Cholesterol metabolism week 3 Flashcards
What is the structure of cholesterol?
(1) the complex 17-carbon ring-structure (four fused rings)
(2) a single OH group at C-3
(3) an unsaturated bond between C-5 and C-6
(4) an 8-membered branched hydrocarbon chain attached to the D ring at position 17
(5) a methyl group (C19) attached at position 10 and another methyl group (designated C-18) attached at position 13.
What is the concentration of cholesterol in plasma? How is cholesterol transported?
How much cholesterol is “free”? What form is the rest of cholesterol in? What FA is typically used to form this cholesterol? What does adding this FA do?
- Cholesterol is a complex lipid with very low solubility in water. Its concentration in plasma is 150 200 mg/100 ml in healthy people, twice as high as glucose.
- Cholesterol is transported in blood by plasma lipoproteins chylomicron (food source), VLDL (liver source), chylomicron remnant, LDL and HDL that bind and solubilize it.
- Only about 30% of total cholesterol is free, the rest is in the form of cholesterol esters where long-chain fatty acids, usually linoleic acid, is attached by an ester bond to the OH group on C-3 of the A ring.
- The fatty acid enhances the hydrophobicity of cholesterol.
What are 4 fxns of cholesterol?
- Cholesterol is the major sterol in humans and a component of virtually all plasma and intracellular membranes. It is especially abundant in myelinated structures of brain and CNS and present in small amounts in the inner membrane of the mitochondria. Most cholesterol in membranes is in the free form and is not esterified.
- Cholesterol is the immediate precursor of bile acids synthesized in the liver that facilitate absorption of dietary triacylglycerols and fat-soluble vitamins. Bile salts, derivatives of cholesterol, also help to solubilize cholesterol in bile, while cholesterol protects membranes of the gallbladder from irritating or harmful effects of bile salts. Cholesterol cannot be catabolized to CO2 and so it is excreted by the liver through the intestine in the form of bile acids.
- Cholesterol is also the precursor for various steroid hormones.
Progesterone
Progesterone
Glucocorticoid
Mineralocorticoid
Female steroid hormones
Male steroids hormones
Although all steroid hormones are structurally related they have widely different properties.
4. The hydrocarbon skeleton of cholesterol is also found in plant sterols, for example, ergosterol, a precursor of vitamin D. Ergosterol is converted in skin by UV to vitamin D2.
In what 3 ways does cholesterol leave the liver?
- Dietary source – delivered in chylomicrons to the periphery and by chylomicron remnants to the liver
- Synthesis – liver and some extrahepatic tissues (delivered to liver by LDL and HDL)
- Cholesterol leaves liver
a. Packaged in VLDL
b. Secreted to bile as free cholesterol
c. Converted to bile acids
What organs have the greatest capacity for cholesterol synthesis?
What molecule is cholesterol synthesized from?
What 2 things need to be supplied for this process?
What is the cellular localization of cholesterol synthesis?
Cholesterol is Synthesized from Acetyl CoA
- Capacity for cholesterol synthesis is greatest in liver, intestine, adrenal cortex and reproductive tissues, including ovaries, testes and placenta.
- All carbons of cholesterol are derived from acetyl CoA and reducing power is supplied by NADPH produced by the Hexose Monophosphate Shunt.
- The pathway is in the cytosol and is driven mostly by hydrolysis of high energy thioester bonds of acetyl CoA and phosphoanhydride bonds of ATP.
List and explain the first 3 steps of cholesterol formation. State what enzymes catalyze these rxns and what is required and/or produced at each step.
What is the committed and rate limiting step?
- In the first step, two acetyl CoA condense to form acetoacetyl CoA, as catalyzed by acetoacetyl CoA thiolase.
- In the next step, a third acetyl CoA is added to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA) as catalyzed by HMG CoA synthase. (The mitochondrial form of this enzyme makes ketone bodies.)nHMG CoA can also be formed from oxidative degradation of Leu.
- HMG CoA is then converted to mevalonate (C6) at the expense of two NADPH, as catalyzed by HMG CoA reductase, the committed and rate-limiting step in cholesterol synthesis.
What is mevalonic acid converted to? What must be done to mevalonate to convert it?
Mevalonate (C6) is decarboxylated (C5) and in the following steps, C5 unit condense to form lanosterol, which is the first steroid containing the ring structure specific of cholesterol and its derivatives.
What is needed to convert lanosterol to cholesterol?
ATP, NADPH
What is the primary site for control of cholesterol synthesis?
HMG CoA reductase
How do dietary cholesterol levels influence cholesterol synthesis?
The cholesterol pool of the body is derived from absorption of dietary cholesterol and biosynthesis primarily in liver and intestine. When dietary cholesterol level is decreased, cholesterol synthesis in liver and intestine increases. When dietary cholesterol increases, synthesis is suppressed.
Explain the intracellular mechanism of suppression of cholesterol biosynthesis by LDL bound cholesterol.
The intacellular mechanism of suppression of cholesterol biosynthesis by LDL-bound cholesterol involves specific LDL receptors.
o LDL binds to the receptor, which extracts LDL from the blood.
o The receptor recognizes only LDL and VLDL, both of which carry apolipoprotein B-100.
o The LDL receptor becomes endocytosed together with the LDL.
o The intracellular vesicles then become endosomes.
o This is called receptor-mediated endocytosis.
o Then, the endosome fuses with a lysosome that contains proteases and cholesterol esterase.
o The LDL receptor separates from LDL and returns to the surface.
o Inside the lysosome, the cholesterol esters of LDL are hydrolyzed by cholesterol esterase to produce free cholesterol and a long-chain fatty acid.
o Free cholesterol then diffuses into the cytoplasm where it inhibits HMG CoA reductase
How is HMG CoA reductase regulated?
- Cholesterol works at the DNA level to suppress synthesis of the reductase through preventing the activation of the transcription factor (sterol regulatory element-binding protein) that binds to the sterol regulatory element on the DNA to promote HMG-CoA reductase.
- Cholesterol also reduces the stability of the mRNA and the newly synthesized protein, both being degraded intracellularly in the presence of high intracellular cholesterol levels.
- Hormonal regulation independent of cholesterol: Insulin upregulates and glucagon down-regulates HMG-CoA reductase gene expression and
- Through phosphorylation-dephosphorylation, its activity. Glucagon promotes phosphorylation inactivation; insulin activates dephosphorylation-activation. Cholesterol can also stimulate hormone independent phosphorylation.
- At the same time, fatty acyl CoA: cholesterol acyltransferase in the ER is activated by cholesterol to promote formation of cholesterol esters, mainly cholesterol-oleate. Accumulation of intracellular cholesterol ester eventually inhibits replenishment of LDL receptors, thereby blocking further uptake.
Insulin: glycolysis –> AcCoA –> energy + FA + cholesterol
Glucagon: AAs and FAs –> energy + ketone body
How do statins decrease cholesterol? What drugs are they often used in conjunction with? What is the fxn of these drugs?
A family of drugs called statins was developed to lower plasma cholesterol levels. Statins (e.g., lovastatin, pravastatin, fluvastatin, cerivastatin, and atorvastatin [Lipitor]) inhibit HMG CoA reductase activity, the rate-limiting enzyme of cholesterol synthesis in the liver by binding to the substrate-binding site of the enzyme. These drugs commonly lower total plasma cholesterol by as much as 50%. These drugs are frequently used in combination with low-cholesterol diet and potentially with cholestyramine and colestipol (which are bile salt-binding drugs that promote excretion of bile salts, and with them, cholesterol, in the stool). They all can, alone or in combination, successfully fight hypercholesterolemia
In what cellular organelle are bile acids produced? The most abundant bile acids in humans are derivatives of what?
The bile acids are the end-products of cholesterol metabolism and are made in the peroxisomes of hepatocytes directly from cholesterol. The most abundant bile acids in humans are derivatives of cholanic acid, that is cholic acid and chenodeoxycholic acid.
What is the composition of primary bile acids?
The primary bile acids are composed of 24 carbons, contain two or three OH groups and have a side chain that ends in a carboxyl group that is ionized at pH 7 (thus, an acid). The negative charge makes the molecule more amphipathic.
What molecular changes to cholesterol occur during the conversion to bile acids?
What enzyme catalyzes the rate limiting step in synthesis of bile acids? What is this enzyme regulated by?
Transformation of cholesterol to bile acids require:
(1) epimerization of the 3E-OH group;
(2) oxidation of the C-5 double bond,
(3) introduction of OH groups at C-7 and C-12 for cholic acid
(4) conversion of the C-27 side chain into a C-24 carboxylic acid
The rate-limiting step in the synthetic pathway is the cholesterol-7-hydroxylase, an ER-associated enzyme in the liver. Then enzyme is down-regulated by cholic acid and upregulated by cholesterol.
What 2 things increase secretion of bile acids/salts (and thus of cholesterol)?
To increase secretion of bile acids/salts (and thus of cholesterol), bile acids sequestrants, such as cholestyramine can be used. Dietary fibers serve the same purpose.
What are 5 causes of bile salt deficiency? How is cholelithiasis treated?
It can be the consequence of one of the following:
1. Malabsorption of bile acids from the intestine
2. Obstruction of the biliary tracts
3. severe hepatic dysfunction
4. excessive feed-back suppression of bile acid synthesis
5. increased biliary bile acid excretion
Treatment: - laparoscopic cholecystectomy
- administration of chenodeoxycholic acid
What is the first enzyme that modifies cholesterol for steroid hormone synthesis? Where is this enzyme located within cells? What does it require?
desmolase, a cythochrome P450 mixed function oxidase of the inner mitochondrial membrane that requires molecular oxygen and NADPH
