VLDL and released into blood
Regulation of HMGR gene transcription by SRE
SREBP binds SCAP (SREBP cleavage activating protein) and SREBP-SCAP complex remains inactive in the ER (by binding INSIG) while there is high cholesterol
Low sterol/cholesterol promotes release of SREBP-SCAP from ER to Golgi where it undergoes proteolysis to release mature SREBP to dimerize and go to nucleus
Binds SRE and promotes transcription of HMGR, LDLR and others
Lipoprotein function
Transport TAGs to tissues, from the intestines or liver
Play role in cholesterol homeostasis, transporting it from site of synthesis, to sites of use and then liver for excretion
Apolipoprotein function
Serve as cell targeting signals that bind to receptors to internalize lipoproteins
Activate various enzymes involved in lipoprotein metabolism and processing
Lipoproteins: highest to lowest concentration of TAGs
Chylomicrons- most TAGs, least protein VLDL IDL LDL HDL - least TAGs, most protein
Apolipoprotein names and functions
ApoB-48: facilitates transport
ApoC-11: Activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver
ApoA-1: activates enzyme that esterifies cholesterol
ApoB-100: Uptake into cells
Chylomicron processing
Nascent chylomicrons are assembled with dietary lipids in small intestine and transported to blood stream
Additional apoproteins are added to create mature chylomicron (ApoC-11 and ApoE supplied by HDL)
Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and FFAs, ApoC-11 is released back to HDL
Chylomicron remnants are endocytosed by the liver via binding of ApoE to its receptor
Mature chylomicron contains what apolipoproteins
ApoE
ApoC11
ApoB48
Abetalipoproteinemia
Lack of ApoB48 and ApoB-100
Inability to produce chylomicrons and results in impaired uptake of fat and fat soluble vitamins from food
Lipid droplets found in small intestine
VLDL, IDL and LDL processing
VLDL assembled in the liver and released into bloodstream with ApoB100, ApoC11 and ApoE
Capillary lipoproteinlipase hdyrolyzes TAGs and ApoC11 is released back to HDL, and IDL remains
Cholesterol in IDL is delivered to liver via ApoE, IDL lose more TAGs and ApoE to become LDL
LDL deliver cholesterol load to liver and peripheral tissues via binding of ApoB100 to LDL receptors on target cells
What is the major carrier of cholesterol in the blood
LDL
LDL main function
Transport cholesterol to peripheral tissues and regulate de novo synthesis of cholesterol at these sites
HDL processing
HDL donates and receives ApoC11 and ApoE from chylomicrons
HDL transfers cholesterol esters to VLDL, IDL and LDL in exchange for TAGs and phospholipids
Exchanges are facilitated by cholesterol ester transfer protein CETP
HDL delivers its cholesterol load to the liver
Beneficial effects of HDL
HDL crucial for maturation of chylomicrons
HDL retrieves cholesterol from other tissues in body to return to liver for excretion
Therefore, HDL scavenges and removes LDL-cholesterol from periphery and transports it to liver
Macrophages and HDL cholesterol transport fail
When HDL transport fails, macrophages become foam cells and facilitate formation of plaques. Macrophages that collect cholesterol from LDL usually transport it to HDL
Tangier disease
Under normal conditions, ApoA1 of HDL binds ABCA1 to facilitate LDL transport
Loss of ABCA1 activity results in Tangier disease, which is characterized by HDL deficiency, accumulation of cholesterol in macrophages and premature atherosclerosis
HDL levels increased by
Antihypercholesteremic drugs, fibrates, estrogens, omega 3 fatty acids
Type I hyperchylomicronemia
Deficiency in ApoC11 or defective lipoprotein lipase, meaning you cant hydrolyze TAGs in chylomicrons and VLDL
Increased chylomicrons and TAGs
Blood separates into cream and clear layers
Abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas
Treat with low fat diet
Type IIa and IIb hypercholesterolemia
LDL receptor is completely (a) or partially (b) defective
Increased cholesterol, forms oxLDL which causes atherosclerosis
Cholesterol >800 w/homozygous mutation (die from coronary artery disease before teenage years w/o liver transplant and LDL apheresis)
Cholesterol 300-500 w/heterozygous mutation
Impaired ability to recognize ApoB100 on LDL
TAGs: Normal (IIa) increased (IIb)
Increased LDL
Increased VLDL (IIb)
oxLDL
Accumulates in endothelial cells
Taken up by macrophages in unregulated manner
Macrophages/foam cells die, cause inflammatory response leading to platelet adhesion and recruitment of smooth muscle cells which causes further plaque development
