April 20, 2016 - Lipids *HUGELY UNFINISHED* Flashcards
NPC1L1
Niemann-Pick C1-like 1
A transmembrane transporter that transports lipids (FA, MG, cholesterol) across the duodenal enterocytes.
The target of ezetimibe
Orlistat
Inhibits pancreatic lipase and causes fat malabsorption.
Marketed for the treatment of obesity, but is rarely used because of significant bloating and steatorrhea.
Ezetimibe
A medication that inhibits NPC1L1 and therefore prevents cholesterol absorption.
It is a cholesterol-lowering agent and is usually used in combination with other treatment.
ApoB48
After absorption, FAs and MGs are resynthesized into TGs and lipids and are then packaged with ApoB48 to form nascent chylomicrons.
This process requires the enzyme microsomal triglyceride transfer protein (MTP).
MTP
Microsomal Triglyceride Transfer Protein (MTP)
Needed to add apoB48 which forms nascent chylomicrons.
MTP Defects
Result in a clinical condition known as “abetalipoproteinemia” which is the absence of ApoB.
With the inability to transfer triglycerides to chylomicrons, essentially fat cannot get inot the body.
LPL
Lipoprotein Lipase
Found on the surface of extrahepatic endothelial cells. This hydrolyzes triglyercides which frees FAs for peripheral tissue such as for energy and storage. This process requires apoC2 as an obligate cofactor.
Without LPL or APOC2, you get a massive increase in triglycerides because the chylomicrons cannot be metabolized and build up in the circulation instead.
LPL / ApoC2 Deficiency
Cause a massive buildup of triglycerides becuase chylomicrons cannot be metabolized and build up in circulation.
LRP1
Pipoprotein Receptor-related Protein 1.
Remnant chylomicron particles are removed by LRP1 and the LDL receptor.
Clearance of chylomicron remnants by LRP1 and the LDL receptor are mediated by apoE
apoE
Required for the removal of chylomicron remnants by LRP1 and the LDL receptor
Mutations in apoE result in a buildup of TGs and total cholesterol because of a build up of remnant particles. This is called dysbetalipoproteinemia.
Summary of Exogenous Pathway
- We eat food
- Fat is broken down and absorbed in the intestine
- TGs and cholesterol are reassembled into chylomicrons with the help of apoB48
- Chylomicrons are then released into the lymphatics and spill over into the veins and enter the circulation where they acquire apoC2 and apoE
- Chylomicrons are quickly chomped up by LPL (which requires apoC2), thus freeing FAs for fuel and storage, leaving the chylomicron remnants behind
- Chylomicron remnants are then removed by the liver via LRP1 and the LDL receptors which recognize apoE
HMG CoA Reductase
The enzyme responsible for cholesterol biosynthesis.
This is the rate-limiting enzyme
Negative feedback from increase cholesterol
VLDL
Very low density lipoprotein
Works with apoB100 to export lipids (TG + cholesterol) from the liver
Once in circulation, VLDL requires apoC2 and apoE
apoB100
Works with VLDL to export lipids from the liver