2. Introduction to Lipids and Lipoprotein Metabolism (Part I) Flashcards
What is the endogenous source of body cholesterol? Which cells are capable of making cholesterol?
- De novo synthesis from Acetyl-CoA
- All cells in the body are capable of making cholesterol
What are exogenous sources of cholesterol?
- Diet
- Dietary sources are really “excess” cholesterol, as all cells can make cholesterol
What justifies that there is an important need for cholesterol?
- Cholesterol is a very energetically expensive molecule
- But, it cannot be oxidized (can’t get ATP back)
What are statins?
Class of drugs that are competitive inhibitors of HMG-CoA reductase
What metabolites does the synthesis of cholesterol produce?
- Various
- They are not solely dedicated to the synthesis of cholesterol
What happens in liver cells after HMG-CoA reductase makes cholesterol?
Cholesterol is released into the blood by hepatocytes
How do statin drugs work?
- Inhibit HMG-CoA reductase by competing with its natural substrate (HMG-CoA)
- Cholesterol synthesis is blocked, lowering levels of cholesterol
How do statins vary?
They look very different, but they are all capable of inhibiting the activity of HMG-CoA reductase
What did this study discover: “Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks of clusters of risk”?
- Child and maternal malnutrition and dietary risks are among the highest risk factors for metabolic disorders
- Cardiovascular diseases, neoplasms, diabetes
- Ample evidence for causation, but people still abuse of certain foods
What transports TG through the bloodstream?
Chylomicrons
Where are certain fatty acids used?
Muscles, liver, heart
What happens when the liver receives TG?
- Repackages it
- TG are transported through the bloodstream via VLDL
What are the two functions of bile acids?
- Emulsification of fats and fat-soluble nutrients
- Activator of bile-salt activated lipase
Where are bile acids found? Where are lipases found?
- Bile acids: small and large intestines
- Lipases: small intestine
What is the function of lipases? Be specific.
Digestion of lipids acquired from the diet (cholesteryl esters, acylglycerols, phospholipids)
What are the four steps to the conversion of cholesterol to bile acids?
- Hydroxylation of the steroid nucleus
- Epimerization of the 3-Beta hydroxyl group
- Saturation of the steroid nucleus
- Side chain cleavage
What happens overall when cholesterol is converted to bile acids?
- Converts the shape of cholesterol from chair-type to a more flat configuration, rendering it POLAR
- Bile acids are amphipathic
- Charged functional groups are on one face of the molecule, uncharged are unable to act with water
Describe the fate of diet-derived lipids in the lumen, when they are absorbed, and they are resynthesized in enterocytes.
- TG –>FA + MG –> TG
- CE –> CH + FA –> CE
- PC –> LysoPC + FA –> PC
- They will bind to transporters for absorption, and will be reassembled in the enterocytes
What is the function of phospholipases?
Breaking down a phospholipid to give you a lysophopholipid and a fatty acid
What transporter brings in free cholesterol?
NPC1L1
What transporters bring in free fatty acids?
- FATP4
- CD36
What transporter is thought to bring in free phospholipids?
MFSD2A
Why are we selective concerning absorption of nutrients?
Because absorption of dietary lipids requires SPECIFIC membrane-bound transporters that are on the surface of enterocytes
Where does the ER process lipids?
- In a specialized compartment in the cell because it is hydrophobic
- In the lumen of ER
What is ACAT? What is its function?
- Lipid-metabolizing enzyme
- Acyl:cholesterol acyl transferase
- Responsible for creating cholesteryl esters from cholesterol in cells
What is MTP? What is its function?
- Lipid carrier protein
- Microsomal triglyceride transfer protein
- Exists at junctions of the ER and other organelles that are involved in the assembly of chylomicrons
Which protein is involved in the assembly of chylomicrons?
MTP
Which enzyme is responsible for creating cholesteryl esters from cholesterol?
ACAT
What are lipoproteins?
Non-covalent complexes of lipids and proteins
Without ______, we can’t form HDL.
Apo A-I
What is Apo B-100 responsible for?
- Extremely large
- Only 48% (from the N-terminal) is found in chylomicrons
- The remaining 52% (C-terminus) is responsible for limiting the size of VLDL-like proteins
What do you need to remove from Apo B-100 to allow the size of the lipoprotein to increase?
52% of Apo B-100 from the C-terminus
What is LCAT?
- Activator of the LCAT enzyme
- Esterifies the cholesterol with a fatty acid in blood (becomes cholesteryl esters)
Differentiates LCAT and ACAT.
- LCAT: creates cholesteryl esters in blood from cholesterol
- ACAT: creates cholesteryl esters in cells from cholesterol
What is particular about Apo E?
- Exchangeable protein
- It can jump to any of the other lipoproteins
Which apolipoprotein can be taken away without affecting their structure?
Apo E
Which lipoproteins are related to Apo A-I? What is their function?
- CM, HDL
- Structure, LCAT activator
Which apolipoproteins serve as an LCAT activator?
Apo A-I, Apo A-IV
Which lipoproteins are related to Apo A-II?
CM and HDL
Which lipoproteins are related to Apo A-IV? What is their function?
- CM, HDL
- LCAT activator
- Satiety?
Which lipoproteins are related to Apo B-48? What is their function?
- CM
- Structure of CM
Which lipoproteins are related to Apo B-100? What is their function?
- VLDL, IDL, LDL
- Structure
- VLDLR and LDLR ligand
Which lipoproteins are related to Apo C and Apo E lipoproteins?
CM, VLDL, IDL, LDL
Which apolipoprotein serves as a lipoprotein lipase activator?
Apo C-II
Which apolipoprotein serves as a lipoprotein lipase inhibitor?
Apo C-III
Which apolipoproteins serve as a ligand for LDLR and VLDLR?
- Apo B-100
- Apo E
What three bands do you see on an agarose gel from lipoproteins?
- Alpha mobility
- Pre-beta mobility
- Beta mobility
- Origin: CM are so big they don’t enter the gel
What is alpha mobility associated with?
- Apo A protein
- Mainly phospholipids
- HDL
What is pre-beta mobility associated with?
- Apo B protein
- TG
- VLDL
What is beta mobility associated with?
- Apo B protein
- Cholesterol
- LDL
Place the lipoproteins in order of lowest to highest density.
CM < VLDL < LDL < HDL
Differentiate higher and lower density lipoproteins.
- Higher density: less lipid and more protein
- Lower density: more lipid and less protein
Which lipoprotein has a density between 0.95 and 1.006 g/mL?
VLDL
Which lipoprotein has a density under 0.95 g/mL?
Chylomicrons
Which lipoprotein has a density between 1.063 to 1.21 g/mL?
HDL
Which lipoprotein has a density between 1.019 and 1.063 g/mL?
LDL
Place the lipoproteins in order of lowest to highest size.
HDL < LDL < IDL < VLDL < CM
What lipoproteins does the liver create?
- VLDL
- Apo A-1 with phospholipids (very efficient acceptor of cholesterol)
How is HDL produced?
As a process of hydrolysis of VLDL and chylomicrons
How is LDL produced?
- Metabolic by-product of VLDL
- As VLDL gets smaller in size in the bloodstream, VLDL gets richer in cholesterol content
- LDL is a cholesterol-enriched version of VLDL
Which lipoproteins have TG as their major lipid?
CM and VLDL
Which lipoprotein has phospholipids as their major lipid?
HDL
Which lipoproteins have cholesteryl esters as their major lipid?
IDL and LDL
Under what form do lipoproteins transport cholesterol?
- As cholesteryl esters
- “I have high-blood cholesteryl esters”
How do the cholesterol moieties of HDL compare to LDL?
Chemically, they are the same
If HDL and LDL cholesterol are the same chemically, what allows them to be “good” or “bad”?
- HDL is good because it does not stick to the arteries, while LDL contributes to plaque build-up
- The way cholesterol is carried through the bloodstream determines their nature
What will a portion of cholesterol be secreted into by the liver? What happens to the secretion?
- Bile (biliary cholesterol)
- Biliary cholesterol will mix with dietary cholesterol (identical in terms of structure)
- Then, they are taken up via NPC1L1
The greater concentration of LDL that we have in the blood makes it more susceptible to ________.
oxidation
What is an efficient acceptor of excess free cholesterol?
HDL3
What is the mechanism of action of HDL3?
- Cholesterol moves from the artery wall into HDL3
- LCAT esterifies the cholesterol in HDL3 into CE
- HDL3 increases in size and becomes HDL2
4.A) HDL2 can be taken up by the liver
B) Cholesterol can be transferred from HDL2 to VLDL or CM; taken up by hepatocytes and hopefully getting rid of
How are fatty acids absorbed from CM?
- CM binds to a protein at cell surface (GPIHBP1) where they interact at the acidic domain
- Lipoprotein lipase also binds to a protein
- CM and LpL are brought together; LpL hydrolyzes TG into MG and FFA
- FFA travels in the blood by binding to albumin
- Albumin brings FFA to a FA transporter to move inside a cell
Which protein do CM bind to at endothelial cell surfaces?
GPIHBPI
Why is UC accessible to HDL?
Because it has a low concentration of cholesterol
Describe the reverse cholesterol transport pathway.
- Movement of UC from peripheral cells onto the surface of HDL
- In HDL, LCAT converts UC into CE, forcing it inside the particle
- CETP transfers CE from HDL to LDL. TG from lower density lipoproteins is given to HDL in exchange.
- Liver parenchymal cells take CE from HDL (direct) and LDL (indirect), and convert CE to UC
What is LCAT?
Lecithin: cholesterol acyl transferase
What is CETP?
Cholestreyl ester transfer protein
Why is the skin of HDL always low in UC concentration?
Because LCAT converts UC into CE, allowing it to accept more cholesterol
What do liver parenchymal cells do with UC?
- Make it into VLDL
- Secrete it directly into bile (biliary cholesterol)
- Convert it into bile acids
How does the structure of phospholipids change as they are lipolyzed?
- They shrink
- Draining of the inside of the phospholipid skin; skin is rough as it is not full anymore
What is the only way to secrete Apo A-1? What is its fate?
- To have them associated with phospholipids in chylomicrons
- They pinch off and become HDL
What is the advantage of having CETP?
- The CE from HDL will be transferred from lower density lipoproteins in exchange for TG
- This allows for HDL to stay in the blood, taking up more UC
What happens to lipoprotein cholesterol when they enter hepatocytes? Why?
- They are unesterified
- Cholesterol is highly bioactive
- Esterification allows the removal of the bioactivity of the pool
What are the four ways liver cells get rid of their unesterified cholesterol pool?
- Lipoprotein assembly (VLDL)
- Storage (as CE in lipid droplets)
- Bile acid synthesis
- Direct secretion to bile (biliary cholesterol)
What is the rate-limiting enzyme for bile acid synthesis in hepatocytes?
Cyp7a1
Which cells are the only cells capable of getting rid of cholesterol through bile?
Hepatocytes
Why do liver cells have many ways to get rid of excess cholesterol?
- Because they handle a lot of cholesterol since they accept lipoproteins
- The pool MUST be maintained or else the cells will die
Differentiate bile acids and biliary cholesterol.
- Bile acids: irreversible conversion
- Biliary cholesterol: kicking out the cholesterol from the liver into bile, excreted in the intestine, and mixes with dietary cholesterol
What are the options for handling cholesterol in cells that aren’t hepatocytes?
- Store as cholesteryl esters
- Excretion
What cells can make hormones out of cholesterol?
Adrenal cells, testes, and ovaries can make steroid hormones
Where is bile stored? What are the components of bile?
- Gallbladder
- Fluid that contains phospholipids, bilirubin, and cholesterol
What would you see if you unfold the liver?
- One sheet of cells is exposed to the blood
- One sheet is exposed to bile
What is the function of cholecystokinin?
Stimulates the contraction of the gallbladder, which forces all of the liquid out
What is the cholesterol pool in hepatocytes a combination of?
Endogenously synthesized cholesterol and diet-derived cholesterol
What cholesterol by-product can’t be reused? Why?
- Bile acids
- Once bile acids are converted, they CANNOT go back to cholesterol
- Thus, cholesterol is eliminated from the system
Define hyperlipidemia.
High concentration of lipids
Define hypolipidemia.
Low concentration of lipids
Define hypertriglyceridemia.
High TG
Define hypercholesterolemia.
High cholesterol
Define combined hyperlipidemia.
High TG and cholesterol
What are the clinical features of abetalipoproteinia?
- Chronic diarrhea (steatorrhea)
- Retinitis pigmentosa
- Ataxia
- Star-shaped RBCs
What is the problem in abetalipoproteinia?
- Low to undetectable circulating CM
- Malabsorption of fats and fat-soluble vitamins
How do you manage abetalipoproteinia?
- Dietary management: restriction of long-chain TG, use medium chain instead
- Since medium chain TG have an easier time of being transported
- Long-chain depend on CM, which are lacking
What can go wrong in terms of lipid absorption and distribution in hepatocytes?
Variations in genes encoding transporters that impact the overall efficiency of lipid uptake
Explain the link between MTP and abetalipoproteinemia.
- A mutation in the gene encoding for MTP
- Without MTP, you cannot transfer lipids to growing CM
- Accumulation of lipids within the enterocyte
- No CM
What happens to hepatocytes in abetalipoproteinia eventually?
- Cholesteryl esters and TG will be put into oil droplets to get rid of
- Eventually, the cell gets too full of lipids and it dies
What are the effects of ezetimibe?
- Competitive inhibitor of NPC1L1
- No cholesterol absorption
What natural substance can act as a competitive inhibitor for NPC1L1?
Plant sterols since they resemble cholesterol, but won’t get absorbed
What is ezetimibe used for?
Drug prescribed to people with hypercholesterolemia
Give an example of a long-range regulatory element.
The sequence in the MCM gene.
What are the three types of epigenetic modifications?
- Methylation of DNA
- RNA-based mechanisms
- Histone post-translational modifications (acetylation of histones)
What are epigenetic modifications used for?
- Used for controlling the use of genetic information during the lifetime of the organism
- Heritable to the next generation only, not long-term
Who discovered the mechanisms behind familial hypercholesterolemia?
Brown & Golstein
Why can FH be reliably diagnosed?
- Fibroblasts can be readily obtained, grown and studied in a lab
- Lipoproteins can be reliably isolated from the blood
- Metabolism of cholesterol can be observed
What are the clinical features of FH?
- High concentration of cholesterol in the blood
- Presences of xanthelasmas and tendon xanthomas
How do FH cells differ in terms of cellular cholesterol (as CE) concentration, rate of cholesterol (UC) synthesis, and HMG-CoA reductase activity?
- High CE concentration
- High UC synthesis
- High HMG-CoA reductase activity
What are the differences between normal and FH fibroblasts in response to lipoprotein (cholesterol) depletion?
- No effect on CE stores (high)
- No effect on rate of UC synthesis
- No effect on HMG-CoA reductase activity
Lipoproteins are (covalent/non-covalent) complexes of lipids and proteins.
non-covalent
