17: Cholesterol I Flashcards
Cholesterol regulates membrane dynamics and is a precursor of ______ acids and ______.
Cholesterol ______ the packing within the hydrophobic core of the bilayer which _______ the mechanical strength while ______ the permeability and fluidity of the membrane.
Cholesterol is of the ______ family.
Cholesterol regulates membrane dynamics and is a precursor of bile acids and salts.
Cholesterol increases the packing within the hydrophobic core of the bilayer which increases the mechanical strength while decreasing the permeability and fluidity of the membrane.
Cholesterol is of the sterol family.
Cholesterol synthesis requires _______, as a precursor, which is initially converted to
_________.
Cholesterol synthesis requires acetyl-CoA, as a precursor, which is initially converted to hydroxymethylglutaryl CoA (HMG CoA).
The conversion of HMG CoA to _______ is catalyzed by HMG CoA reductase. HMG
CoA reductase is the key regulatory enzyme and is the rate limiting step in _________
biosynthesis.
The conversion of HMG CoA to mevalonate is catalyzed by HMG CoA reductase. HMG
CoA reductase is the key regulatory enzyme and is the rate limiting step in cholesterol
biosynthesis.
Bile salts are required for fat _______ and micelle formation in the small intestine.
Bile salts are required for fat emulsification and micelle formation in the small intestine.
Bile salts are recycled via the _________ circulation.
Bile salts are recycled via the enterohepatic circulation.
Bile salt deficiency can lead to _______ disease or __________.
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile _____ compounded with a cation, usually sodium.
Bile salts are made in the _____ & secreted into the bile. The bile salts are stored in the gallbladder until released into the _____ with the bile during a meal to act as detergents.
Movement of cholesterol into the bile must be accompanied by ____ ____ & _______ secretion.
If this dual process is disrupted by a ______ of bile salt production or increased ______ secretion–cholesterol cannot be solubilized by the bile salts & phospholipids.
Therefore, ______ of the cholesterol in the gallbladder forms _____, which is called cholelelithiasis. This is treated by a cholecyctectomy.
Bile salt deficiency can lead to cholesterol gall stone disease or cholelithiasis.
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium.
Bile salts are made in the liver & secreted into the bile. The bile salts are stored in the gallbladder until released into the intestines with the bile during a meal to act as detergents.
Movement of cholesterol into the bile must be accompanied by bile salt & phospholipid secretion.
If this dual process is disrupted by a decrease of bile salt production or increased cholesterol secretion–cholesterol cannot be solubilized by the bile salts & phospholipids.
Therefore, precipitation of the cholesterol in the gallbladder forms gallstones, which is called cholelelithiasis. This is treated by a cholecyctectomy.
Liver = _____ homeostasis. Sources of Liver’s cholesterol pool = ____ & _____ in liver & other tissues. Cholesterol leaves liver unmodified in _____, converted by bile salts/acids into ______, or as VLDL in the _______. Influx vs efflux imbalance of cholesterol can lead to deposits of cholesterol on vessels.
Liver = cholesterol homeostasis. Sources of Liver’s cholesterol pool = diet & de novo synthesis in liver & other tissues. Cholesterol leaves liver unmodified in bile, converted by bile salts/acids into intestine, or as VLDL in the circulation. Influx vs efflux imbalance of cholesterol can lead to deposits of cholesterol on vessels.
See Cholesterol structure, pg. 356
Cholesterol is made by all cells except ______. The majority is made in the ______, _______, ____ ______, & _______ tissues. All carbons in cholesterol are given by _______ & _______ provides the reducing equivalents. Cholesterol biosynthesis occurs in the _____ ER.
Cholesterol is made by all cells except RBC’s. The majority is made in the liver, intestines, adrenal cortex, & reproductive tissues. All carbons in cholesterol are given by Acetyl CoA & NADPH provides the reducing equivalents. Cholesterol biosynthesis occurs in the smooth ER.
Steps of Cholesterol biosynthesis
2 Acetyl CoA condense & form Acetoacetyl CoA by Thiolase.
A third molecule of Acetyl CoA is added by HMG CoA synthase which forms HMG CoA
HMG CoA becomes Mevalonate by HMG CoA reductase, the rate limiting step in cholesterol biosynthesis. 2 NADPH are needed for the REDUCTION. There is inhibition of this enzyme when there is increased Cholesterol.
8 steps from Mevalonate to Cholesterol:
- Mevalonate becomes 5-pyrophosphomevalonate
- Isopentyl pyrophosphate is formed from the decarboxylation of the 5-pyrophosphomevalonate, which requires ATP.
- IPP isomerizes to 3,3-dimethylallyl pyrophosphate.
- IPP & DP condense to form the 10 carbon geranyl pyrophosphate.
- A second molecule of IPP condenses with GPP to form a 15 C farnesyl pyrophosphate.
- 2 molecules of FPP combine & become Squalene. 3 ATP are hydrolyzed per Mevalonate made into IPP; hence, 18 ATP are needed to make Squalene.
- Squalene is converted to Lanosterol by an enzyme that uses molecular Oxygen & NADPH. The hydroxylation of Squalene triggers the cyclization of Squalene to Cholesterol.
- Conversion of Lanosterol to Cholesterol is a multistep process. Smith-Lemli-Opitz Syndrome is an autosomal recessive disorder of Cholesterol biosynthesis caused by a partial deficiency of 7-dehydrocholesterol-7-reductase, the enzyme that reduces 7-dehydrocholesterol to Cholesterol.
Describe the control that HMG CoA reductase is under
HMG CoA reductase is under many levels of control.
Its gene is under the control of transcription factor SREBP-2. When Cholesterol is low, SREBP enters the nucleus and stimulates HMG CoA reductase mRNA transcripts which increases the enzyme & therefore, Cholesterol synthesis.
When Cholesterol is high SREBP binds to the sterol sensing domain SCAP & Cholesterol synthesis decreases.
When Cholesterol levels are high there is proteasomal degradation of HMG CoA reductase which leads to reduced Cholesterol biosynthesis.
HMG CoA reductase is controlled by an AMP-activated protein kinase & a phosphoprotein phosphatase. The phosphorylated form of the enzyme is INACTIVE & the dephosphorylated form is active. Hence, when ATP is low & AMP is high HMG CoA reductase is INACtiVE. LOW ATP = LOW HMG CoA reductase.
Insuline & thyroxine increase HMG CoA reductase & glucagon & glucocorticoids decrease HMG CoA reductase.
What are Statins?
Statin drugs are analogues of HMG & they are competitive inhibitors of HMG CoA reductase = HMG-CoA reductase inhibitors. They are used to decrease Cholesterol levels in the plasma.
The ______ nucleus of Cholesterol is eliminated from the body by conversion to bile acid & bile salts. Some cholesterol is eliminated in the ______ or by secretion into the bile which carries it to the ______. If bacteria get their ands on cholesterol on its way to intestine, they ______ it to coprostanol & cholestanol = prominent in feces.
The sterol nucleus of Cholesterol is eliminated from the body by conversion to bile acid & bile salts. Some cholesterol is eliminated in the feces or by secretion into the bile which carries it to the intestine. If bacteria get their ands on cholesterol on its way to intestine, they reduce it to coprostanol & cholestanol = prominent in feces.
Bile = ____ + _______ ______. It passes from the liver where it is made into the gallbladder for storage & concentration & it eventually makes its way into duodenum.
Bile acids have steroid nucleus. Has pKa of _____ which = pH of the duodenum lumen so _____% of the bile acids are protenated &_____% are deprotenated.
Bile acids have a _____ face & a ______-___ face = they can act as emulsifying agents preparing lipids to be digested by pancreatic digestive enzymes.
Bile = bile salts + phosphatidyl choline. It passes from the liver where it is made into the gallbladder for storage & concentration & it eventually makes its way into duodenum.
Bile acids have steroid nucleus. Has pKa of 6 which = pH of the duodenum lumen so 50% of the bile acids are protenated & 50% are deprotenated.
Bile acids have a polar face & a non-polar face = they can act as emulsifying agents preparing lipids to be digested by pancreatic digestive enzymes.
Describe Bile acid synthesis
Describe the steps of BILE acid synthesis:
OH groups are added to the sterol ring
A double bond is reduced
3 carbons are removed
Rate limiting step = addition of OH @ C 7 of Cholesterol, making it a 7-1-hydroxycholesterol–rxn needs O2 & NADPH. Expression of this enzyme is downregulated by bile acids/
Before Bile acids leave the liver they are conjugated with serine or taurine (a product of cyteine metabolism). This conjugation makes the bile salts–i.e., they are fully ionized @ the alkaline pH of bile; this also makes them better detergents because it increases their amphipathic nature. Hence, only conjugated forms are found in Bile.
Intestinal flora in the form of bacteria can remove glycine & taurine from conjugated bile salts. They can also remove the OH group from C7 which makes many secondary bile acids.
Decribe Enterohepatic circulation
After the liver secretes bile salts into the bile, they are reabsorbed in the terminal ileum of the intestine by a sodium bile salt co-transporter & returned to the blood by a different co-transporter. Albumin then binds & transports the bile salts in the blood & bring it to hepatozytes which take up the bile salts from the blood using a sodium-bile cotransporter.
Enterohepatic circulation = the process of release of bile salts made in the liver into the bile, their passage thru the bile duct to the duodenum where some is deconjugated & dehydroxulated to secondary bile salts & their movement to the ileum where 95% is returned to the liver via the PORTAL VEIN & 5% gets pooped out in the feces.
