Cholesterol Metabolism Flashcards
Main function of cholesterol
What 3 things do cholesterol synthesize
Structural component in cell membrane (helps control fluidity)
Steroid hormones, bile acids, and vitamin D
What is the biggest source of cholesterol
De novo synthesis
Which cells in the body require cholesterol
All of them since it is a major component of cell membranes
- Main site of de novo cholesterol synthesis
2. 4 other places where de novo cholesterol synthesis occurs
- Liver
2. Adrenal cortex, skin, placenta, and testes/ovaries
Starting molecule for cholesterol synthesis
Acetyl CoA
What other two things are required to start cholesterol synthesis
Citrate (to shuttle acetyl CoA from mitochondria to cytoplasm) and NADPH
What is the main idea of the first two steps of cholesterol synthesis
Both steps involve adding a CoA
2 major steps to know about in cholesterol synthesis are doing what?
- Synthesis of HMG CoA (6 carbons)
2. Formation of mevalonate (6 carbons)
What is the rate limiting enzyme in cholesterol synthesis
What is clinically significant about it
HMG CoA reductase (turns HMG CoA to mevalonic acid)
Statin drugs target this
What kind of inhibitor are statins to HMG CoA reductase?
What does this type of inhibitor do to Km/Vmax
~what happens with noncompetitive inhibition
Competitive
Km increases, Vmax unchanged
~Km unchanged, Vmax decreases
What is the next significant thing to be formed after mevalonic acid
2 of these condense to form
Farnesyl pyrophosphate (15 carbons)
Squalene (30 carbons)
Squalene is converted to
Lanosterol
What two things need to happen in order for lanosterol to be converted to cholesterol
Shortening of carbon chain from 30-27; requires 7-dehydrocholesterol reductase (formed by farnesyl)
Smith-Lemli-Opitz syndrome (SLOS) is a defect in ?
Defect in this enzyme causes?
7-dehydrocholesterol reductase
Increase in vitamin D (7-dehydrocholesterol reductase converts 7-dehydrocholesterol into cholesterol. 7-dehydrocholesterol is precursor for vitamin D, so if it is not being converted to cholesterol, vitamin D will be made in excess)
~increased levels of 7-dehydrocholesterol/ vitamin D and decreased levels of plasma cholesterol
Clinical findings in SLOS
Microcephaly, distinctive faces, cleft palate, organ malformations, syn/polydactyly, fork toe, and genital abnormalities
How is SLOS treated
With statins
Farnesyl pyrophosphate is building blocks for which 3 biological molecules
Dolichol, heme A, and ubiquinone
- Where is dolichol used
2. Where are Heme A and Ubiquinone used?
- N-linked oligosaccharide synthesis/ lipid anchors proteins in intracellular membranes
- ETC
Difference in energy state of the body for cholesterol synthesis / ketone body synthesis
What enzyme does each use thats different
Cholesterol happens in well fed, ketone bodies happens in fasting
Cholesterol= cytoplasmic HMG CoA synthase Ketone= mitochondrial HMG CoA synthase
What is prenylation of proteins
Attaches proteins to any surface
When would dolichol, heme a, ubiquinone and prenylation of proteins be reduced
Anything that blocks HMG CoA reductase will reduce amount of these intermediates - myoglobinuria
What else can happen if HMG CoA reductase is blocked?
Rhadomyolysis- excess muscle breakdown
Cholesterol synthesis requires __ and is enhanced by ___
Requires acetyl CoA and enhanced by insulin
What is the most important factor for determining rate of cholesterol produced
Amount of cholesterol taken up by cells during lipoprotein metabolism
Hepatic synthesis of cholesterol is inhibited by
Dietary cholesterol
How does insulin induce the key enzyme
By upregulating HMG CoA reductase gene (mRNA production) and activating key enzyme
So what activates and inhibits HMG CoA reductase
Activated by insulin / dephosphorylation
Inactivated by phosphorylation
Explain the sterol dependent regulation of HMG CoA reductase gene expression
Sterol dependent regulation requires the presence of SREBP which is always under the control of SCAP. Both are usually in SER, then go to golgi apparatus which has proteases to break the bond between SCAP and SREBP, thus releasing SREBP to nucleus where it acts as a transcription factor that increases the expression of the gene for HMG CoA reductase - to form more cholesterol
What will happen to SREBP when cholesterol is high
When cholesterol is high, SREBP will bind with SCAP again to remove transcription factor
(So high cholesterol puts them together, low cholesterol breaks them apart)
- What are the two primary bile acids?
2. What are the two secondary?
- Cholic acid and chenodeoxycholic acid
2. Deoxycholic acid and lithocholic acid
4 functions of bile acids
- Provides mechanism for excess cholesterol excretion
- Prevents precipitation of cholesterol in gallbladder
- Facilitates digestion of dietary triacylglycerols
- Facilitates intestinal absorption of fat soluble vitamins
3 components of bile
- Bile acids (85%)
- Cholesterol (10%)
- Phospholipids (5%)
What is the starting point for bile acid synthesis
Site of bile acid synthesis?
Cholesterol
Liver
What is the rate limiting enzyme in bile acid synthesis
7 alpha hydroxylase
Name 4 bile salts produced from bile acid synthesis
What are these 4 considered
Glycochalic acid, taurocahlic acid, glycochenodeoxycholic acid and taurochenodeoxycholic acid
Primary bile acids
How do bile acids form bile salts
Bile acids are conjugated in the liver by glycine and taurine to form bile salts
How much bile acids do adults produce a day from cholesterol in the liver
3-5 grams
- Where are bile salts stored
2. What secretes bile
- Gallbladder
2. Hepatocytes
What are the 2 secondary bile acids
Deoxycholic acid and lithocholic acid
Whats the difference between primary and secondary bile acids
Secondary are ones that have already traveled to the small intestine and are now being reused in the liver to complete process again (along with more primary)
What does the rate limiting enzyme of bile acid synthesis (7 alpha hydroxylase) require
O2 and NADPH
Allosteric activator of bile acid synthesis?
Cholesterol (induces transcription of enzyme)
What is an allosteric inhibitor of bile acid synthesis
Increased bile acids
~bile acids regulate HMG CoA reductase activity via SREBP pathway
Main function of cholestyramine
What effect would this have
It is a bile acid sequestrant that prevents absorption of bile acid and promotes their excretion
Removing bile acids relieves inhibition so now more cholesterol can be diverted to bile acid synthesis
What increases LDL receptor expression?
Decreased cholesterol in the cells (allows hepatocytes to remove more LDL from blood)
4 pharmacological effects of cholestyramine
- Prevents cholesterol recycling
- Increases fecal loss of LDL
- Lowers serum LDL
- Treatment for hypercholesterolemia
What causes gallstone formation (cholelithiasis)
If more cholesterol enters the bile than can be solublised by bile salts and phospholipid
~so decreased bile acids in the bile
Since decreased bile acids in the bile cause gallstones, what are some factors that could contribute to not have enough bile acids?
Malabsorption of bile acids from intestine, obstruction to biliary tract, hepatic dysfunction (decreases bile salt synthesis), or accelerated recycling of bile acid
Risk factors for cholelithiasis
Fat, forty, fertile, female, and flattulent
Function of 21-hydroxylase
Enzyme used in steroid hormone synthesis
What are the 3 main hormones of steroid synthesis (in order that they are seen in the pathway)
17 alpha hydroxylase
21 alpha hydroxylase
11 beta hydroxylase
Deficiency in 21 alpha hydroxylase will prevent
Synthesis of aldosterone and cortisol
What effects will 21 hydroxylase deficiency have on the body
Will increase testosterone (exaggerated external genitalia), hypoglycemia, lack of glucocorticoids/mineralcorticoids
17 alpha hydroxylase deficiency leads to
How does this present
No cortisol produced, diminished sex hormones produced
Males-ambiguous genitalia, females- no 2nd sex characteristics; increased corticosterone secretion causes salt/fluid retention resulting in hypertension (ringing in ears) and increased aldosterone(progesterone will make more since it cannot make anything else)
11 beta hydroxylase deficiency has similar symptoms to
How does it present
21 alpha hydroxylase deficiency
Decrease in serum cortisol and aldosterone, hypertension, exaggerated genitalia
Function of glucocorticoids
Maintain blood glucose levels
