20 - Antihyperlipidemics Flashcards
Describe how chylomicrons form
- Lipids are consumed
- Gall bladder secretes bile
- Cholesterol and other fats form micelles
- Micelles are absorbed through the intestinal wall
- Cholesterol enters the enterocytes through NPC1L1 *** (Niemann-Pick C2-like 2 protein)
- Enterocytes are intestinal absorptive cells found in the epithelium of the small intestine
- Once in the enterocyte, fatty acids and monoglycerides are re-esterified to form triglycerides
- Cholesterol is re-esterified to form cholesteryl esters
- Triglycerides and cholesteryl esters are combined to form a chylomicron lipoprotein
Describe how HDLs interact with chylomicrons
- Once chylomicrons enter the circulation, HDL transfers apo E and apo C-II to chylomicrons
- Eventually LPL (lipoprotein lipase) breaks down triglycerides and facilitates capillary absorption for tissue use and storage
How are VLDLs synthesized?
VLDLs
- Triglycerides in the liver (either from de novo synthesis or plasma) form VLDLs
- Cholesteryl esters (small amount), Apo B-100, Apo E and Apo C-II are added
- Enter circulation then dump off most of the triglycerides into tissues via LPL (same as chilomicrons)
What are IDLs?
Empty VLDLs
- After most of the triglycerides are depleted from VLDL, the remnants, which are called intermediate density lipoprotein (IDL), are released into the circulation.
What happens to IDLs?
- Half travel in plasma to liver where they are endocytosed
- Half get converted to LDL (low density lipoprotein) when additional triglycerides are removed
How are LDL, VLDL, IDL and chylomicrons cleared from plasma?
Chylomicrons - lipoprotein lipase (LPL) breaks down chylomicron triglycerides into glycerol and fatty acids
VLDLs - LPL also breaks down triglycerides in VLDLs, then VLDLs become IDLs
IDLs - half get endocytosed by liver, half get converted to LDLs
LDLs - get taken up by the liver where cholesterol is extracted and repackaged, some into VLDLs
Describe cholesterol metabolism and excretion
- The liver is the only place where cholesterol can be eliminated (cholesterol cannot be oxidized to CO2 and H20)
- Cholesterol can be converted into bile acids and bile salts in the liver and secreted into the intestines
- Free cholesterol can also be secreted into bile
- About 5% of bile acids and salts are excreted in the feces daily, while 95% of bile acids and salts are reabsorbed and returned to the liver
How are fatty acids delivered to the extrahepatic tissue?
Chylomicrons triglycerides are broken down by LPL and fatty acids enter tissue
LDLs are taken up by liver or other tissues - Extrahepatic tissues endocytose LDL and use the cholesterol for multiple purposes such as lipid bilayer synthesis or steroid synthesis
Apo A-I
- Associated with HDL, chylomicrons
- Functions as a structural protein for HDL, activates LCAT, and is the ligand for SR-B1
Apo A-II
- Associated with HDL, chylomicrons
- Functions as structural protein for HDL
Apo B-48
- Associated with chylomicrons and chylomicron remnants
- Functions as structural protein for chylomicrons
Apo B-100
- Associated with VLDL, IDL, LDL, Lp(a)
- Functions as a structural protein for VLDL, LDL, IDL and a ligand for binding to the LDL receptor
Apo C-II
- Associated with chylomicrons, VLDL, HDL
- Functions as a cofactor for LIPOPROTEIN LIPASE (LPL) ***
Apo E
- Associated with chylomicrons, VLDL, IDL, HDL
- Functions as a ligand for binding LDL receptor and remnant receptors
What is hyperlipidemia?
- Elevation of total cholesterol
- Elevation in LDL cholesterol
- Elevation in triglycerides (VLDL and/or chylomicrons)
- Low HDL cholesterol
- Combination of the above abnormalities
There are two categories
- Hypertriglyeridemia
- Hypercholesterolemia)
