T11-12 Lipid Digestion and Absorption Flashcards
A single alcohol functional group can form how many hydrogen bonds?
2
An un-ionized carboxyl group forms how many hydrogen bonds?
3
Is glucose hydrophobic or hydrophilic?
hydrophilic, because of its many -OH groups
Which three classes of molecules are considered to be amphipathic?
fatty acids; phospholipids; cholesterol
Which two classes of molecules are considered to be hydrophobic?
triglycerides; cholesteryl esters
Describe the solubility of fatty acids in water.
low, but finite, solubility in water
How are fatty acids transported in blood? (2)
transported as part of a triglyceride (glycerol backbone + 3 fatty acids); or attached to albumin
Describe the solubility of cholesterol in water.
no solubility in water — it exists at the aqueous/lipid interface
Do most fatty acids have an even or odd number of carbons?
most have an even number of carbons
List the four major groupings of fatty acids and the associated criteria.
short chain (<6 carbons)
medium chain (6-12 carbons)
long chain (13-21 carbons)
very long chain (>20 carbons)
Differentiate between saturated, monounsaturated, and polyunsaturated fatty acids.
saturated = 0 double bonds
monounsaturated = 1 double
polyunsaturated = more than 1 double bond
What are the most common long-chain fatty acids in the human diet?
stearic acid (C18:0)
oleic acid (C18:1)
linoleic acid (C18:2), both double bonds in cis configuation
Why are free fatty acids dangerous? What is a consequence of this property?
they are soaps/detergents that can destroy biological membranes
therefore, FFAs have to be stored as triacylglycerol
Which molecule is the major energy source for all eukaryotes?
triacylglycerol
Describe the hydrophilicity/hydrophobicity of triacylglycerol.
Triacylglycerol is very hydrophobic
In adipose tissue, how are triacylglycerols stored?
stored into one large lipid droplet
How much triglyceride is consumed by the typical American each day?
50-100 grams per day, with 50% from plants and 50% from animals
Describe the relationship between fatty acid saturation and phase of matter.
more saturation (i.e. more C-H bonds and fewer C=C double bonds) means the fat will be more solid at room temperature
Why are plant fats more liquid and animal fats more solid at room temperature?
plant fats = higher proportion of 18:1 and 18:2 unsaturated fatty acids
animal fats = higher 16:0, 18:0 saturated fatty acids
What is an exception to the general trend that plant fats are liquid at room temperature?
tropical plant fats (coconut oil or palm oil) have larger proportions of saturated long-chain fatty acids, so they are more solid at room temperature
What are the major dietary plant sterols? (2)
sitosterol
campesterol
Describe the cholesterol content of meat.
1.4 mg cholesterol per gram
Describe the cholesterol content of egg yolks.
250 mg (surprisingly high)
On average, how much cholesterol and plant sterol do humans eat per day?
300 mg cholesterol
200 mg plant sterol
Describe how well (i.e. the extent) dietary triacylglycerides, dietary cholesterol, and dietary plant sterols are absorbed in humans.
intestine absorbs:
100% of dietary triacylglycerols (remember, fat is energy)
50% of dietary cholesterol
<5% of dietary plant sterols
Lipid absorption occurs in what organ?
small intestine (composed of smaller duodenum + longer jejunum and ileum)
What is the precursor to bile acids?
cholesterol
Describe how cholesterol is converted to a bile acid, and the consequences of this conversion.
27-carbon cholesterol (hydrophobic) has 3 carbons removed and additional hydroxyl groups added on one surface to create a hydrophilic 24-carbon bile acid
What are the three biliary lipids that pass through the bile duct?
bile acids
cholesterol
phospholipids
Describe the pathway of biliary lipids synthesized in the liver.
liver → bile canaliculi → common bile duct → pancreas → duodenum
Cholesterol is either synthesized in the liver or synthesized de novo in peripheral tissue. How is cholesterol synthesized in peripheral tissue sent to the liver?
reverse cholesterol transport pathway
Where is cholesterol esterase synthesized?
acinar cells of pancreas
Bile acids, cholesterol, and phospholipids drain through bile canaliculi, through the common bile duct, and toward the pancreas. Once in the pancreas, what substances are added to this mixture? (2)
digestive enzymes (pancreatic lipase + co-lipase)
cholesterol esterase
Through which structure do pancreatic enzymes enter the common bile duct?
pancreatic duct
Describe the triacylglycerol-hydrolyzing properties of pancreatic lipase and co-lipase.
pancreatic lipase and co-lipase hydrolyze C1 and C3 ester linkages, resulting in 2 free fatty acids + 1 2-monoacylglycerol
How do mixed micelles form?
bile acids + emulsified fats + free fatty acids + 2-monoacylglycerol = mixed micelle
Beyond the four “core” substances that make up a mixed micelle, what three other substances can be incorporated into mixed micelles?
unesterified cholesterol
plant sterols
fat soluble vitamins (ADEK)
What is the function of pancreatic cholesterol esterase in the context of intraluminal digestion?
pancreatic cholesterol esterase converts cholesterol esters → free cholesterol + fatty acids, which are incorporated into mixed micelles
What structure must the lipid components of mixed micelles cross in order to reach the enterocytes of the duodenum and jejunum?
must cross apical membrane (i.e. luminal surface)
What is NPC1L1 and what is its function?
transmembrane sterol transporter that transports unesterified cholesterol + plant sterols into enterocytes via apical membrane
What is ABCG5/ABCG8 and what is its function?
sterol transporter on apical membrane that pumps out plant sterols and some cholesterols, thereby limiting amount of sterols absorbed
Why is cholesterol re-esterified once it enters an enterocyte?
because free cholesterol is toxic to enterocytes/most absorptive cells
What enzyme carries out the re-esterification of cholesterol in enterocytes? Describe the location and properties of this enzyme.
acetyl-CoA acetyltransferase (ACAT)
located in ER
attaches long-chain FA to 3-β-OH group of sterol
What drives plant sterols to leave enterocytes via ABCG5/ABCG8? In other words, what physical property doesn’t keep them in the cell?
ACAT’s preferred substrate is unesterified cholesterol instead of plant sterols
Draw out a diagram showing the esterification of cholesterol and plant sterols in enterocytes by ACAT.
What is the fate of the free fatty acids and 2-monoacylglycerol that enter enterocytes?
FFA + 2-MAG are re-esterified to form triglycerides, because free fatty acids are detergents and therefore toxic
What are the two possible pathways for the re-esterification of FFAs and 2-MAGs into TGs?
monoacylglycerol pathway
glycerol-3-phosphate pathway
Describe the monoacylglycerol pathway of FFA/2-MAG re-esterification in enterocytes.
2-MAG + fatty acid-CoA → [MG acyltransferase] → 1,2 diacylglycerol (DAG)
a second fatty acid-CoA is added → [DG acyltransferase] → TG
Describe the glycerol-3-phosphate pathway of FFA/2-MAG re-esterification in enterocytes.
3-glycerophosphate (derived from glucose) backbone + fatty acid-CoA → 1,2-diacylglycerol phosphate → [PA hydrolase] → 1,2 diacylglycerol → [DG acyltransferase] → TG
What is the composition of lipid droplets in enterocytes?
contain 100% of TG
50% of cholesterol
small fraction of plant sterols
Describe how ApoB-48 is synthesized.
ApoB mRNA transcribed in nucleus → transported to cytoplasm → cytosine deaminase changes CAA to UAA stop codon at 48% mark → ApoB-48 forms
Describe the relationship between the LDL receptor binding domain and ApoB-48.
LDL receptor binding domain is in the C-terminal half of ApoB-100 and therefore not included in ApoB-48.
(T/F) Cytosine deaminase is synthesized in the liver.
False. Cytosine deaminase is not synthesized in the liver, meaning that only ApoB-100 is formed in the liver.
Where does initial chylomicron synthesis occur?
in the ER of enterocytes
[lecture slides say ER + Golgi]
Describe how the chylomicron forms in the ER of enterocytes (specifically, what is added to make the chylomicron). (3)
ApoB-48 forms
re-esterified TGs + re-esterified CEs + phospholipids join
fat soluble vitamins (ADEK) + ApoAI join
The initial chylomicron assembly process is dependent on what protein?
microsomal TG transfer protein (MTTP)
What is the function of microsomal TG transfer protein (MTTP)?
transfers TG to ApoB to form TG-rich particles
Following the formation of the nascent CM in the ER of the enterocyte, what happens?
CM goes through ER → Golgi complex → enterocyte basolateral membrane → lacteal (lymphatic vessel)
The secretion of newly-formed CMs out of the enterocyte basolateral membrane requires what protein?
Sar1b
Following secretion out of the enterocyte’s basolateral membrane, what further modifications are made to CMs?
CM interacts with HDL and acquires ApoCII and ApoE
Describe the weight composition of CMs.
over 90% of weight is made up of TGs
What is the functional purpose of cholesterol/phospholipids/apolipoproteins on the surface of CMs?
help to solubilize the particle
Lacteals in the lymphatic system eventually lead to what structure?
leads to thoracic duct
The thoracic duct empties into
venous circulation, therefore bypassing the liver
Differentiate between sugars/amino acids and lipids in terms of how they are metabolized and transported throughout the body. (2)
sugars/amino acids absorbed from intestine into blood capillaries and delivered directly to liver via portal vein
lipids transported to systemic venous circulation via lacteal/thoracic duct, allowing lipids to bypass liver and be directly delivered to peripheral tissue
What is postprandial hyperlipidemia?
phenomenon of opalescent plasma resulting from large CMs refracting light
As CMs circulate throughout the body, what enzyme do they encounter?
lipoprotein lipase (LPL)
Where is lipoprotein lipase synthesized?
adipocytes
myocytes
cardiomyocytes
Write out/describe the pathway/mechanism of lipoprotein lipase action.
LPL released into interstitial space → binds to GPIHBP1 on subendothelial surface of capillaries → GPIHBP1 escorst LPL to vascular surface by crossing endothelial cell → ApoCII on circulating particle interacts with LPL to promote hydrolysis of TGs in CM core
What happens to fatty acids liberated by the action of lipoprotein lipase interacting with ApoCII on circulating CMs?
free fatty acids either cross the endothelium into the adipocyte/myocyte/cardiomyocyte OR become bound to albumin and are transported back to the liver
What happens to free fatty acids liberated by lipoprotein lipase action that cross the endothelium and enter the adipocyte/myocyote/cardiomyocyte?
if entering adipocytes → re-esterified to TG and stored
if endering myocytes/cardiomyocytes → oxidized
Describe the process of intravascular metabolism of CMs to CM remnants.
once 75% of TG is removed from CM core, ApoCII and ApoAI transferred back to HDL
ApoE becomes exposed on surface of CM remnant
Describe how CM remnants are cleared by the liver.
exposed ApoE binds to LDL receptor on surface of hepatocytes
CM remnant-LDL receptor complex uptaken into cell via receptor-mediated endocytosis
What are the possible fates of dietary lipids once CM remnants have been cleared by the liver?
oxidized
re-esterified by ACAT and stored in lipid droplets
re-esterified by ACAT and packaged into TG-rich lipoproteins (called VLDLs)
At what point is lipid absorption in the body considered “complete?”
after VLDL formation and VLDL transport of lipids + fat soluble vitamins from liver to peripheral tissue
Which tissue/organ is primarily responsible for clearing CM remnants?
liver
What are the three major nutrients of humans?
sugars
protein
lipids
What is the most dense component of the human diet?
fat is the most dense, in terms of kcal/mol
Describe the effect of fatty acid “bending” on membrane fluidity.
bending → can’t pack as closely → more fluid
What is the primary structural difference between animal sterols and plant sterols?
the difference is in the side chains
In what structure do mixed micelles form?
duodenum
(T/F) Cholesterol in the diet is essential.
False. Cells can produce cholesterol endogenously.
(T/F) Triacylglycerol in the diet is essential.
True. Triacylglycerols are the primarily fuel/energy source.
Describe the relationship between ApoB-48, ApoB-100, enterocytes, and hepatocytes.
The ApoB protein is expressed in both enterocytes and hepatocytes. However, in enterocytes, cytosine deaminase introduces a premature stop codon that results in 48% of the protein being expressed.
In short: ApoB-100 found in hepatocytes; ApoB-48 found in enterocytes
Mutatins in the Sar1b protein would result in what clinical presentations? (3)
skinniness
no appetite
indigestion
(T/F) ApoB never leaves the chylomicron.
True. Unlike ApoCII and ApoAI, it never leaves the chylomicron.
Why are chylomicrons transported to circulation using the lympathic system instead of the normal portal circulation system?
this is in order to bypass the liver and go directly to other tissues
What would be the complaints of a patient in whom ApoB is mutated/defective? (3)
gas/bloating
lack of appetite
failure to thrive
What would be the complaints of a patient with a defective MTTP enzyme?
same complaints as someone without functional ApoB — only difference is in the inheritance pattern
