Lecture 44 Flashcards
Cholesterol is a major component in:
Cell plasma membranes
Describe plasma membrane cholesterol
Cholesterol is an amphipathic molecule, meaning, like phospholipids, it contains a hydrophilic and a hydrophobic portion. It slightly immobilizes the outer surface of the membrane and makes it less soluble to very small water-soluble molecules that could otherwise pass through more easily
In order of very low levels to very high levels, what cellular components (4) have cholesterol?
1) Rough ER (Lowest amount of cholesterol)
2) Smooth ER
3) Golgi
4) Plasma membrane
What are 5 major classes of steroid hormones derived from cholesterol?
1) Progestagens
2) Glucocorticoids (subclass of progestagens)
3) Mineralocorticoids (subclass of progestagens)
4) Androgens (subclass of progestagens)
5) Estrogens (subclass of Androgens)
What are key characteristics of cholesterol?
1) Made up of 27 carbons, all derived from acetate
2) C3 has a hydroxyl group
3) C17 has a side chain with 8 carbons
Where does cholesterol come from?
1) Synthesized primarily in the liver & intestine
2) Not required in the diet
3) Intestinal uptake from diet
How is cholesterol eliminated from the body?
1) Converted into bile acids & bile salts in the liver
2) Stored in gall bladder or secreted into the intestine
3) Small % excreted in feces
What are cholesterol esters?
1) Esterification at C3 with fatty acid
2) Primary form transported in plasma
3) Packaged in lipoprotein particles (LDL, HDL, etc.)
How is HMG CoA synthesized?
1) 2 Acetyl CoA undergo a reaction catalyzed by thiolase to release CoA and transfer the acetyl group to form 2-acetoacetyl CoA
2) 2-acetoacetyl CoA undergoes a reaction with acetyl CoA catalyzed by HMG CoA synthase to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA) and release CoA
3) Reactions occur in the cytosol, mitochondria, & peroxisomes
How is Mevalonic Acid synthesized?
1) HMG CoA undergoes a reaction catalyzed by HMG CoA reductase, oxidized 2 NADPH, releases a CoA, & forms Mevalonic acid in the ER (rate limiting step)
2) Mevalonic acid can undergo a series of reactions to form cholesterol
How is cholesterol synthesized from Mevalonic Acid?
Mnemonic: My Porsche Is Darn Good For Seeing London
1) Kinases phosphorylate mevalonic acid using ATP to produce 5-pyrophosphomevalonic acid (cytosol, mitochondria & peroxisomes)
2) A decarboxylase uses ATP to produce Isopentyl pyrophosphate (IPP) from 5-pyrophosphomevalonic acid (Produces 3 ATP + 2 NADPH) (ER)
3) An isomerase produces 3,3-Dimethylallyl pyrophosphate (DPP) (Produces 3 ATP + 2 NADPH) (peroxisomes)
4) An FPP transferase uses inorganic phosphate to produce Geranyl pyrophosphate (GPP) (Produces 3 ATP + 2 NADPH) (peroxisomes)
5) An FPP transferase uses inorganic phosphate to produce Farnesyl pyrophosphate (FPP) (peroxisomes)
5) A squalene synthase produces squalene from Farnesyl pyrophosphate (FPP) (peroxisomes)
6) Squalene monoxygenase produces lanosterol from squalene (peroxisomes)
7) Cholesterol is produced from lanosterol (ER + peroxisomes)
How is cholesterol regulated through gene expression?
1) Increase in intracellular cholesterol causes a decrease of transcription of nearly all genes encoding proteins in the cholesterol synthesis pathway
2) A decrease in intracellular cholesterol causes an increase in transcription of cholesterol synthesis proteins
What is the transcription factor responsible for cholesterol gene expression?
The transcription factor regulating cholesterol synthesis genes is SREBP-sterol responsive element binding protein
What is Sterol Regulatory Element Binding Protein (SREBP)?
1) a transmembrane protein
2) has a DNA binding domain
3) has a SCAP interacting domain
What is SREBP Cleavage Activating Protein (SCAP)?
1) a transmembrane protein
2) has a sterol sensing domain
3) binds to SREBP in the ER
4) when ER sterols are low, SCAP-SREBP move to the Golgi
What do protease 1 and 2 do?
1) localized to the golgi
2) responsible for the two step cleavage of SREBP resulting in soluble, cytosolic SREBP
What is mature, proteolytically processed SREBP?
1) translocates from the Golgi to the nucleus
2) Activates the expression of cholesterol synthesis genes
What are the steps to?
1) When sterol levels are low, SCAP and SREBP are transported to the golgi
2) Protease 1 cuts a connection to SREBP
3) Protease 2 releases SREBP
4) SREBP translocates to the nucleus causing transcriptional activation of sterol responsive element (SRE) controlled genes
How does cholesterol regulate the stability of HMG CoA reductase?
1) Increased intracellular cholesterol causes a reduction in the stability of HMG CoA reductase (misfolding and degradation)
2) Decreased intracellular cholesterol causes an increase in the stability of HMG CoA (proper protein folding)
What happens when HMGR is phosphorylated?
1) HMGR is phosphorylated by an AMP activated kinase (AMP kinase - not the same as cAMP kinase)
2) Low levels of ATP & high levels of AMP causes AMP activated kinase activation, HMGR phosphorylation, & decreased cholesterol synthesis
How is HMGR expression hormonally regulated?
1) Insulin stimulates HMGR expression & activity
2) Glucagon inhibits HMGR expression & activity
What are competitive drug inhibitors of HMGR?
1) Statins competitively inhibit HMGR because they mimic the transient intermediate mevadyl CoA
2) Examples: Mevacor, altocor, pravachol, zocor, lipitor, baycol, & lescol
What does zetia (ezetimibe) do?
1) acts on small intestine brush border)
2) does not enter the bloodstream, no side effects
3) inhibits absorption of cholesterol
4) does not block absorption of triglycerides or fat soluble vitamins
What does vytorin (ezetimibe + simvastatin) do?
1) ezetimibe is administered in combination with a simvastatin
2) further reduces total cholesterol levels as compared
to statin alone
3) blocks cholesterol absorption in the intestine and
cholesterol synthesis in the liver
4) permits reduced doses of statins, which have
side effects
