Skildum- Cholesterol Metabolism Flashcards
What are the functions of cholesterol?
Membranes- adjusts fluidity/rigidity
Bile Acids
Steroid hormones
Vitamin D
What are states of circulating cholesterol?
Free or esterified
What is the one precursor of cholesterol and what are it’s sources in the body?
Acetyl Co A
Pyruvate dehydrogenase
beta oxidation of fatty acids
oxidation of ketogenic amines
What are the 4 stages of cholesterol synthesis? YOU SHOULD KNOW THIS
- Three acetyl CoAs make mevalonate (six carbons)
- Mevalonate converted to isoprenes (5 carbons)
- Six isoprenes condense to form squalene (30 carbons)
- Squalene is cyclized and converted to cholesterol (27 carbons)
What is the key regulatory enzyme?
HMG CoA reductase
Where does cholesterol synthesis happen?
Cytosol
Does cholesterol synthesis produce energy or take energy?
Takes A LOT of energy
What is the first step in cholesterol synthesis?
Three Acetyl CoAs condense to form HMG-CoA. HMG CoA reductase removes coenzyme A and reduces the aldehyde to an alcohol to form mevalonate.
What is HMG CoA synthase regulated by?
transcription
degradtation
phosphorylation
Why is HMG CoA an important drug target?
Inhibiting HMG CoA significantly reduces the amount of cholesterol synthesized de novo.
How is HMG CoA transcriptionally regulated?
When cholesterol is abundant– (SREBP) is sequestered in intracellular membranes in complex with SREBP cleavage activating protein (SCAP).
When cholesterol levels drop, SCAP cleaves the DNA binding domain of SREBP, which then translocates to the nucleus and regulates transcription of HMG CoA reductase.
Where is HMG CoA reductase located?
In intracellular membranes
How do sterol levels influence HMG CoA reductase?
Promote proteolysis of HMG CoA reductase
What happens to HMG CoA reductase in fasted/low e conditions?
HMG CoA reductase is phosphorylated by AMP-K
How is AMP-K activated?
AMP-K is activated by phosphorylation and allosterically activated by AMP and sterols
How does insulin affect cholesterol synthesis?
Insulin promotes cholesterol synthesis by activating phosphatases that dephosphosphorylate HMG CoA reductase
Why are isoprenes relevant?
Both isoprenes that are synthesized are used in subsequent reactions in cholesterol synthesis.
How are bile acids used in digestion?
To emulsify dietary fat. To be effective detergente, bile acids must be amphipathic.
What is the rate limiting step in bile acid synthesis?
Hydroxylation at the #7 carbon of cholesterol by 7a-hydroxylase; bile acids inhibit this enzyme.
Why to Bile acid’s side chains bond to AA?
Bile acids’ side chains can bond to the amino acids taurine and glycine to form bile acid conjugates. Conjugates are better detergents than unconjugated bile salts.
How are bile salts recycled?
Bile salts are efficiently recycled. They can be degraded by gut bacteria to remove amino acid conjugates and the hydroxyl at carbon 7; these are secondary bile salts.
Eventually they are excreted in feces
Where does cholesterol synthesis occur?
The liver.
- Cholesterol produced in liver goes out in form of lipoprotein particles. These maintain cholesterol homeostasis in other tissues of the body.
- The liver can export cholesterol in the form of cholesterol esters or bile acids.
What do bile salts do?
Bile salts act as detergents and make dietary fats soluble and accessible to lipase.
What are the 2 important things to remember about chylomicrons?
- Enter lymphatic circulation first then are transported to the blood.
- ApoB-48–Defines it as regulated protein not just fat floating around, gives cells a tag to bind and locate
What is NPC1L1?
NPC1L1 exists at brush border—is important for transporting cholesterol into the cell and is an important drug target in pts.
How does a nascent chylomicron become a mature chylomicron?
In the blood, HDL particles transfer ApoCII to nascent chylomicrons to make mature chylomicrons. ApoCII activates lipoprotein lipase (LPL).
What does esterification do? What enzyme is involved?
Esterification to a fatty acid makes cholesterol even less soluble. Cholesterol exported by the liver is often esterified to the unsaturated fatty acid linoleate.
Cholesterol esters are then used to make membranes or packaged in VLDL for export to other tissues.
Acyl-CoA-cholesterol acyltransferase (ACAT) catalyses the reaction.
How does nascent VLDL become mature VLDL?
VLDL secreted from the liver is nascent VLDL. To become mature VLDL, it receives ApoCII and ApoE from circulating high density lipoprotein (HDL).
What is the structure of the LDL receptor and what does it do?
Lipoprotein particles can be endocytosed in target cells that express appropriate receptors. Macrophages use scavenger receptors SR-A1 and AR-A2. Most other cells use the LDL receptor. The LDL receptor’s ligand binding domain binds ApoB100.
What is the normal function of the LDL receptor?
- Binds to ApoB100
- Cell membrane invaginates and forms membrane bound particle
- Fuses with endosome, lysosome comes in with degradation enzyme.
- Proteins digested down to AA, Fat digested down to FA, cholesterol isn’t digested but can be recycled and used for other purposes.
- Receptor can get recycled and re-expressed on cell membrane
What are secondary bile salts?
Removal of second hydroxyl and more likely to be lost through GI tract.
What are steroid hormones?
Derived from cholesterol. They are synthesized in the adrenal cortex and the gonads
What is the role of androgens?
testosterone > male development
What is the role of estrogens?
estradiol > female development
What is the role of progestins?
progesterone > maintains pregnancy, female development
What are the highlights of steroid hormone synthesis?
Removal of most of the side chain to form pregnenolone is the first step in the synthesis of all steroid hormones; this takes place in the mitochondria. Oxidation of the #3 carbon forms progesterone.
The side chain is left on to make aldosterone and cortisol.
The side chain is completely removed to make testosterone, estradiol and estrone.
The same enzymes catalyze multiple steps.
What is congenital adrenal hyperplasia?
Can result in mutation in steroid hormone biosynthesis genes, e.g. Cyp21. In these patients circulating aldosterone and cortisol are decreased, and androgens are increased.
How is vitamin D formed?
Formation of the most potent form of vitamin D, 1,25-dihydroxycholecalciferol (a.k.a. calcitriol), requires reactions in the skin, liver, and kidney
What is the role of vitamin D?
An important regulator of calcium homeostasis. Its receptor is a ligand activated transcription factor, but its synthesis differs from that of steroid hormones.
What is the function, source and proteins of chylomicrons?
transfer dietary fat from gut to tissues
intestinal epithelial cells
ApoB48, Apo CII, ApoE
What is the function, source and proteins of chylomicron remnants?
Return apoproteins to liver
Remnant of chylomicron
ApoB48, ApoE
What is the function, source and proteins of VLDL?
Transfer fat produced by dietary carbohydrates to tissues
liver
ApoB100, ApoC1, ApoCII, ApoCIII, Apo E
What is the function, source and proteins of IDL?
Return lipids to the liver
Remnant of VLDL
Apo B100, Apo CI/II/III, ApoE
What is the function, source and proteins of LDL?
Deliver choleseterol to the cells
Remnant of IDL
ApoB100
What is the function, source and proteins of HDL?
Deliver cholesterol to cells, liver; deliver ApoCII particles
Liver and intestine
ApoA1, ApoA, ApoCI/II, LCAT
What do mutations in the LDL receptor cause and what symptoms are a result of this mutation?
- Familial hypercholesterolemia.
- Symptoms:
hyperlipidemia–increased number of fat particles
premature CVD
xanthomas–cholesterol rich tumors that form in body
Pathology: Can’t take up LDL particles by normal means, so they’re taken up by macrophages which form plaques and cause circulatory problems.
What happens when the amount of LDL exceeds the capacity of the LDL receptor?
- Accumulation of LDL
- FA are oxidized and damaged, taken up by macrophages which swell up and become foam cells
- Create artherosclerotic plaque
What is the role of glucocorticoids?
Cortisol–stress hormone of fasted state
What is the role of mineralocorticoids?
Aldosterone–salt re-uptake in kidneys, regulates fluid volume
What is congenital adrenal hyperplasia? Patients with CAH present what symptoms?
Cyp 21 results in masculization
How are steroid hormones regulated?
- Transcriptional regulation.
- They diffuse through cell membranes and bind ligand activated transcription factors.
- Cortisol transcriptionally upregulates PEP-CK, an important gluconeogenic enzyme.
What proteins are regulated by Vit D?
Calcium transport proteins: calbindin, TRPV6, PMCA1b
