Week 6: Cholesterol Metabolism Flashcards
What is cholesterol and what is it a precursor for?
Cholesterol is a four-ringed saccharide that is used to make steroid hormones, bile acids, and Vitamin D, and is also found within lipid rafts of the cell membrane. We make most cholesterol ourselves, but some also comes through our diet.
Where does cholesterol synthesis begin, and what is needed? What enzymes mediate this three-part process, and which step is rate-limiting?
(1) Cholesterol synthesis begins in the ER, and begins with 2 Ac-CoA molecules. They are joined by acetyl-CoA acyl transferase.
(2) Then, another acetyl-CoA is added via HMG-CoA synthase, forming HMG-CoA.
(3) Then, HMG-CoA reductase (RATE-LIMITING) converts HMG-CoA into mevalonate, removing a CoA-SH and H2O in the process
How does SREBP regulate cholesterol synthesis?
(1) Decreased cholesterol levels cause INSIG-1 to be cleaved from the INSIG-1/SCAP/SREBP molecule.
(2) Then, SREBP is cleaved from the SCAP/SREBP molecule by enzymes, moving to the nucleus to bind to a sterol regulatory element.
(3) This allows for transcription of the HMG-CoA reductase gene, increasing the presence of HMG-CoA reductase enzyme and speeding up endogenous cholesterol synthesis.
What is critical about the squalene step in cholesterol metabolism?
Squalene is the last linear molecule in the formation of cholesterol before it becomes a ring structure. This is also the linear acyl molecule that helps sharks, whales, and other sea creatures float!
What is the significance of 7-dehydrocholesterol?
If it is hit by a photon (i.e. if you are not a vampire), it can become Vitamin D3, which plays a critical role in cholesterol and phosphate metabolism.
What can cholesterol become in the liver? How are these materials recycled?
Cholic acids and chenodeoxycholic acids, both of which can be conjugated with amino acids taurine and glycine. This forms taurocholic and taurochenodeoxycholic acids, and glycocholic acid and glycochenodeoxycholic acid, respectively. They are stored in the gallbladder, and are released during digestion. They can be recycled by the hepatic portal vein, in a process called enterohepatic circulation.
How and where is cholesterol used to make steroid hormones, and what are they?
Cholesterol is used by the adrenal glands to make the steroid hormones cortisol (stress/fight or flight response) and aldosterone (BP regulation), and is modified by enzymes present there.
Cholesterol is also used by the gonads to make testosterone in males, and estradiol and progesterone in females.
What is the most heavily regulated step in cholesterol synthesis?
HMG-CoA to mevalonate, mediated by HMG-CoA reductase
How do oxysterols contribute to regulation of the activity of HMG-CoA reductase? How does this molecule relate to SREBP?
Oxysterols are made as a small portion of cholesterol (kind of like F 2,6-BP is a proxy for F16BP in glycolysis), and when present in high amounts, cause HMG-CoA reductase to undergo ubiquitylation and degradation in the 26S proteasome. This degradation is mediated by the same enzymes that regulate SREBP. Thus, as cholesterol levels rise, the amount of rate-limiting enzyme is decreased.
What effect does insulin have on cholesterol synthesis? What about glucagon?
Insulin increases the activity of HMG-CoA reductase, and increases cholesterol synthesis. It is phosphorylated/inactivated in the presence of glucagon, and decreases activity. HMG-CoA reductase is associated with the “lipogenic liver” (FA-synthesizing) in the well-fed state.
How is cholesterol transported in the bloodstream?
Cholesterol is transported via lipoproteins in the bloodstream, which are composed of a core of very hydrophobic lipids surrounded by a shell of polar, hydrophilic lipids and a variety of proteins.
What are the different kinds of lipoproteins?
Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate and low density lipoproteins (IDL and LDL)
and high density lipoproteins (HDL)
What are the properties of chylomicrons?
These particles are the largest and least dense of the lipoproteins. They transport dietary lipids from the intestine to the liver and other tissues.
What are the properties of VLDL?
TAGs, cholesterol and phospholipids are transported from the liver to “needy” tissues by VLDL molecules. VLDLs can also be converted to other types, including IDL and LDL.
What are the properties of IDL and LDL?
When depleted of TAGs, VLDL remnants are given the name intermediate/low density lipoproteins. They can deliver cholesterol to tissues for various purposes, but constitute “bad” cholesterol. The exposure of IDL/LDL to vascular tissues is believed to induce an inflammatory response that can lead to atherosclerosis.
What are the four main kinds of storage and membrane lipids? Describe their structure.
(1) TAGs
(2) Glycerophospholipids (phosphate group and alcohol on one branch)
(3) Sphingosines (phosphate group/choline OR sugar moiety)–most readily IDd by ammonia group attached
(4) Cholesterol
What is the common precursor to TAGs and glycerophospholipids?
Phosphatidic acid. Attachment of a head group (serine, choline, etc) forms the glycerophospholipid, esterification of another acyl group (long chain acid) forms the TAG.
What are the two different ways by which headgroups can be attached to DAGs in forming the glycerophospholipid?
Either the DAG itself is activated, and the -OH moiety on the future headgroup attacks nucleophilically (like serine), or the headgroup is activated, and the -OH group on the DAG attacks the a-phosphate attached to the headgroup nucleophilically.
What is the key factor that helps us identify plasmologens? What is their function?
Ether linkages, as opposed to ester (in glycerophospholipids and TAGs) linkages. They protect agains ROS’ and consititute platelet-activating factor.
