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What is the substrate for both cholesterol and FA synthesis? Which tissues synthesize cholesterol? (4) Where in cell does this take place? (2)
4th tissue has 3 subcomponents.
Acetyl CoA. Almost all tissues synthesize cholesterol, but mostly liver, intestine, adrenal cortex, reproductive tissues (ovaries, testes, placenta)
Takes place in cytosol and ER.
What are the 3 main functions for cholesterol? (3)
- 1. Membrane structure
- 2. Precursor for steroid hormones, vitamin D, bile, etc
- 3. Modulating fluidity of cell membranes
How is cholesterol degraded? What are the sources of cholesterol (3) and what is their path (1) to products? (3)
It's not - it's generally excreted via feces
Dietary cholesterol, de novo cholesterol from liver, and chol from extrahepatic tissues (HDL) --> liver cholesterol pool --> secretion of VLDL, free cholesterol into bile, conversion to bile acids/salts.
What are the 2 important regulatory enzymes in cholesterol synthesis? From cholesterol, what else can be produced? (6)
HMG CoA Synthase and HMG CoA Reductase
Steroid hormones, vitamin D, bile acids, lipoproteins, sonic hedgehog (needed for morphogenesis for face), cholesteryl esters (free cholesterol can undergo catalysis via ACAT and LCAT to form cholesteryl esters).
What are the 6 ways that the liver interacts with cholesterol?
- 1. Takes up cholesterol from diet/peripheral tissues
- 2. Esterifies cholesterol to form CEs
- 3. Stores cholesterol esters in lipid droplets (w/ TAG)
- 4. Secretes cholesterol & CEs in VLDL
- 5. Synthesizes de novo cholesterol
- 6. Synthesizes bile acids/salts from cholesterol and secretes both free cholesterol & bile acids/salts into gallbladder.
How do macrophages in atherosclerotic plaques interact with cholesterol? 4
- 1. Take up cholesterol from lipoproteins in blood
- 2. Esterify cholesterol to form CEs
- 3. Store CEs in lipid droplets (like liver)
- 4. Synthesize own cholesterol
How is cholesterol synthesis regulated? (5)
1. SREBP-2 - Low levels of sterols - SREBP-SCAP complex ER-Golgi transport to increase tx of HMG CoA Reductase. High levels of sterols: SREBP-SCAP complex cannot be transported and reductase binds to INSIG (ubiquitination and proteasomal degradation of reductase)
2. AMPK & Protein phosphatase - P'lated = inactive. Dep'lated = active. Like FA synthesis, low ATP levels means low cholesterol synthesis.
3. Insulin & Glucagon: insulin increases synthesis of HMG CoA Reductase, while glucagon decreases it.
4. Cholesterol feedback inhibits both HMG CoA Reductase & Synthase
5. Statin drugs competitively inhibit HMG CoA Reductase
Cholesterol, phospholipids, bile bile acids transporters? NPC1L1, ABC transporters, etc.
SHOULD I MAKE A FLASHCARD FOR THIS>
How are cholesterols absorbed? 4 steps
- 1. Cholesterol is taken up from micelles & NP1L1 transprots cholesterol into enterocytes
- 2. Once uptaken, cholesterol is re-esterified into CE via ACAT (acyl CoA cholesterol acyltransferase)
- 3. CEs join TAGs, PLs, and ApoB48 to form chylomicrons.
- 4. Chylomicrons --> Golgi --> lymph --> all over the body.
What is the only significant mech for cholesterol excretion? Can bacteria regenerate bile acids?
Bile salts - metabolic product of cholesterol AND sobulizer of cholesterol in bile.
Yes, about 95% is reabsorbed in ileum and reused.
Define lipoproteins. What are the 4 types? How do they differ (4)
Lipproteins - spherical aggregates of specific proteins (apolipo/apoproteins) & lipids. NOT MOLECULES.
Includes VLDL, LDL, HDL, and chylomicrons.
Differ based on protein:lipid ratio, density, size, site of origin
What is on the outside of a lipoprotein? (3) Inside? (2)
What are the overall functions of apolipoproteins? (4)
- Outside: Polar - Apolipoproteins, PLs, cholesterol
- Inside: Nonpolar - TAGs & CEs
Apolipoproteins - structural, enzyme activators, receptor site binders and blockers
What are the 5 types of apolipoproteins? Where is each found? What is their function?
- ApoB100 (VLDL, IDL, LDL) - Structural protein for VLDL, ligand for LDL receptor
- ApoB48 (Chylomicrons & chyloremnants) structural protein - lacks LDL-R binding domain so depends on ApoE for LDL-R binding.
(chylo, VLDL, IDL, HDL, chylo remnants) Ligand for binding IDL and VLDL to LDL-R and LRP (LDL-related R protein).
- HDL, chylomicrons - activates LCAT & is structural protein of HDL
(chylos, VLDL, IDL, HDL) activates LPL. Insuiln promotes synthesis of ApoCII. LPL degrades TAGs in lipoproteins into FAs.