Sources of Cholesterol
Rate limiting enzyme of cholesterol production
Fates of Cholesterol
Lipid and cholesterol transport systems make use of the same ____.
Lipid and cholesterol transport systems make use of the same lipoprotein transporters.
Chylomicrons deliver dietary fat that is ____; VLDL delivers fat that is ____.
Chylomicrons deliver dietary fat that is absorbed in the intestine; VLDL delivers fat that is produced by the liver.
enterohepatic circulation of bile acids
Bile acids are excreted from the gall bladder, used to emulsify fat in the gut, and then many are reabsorbed and delivered back to the liver.
Consequences of elevated LDL
Cholesterol and Cholesteryl esters
Schematic of LDL
Scale of Lipoproteins
A lipoprotein stripped of all its lipids.
Core protein of HDL. Activates LCAT, the enzyme that triggers reverse cholesterol transport from cells to HDL
ApoB48 and B100 relationship
These proteins are both expressed from the same gene, and are made by the small intestine and liver, respectively
In the liver, the full length apolipoprotein is made (100% of full length, so it is called ApoB100). This protein acts as a scaffold for the VLDL particle, and thus is also found in the derivative particles IDL and LDL. It acts as the major binding site for the LDL receptor and is thus responsible for uptake of the LDL particle by the liver.
In the small intestine, a shorter version (48% of full length) of ApoB is produced (hence ApoB48). This protein acts as the scaffold for a chylomicron. Since it lacks the C-terminal region of ApoB100, it cannot bind the LDL-receptor, and thus chylomicron remnants rely primarily on ApoE for uptake by the liver.
Activates lipoprotein lipase
Triggers clearance of some VLDL particles and all chylomicron remnants.
Apo C and E relationship
Secreted by the liver and intestine into the blood stream, where they then bind the nascent lipoprotein particles.
Apo E and C can also be transferred between HDL, VLDL and chylomicrons.
Common Pathway for Lipoprotein Production
microsomal triglyceride transfer protein
Responsible for loading VLDL (liver) and chylomicrons (intestine) with triacylglycerides within the ER as the apolipoproteins are being translated. This step is called lipidation.
Enterocytes secrete chylomicrons into ___. Hepatocytes secrete VLDL into ___.
Enterocytes secrete chylomicrons into lacteals, which then drain into local lymphatics and eventually enter venous circulation via the thoracic duct. Hepatocytes secrete VLDL into the bloodstream directly.
Life of a chylomicron
Fatty acid and glycerol absorption and packaging into chylomicrons (within enterocytes)
Niemann-Pick C1–like 1 (NPC1L1) protein
A cholesterol transporter located within the apical membrane of an enterocyte. Responsible for dietary cholesterol absorption.
Small molecule inhibitor of NPC1L1. Prevents/lessens dietary cholesterol absorption.
Dietary cholesterol absorption diagram
Lacteals and Gut Lymphatics
Location of the cysterna chyli
Just posterior to the pyloric sphinctre and just right of the abdominal aorta.
ApoC-II and ApoE in chylomicron metabolism
Apo C-II is required to ___, whereas ApoE promotes ___.
Apo C-II is required to activate lipoprotein lipase, whereas ApoE promotes the uptake of the chylomicron remnant by the liver.
Nascent chylomicron's apolipoproteins
Mature chylomicron's apolipoproteins
Chylomicron remnant's apolipoproteins
ApoC-II and ApoE in VLDL metabolism
Nascent VLDL's lipoproteins
Mature VLDL's lipoproteins
IDL / VLDL remnant's lipoproteins
(The same as VLDL, IDL just has had some triacylglycerides removed)
Why not just secrete VLDL and chylomicrons with ApoC-II and ApoE? What function does necessiting their pickup from HDL serve?
If VLDL and chylomicrons were secreted in the mature form, they would only deliver triacylglycerides to tissues local to their secretion site. Necessiting the pickup of ApoC-II and ApoE ensures wide dissemination of the triacylglycerides throughout the body.
LDL / IDL remnant's lipoproteins
By the time a VLDL particle reaches the LDL stage in its lifecycle, it is. . .
. . . mostly cholesterol-containing. Its triacylglycerides have pretty much all been absorbed.
The presence of apoB100 as the only protein in the particle ____. This enables ____.
The presence of apoB100 as the only protein in the particle slows the rate at which it is taken up by the liver. This enables other tissues to use their LDL receptors to take up the cholesterol-rich particle, enabling delivery of cholesterol to other tissues
Lipoprotein lipase is secreted by ___, and then ___.
Lipoprotein lipase is secreted by adipose tissue, skeletal muscle, and cardiac muscle, and then moves through extracellular fluid and across the capillary wall to the lumen of the capillary.
Lipoprotein lipase secretion by muscle vs by adipose tissue
- Adipose tissue:
- Secreted in response to insulin
- Inhibited by glucagon/epinephrine/cortisol in fasted state
- Secreted in response to insulin
- Inhibited by glucagon/epinephrine/cortisol in fasted state
- Production inhibited by insulin (since muscle favors glucose as fuel)
- Activity stimulated by exercise and fasting
Regulation of lipoprotein lipase regulation is largely ___ in adipose tissue vs muscle tissues.
Regulation of lipoprotein lipase regulation is largely reversed in adipose tissue vs muscle tissues.
Lipoprotein lipase action
Lipoprotein lipase regulation diagram
Angiopoietin-like 3 and 4
Proteins that are secreted by tissue such as adipose and muscle and released locally into capillaries where they can inhibit LPL
The main contributors to atherosclerotic plaques are ____.
The main contributors to atherosclerotic plaques are cholesterol-rich chylomicron remnants and LDL.
Inhibits LPL activity. A mechanism for keeping lipoproteins in the bloodstream longer so that they can be disseminated. Contributor to atherosclerotic/cardiovascular disease.
Cellular regulation of cholesterol
When cellular cholesterol levels are low, the cell increases expression of ___ and of ___
When cellular cholesterol levels are low, the cell increases expression of the LDL receptor and of HMG CoA reductase
When cholesterol is low, this triggers the recruitment of a transmembrane protein called SREBP to SCAP (a CopII-associated receptor), enabling SREBP trafficking from the ER to the Golgi apparatus.
In the Golgi, there is a serine protease that can cleave SREBP, which renders it sensitive to another protease (metalloprotease). Proteolysis releases the basic helix-loop-helix (bHLH) domain of SREBP from the membrane, so it can then move to the nucleus where it binds and activates the SRE (sterol response element).
Thus, SREBP is a regulatory transcription factor that increases the expression of the LDL receptor and HMG CoA reductase.
The cell's cholesterol sensor
SCAP is the CopII-associated receptor for SREBP. It enables SREBP traffic and subsequent transcription when cholesterol is low, but when cholesterol is high SCAP is sequestered by Insig, which blocks its interaction with SREBP.
Introduction to LDL-mediated pathology and foam cells
Unlike conventional LDL receptors, which ____, the scavenger receptor ____.
Unlike conventional LDL receptors, which are downregulated when the cell has sufficient cholesterol, the scavenger receptor remains active even when cholesterol is abundant
This is why macrophages can keep taking up LDL without inhibition and form foam cells, which are so clogged with lipid droplets that they can no longer function.
LDL pathogenesis diagram
Reverse Cholesterol Transport
HDL particles can be taken up by ____.
HDL particles can be taken up by scavenger receptors on the liver cell or on other cells that consume a lot of cholesterol (steroid producing cells).
Reaction catalyzed by LCAT
Indirect reverse cholesterol transport
Here, about 1/3 of the cholesterol present in HDL is moved to B-100 containing lipoproteins (IDL/LDL/VLDL) in exchange for triglycerides.
Conversion of cholesterol to bile acid
Regulation of bile acid production
Nuclear hormone receptor in hepatocytes activated by cholesterol. Induces expression of genes that convert cholesterol to bile acids (CYP7A1) and other genes that enhance biliary cholesterol secretion
Nuclear receptor in hepatocytes that is activated by bile acids. Triggers transcriptional upregulation of bile acid secreting transporters, which pump bile acids into the bile duct.
Recirculation of bile salts
The fatty acids that form triglycerides present in VLDL are derived from ___.
The fatty acids that form triglycerides present in chylomicrons are derived from ___.
The fatty acids that form triglycerides present in VLDL are derived from those synthesized by the liver AND those absorbed through the diet.
The fatty acids that form triglycerides present in chylomicrons are derived from those absorbed through the diet.
The ability of the statin drugs to lower LDL levels in the blood is best explained by
An increased rate of clearance of LDL from the blood stream
Low cellular biosynthesis of cholesterol makes the cell rely more on LDL receptor expression. LDL-R is upregulated by the SCAP/Insig/SREBP system, resulting in a greater rate of clearance of LDL from the bloodstream.
LDL can be taken up by receptor mediated endocytosis in ____.
LDL can be taken up by receptor mediated endocytosis in most tissues
Statins are ___ in familial hyperlipidemia.
Statins are of little therapeutic value in familial hyperlipidemia.
LDL-R internalization in the liver is an important part of a statin's mechanism of action, and so deficiency in the ability to endocytose the LDL-R makes statins substantially less effective.
SCAP essentially senses ___.
SCAP essentially senses the concentration of cholesterol in the lipid bilayer of the ER.