Biochemistry Cholesterol Metabolism Flashcards
Which tissues synthesize cholesterol
essentially all nucleated cells - Liver accounts for 50% of synthesized cholesterol, steroid hormone producing cells are also very active
where is cholesterol synthesized within the cell
cytosol and endoplasmic reticulum
What are the carbon atoms of cholesterol derived from
acetyl-CoA
What is the rate limiting step/major control point of cholesterol metabolism? What drugs inhibit this step?
HMG CoA-reductase - inhibited by statins
Where is HMG-CoA reductase found
it is an endoplasmic reticulum embedded enzyme
formation of isopentenyl diphosphate includes what steps
4 steps, sequential phosphorylation by 3 kinases (3ATP) and decarboxylation
What reaction is synthesized by HMG-CoA reductase
HMG CoA is reduced to mevalonate
What cofactors are required by HMG-CoA reductase
2 NADPH + 2H+
describe the formation of a squalene
1.) 2 isoprenoid units are used to form geranyl diphosphate 2.) A thrid isoprenoid unit is added to form darnesyl diphosphate 3.) two farnesyl diphosphates are used to synthesize sqalene
Name the positive regulators of HMG CoA reductase
Promote dephosphorylation of HMG CoA reductase : 1.) Insulin 2.) Thyroxine (thyroid hormone)
Name the negative regulators of HMG CoA reductase
Promote phosphorylation of HMG CoA 1.) Glucagon 2.) Glucocorticosteroids 3.) Cholesterol
Describe: Squalene to Lanosterol
1.) Squalene epoxidase (requires NADPH and O2) 2.) Lanosterol cyclase
What is the first sterol produced in the pathway to cholesterol
Lanosterol
Name the five steps between lanosterol and cholesterol
1.) Removal of methyl group at C14 2.) Removal of 2 methyl groups at C4 3.) Reduction of C24 double bond 4.) Moving the double bond from 8-9 to 5-6
where does the conversion of lanosterol to cholesterol take place
in the endoplasmic reticulum
what are the “Other products” produced in the cholesterol synthesis pathway
1) Prenylated proteins 2.) Dolichol 3.) Ubiquinone
Prenylated proteins
membrane associated proteins (GTP-binding proteins) prenylated with farnesyl or geranylgeranyl residues. Function: Anchor protiens to the membrane
Dolichol
formed from farnesyl diphosphate plus up to 16 more isopentyl residues. Dolichol is required for the synthesis of N-linked glycoproteins
Ubiquinone
formed from farnysyl diphosphate plus 3-7 isopentenyl residues. Required for the electron transport chain
Fates of cholesterol in the liver
1.) Formation of cholesteryl esters that get transported to other tissues 2.) Secreted into bile 3.) Synthesized into bile acids and bile salts
what enzyme is involved in cholesteryl ester synthesis
ACAT (Acyl CoA-cholesterol acyltransferase
Tissues use cholesteryl esters for what
1.) Steroid hormone synthesis 2.) Vitamin D synthesis
What are the only ways we have to get rid of cholesterol
1.) Secrete it into bile 2.) Synthesize into bile acids and their salts
What is the only way the body can open the steroid ring
Convert to vitamin D
What is the committed step of bile acid synthesis
7a-hydroxylase
What is the main organ for control of whole body cholesterol metabolism
Liver
Major site of cholesterol synthesis
Liver
Liver secretes cholesterol into the blood stream via
VLDL
What are the three regulatory targets of the liver
1.) HMG-CoA reductase (cholesterol synthesis) 2.) LDL receptor 3.) 7a-Hydroxylase (bile acid synthesis)
Transcriptional control of cholesterol synthesis
SREBP (sterol-regulatory element binding protein) binds to the SRE (sterol regulatory element) of HMG-CoA reductase to stimulate transcription of the gene. Elevated amounts of cholesterol will prevent SREBP binding - instead it interacts with SCAP (SREBP cleavage activating protein) which contains a sterol binding domain, as long as cholesterol is around the SREBP stays bound to SCAP within the ER. When cholesterol levels fall cholesterol leaves the SCAP binding site and the SREBP: SCAP complex then moves to the golgi where SREBP is released and allowed to travel to the nucleus to bind SRE
Proteolysis of HMG- CoA reductase
when the sterol sites are occupied by cholesterol the enzyme is more susceptible to proteolysis
Regulation of HMG CoA reductase through phosphorylation/dephosphorylation
HMG-CoA reductase is less active when phosphorylated
what regulates the synthesis of LDL receptors
intracellular cholesterol content
Transcriptional control of LDL receptors
under the same control as HMG-CoA reductase = SREBP binding to SRE of the LDL receptor gene. Elevated cholesterol will prevent the binding to the LDL receptor gene (same mechanism as HMG-CoA reductase)
What promotes the destruction of LDL receptors
PCSK9
What represses the syntheis of 7a-hydroxylase
increased bile acids in the liver - bile acid binds farnesyl X-receptor (FXR) and this complex supresses 7a-hydroxylase synthesis
