Digestion, lipogenesis, lipid transport Flashcards
List the 5 classes of plasma lipids.
How are they transported in the blood?
- TAGs
- phospholipids (PLs)
- cholesterol
- cholesterol esters (CEs)
- FFAs
⇒ for transport in blood FFAs bound to albumin, rest transported bound to lipoproteins
What are the 4 major groups of lipoproteins?
Function?
Density and size?
decreasing in size, increasing in density
- chylomicrons: derived from intestinal absorption of TAGs
- VLDL: derived from the liver for the export of TAGs
- LDL: representing final stage in catabolism of VLDL
- HDL: involved in cholesterol transport and VLDL, chylomicron metabolism
How does TAG, cholesterol, CE and PL content vary in the different lipoproteins?
- TAG content decr. w/ decr. in size
- C/CE content: incr. w/ decr. in size, HDL has most though
- PL content: incr. w/ decr. in size
There is another nomenclature for some lipoproteins.
Explain.
according to electrophoretic properties
smallest move fastest, hence α
- HDL = α-lipoproteins
- LDL = β-lipoproteins
- VLDL = pre-β-lipoproteins
cholymicrons can’t move in electrophoresis
What are apoproteins?
Distinguish btw the 2 structural groups.
protein moiety of a lipoprotein, 2 classes:
- apo B48, B100: lipid-soluble, partially embedded into PL layer → cannot be exchanged btw lipoproteins
- apo A, C, D, E: water-soluble, floating on top of PL layer → can be exchanged btw lipoproteins
B48 means 48% of B100 due to stop signal for translation
What are the functions of
- apo AI, II
- apo B48, B100
- apo CI, II, III
- apo D
- apo E
- apo B48: structural element of chylomicrons
- apo B100, E: LDLR-R ligands, responsible for internalization of lipoprotein
- apo CII: activator of lipoprotein lipase
- apo AII, CIII: inhibitor of lipoprotein lipase
- apo AI, CI, D: activator of LCAT
<span>LCAT = apo CI, AI, D</span>
Where are the different apoproteins synthesized?
- apo AI, II
- apo B48, B100
- apo CI, II, III
- apo D
- apo E
- apo B48 in intestine (structural element of chylomicrons)
- apo AI in intestine and liver
⇒ rest: ONLY in liver
Describe the general steps in digestion of lipids.
- lipases start cleaving ingested TAGs, mainly in duodenum
- bile added → emulsification of FAs, MAGs and cholesterol into micelles, also containing lipid soluble vitamins
- mainly taken up into intestinal epithelium
- resynthesis of TAGs for transport
- assembly of chylomicrons, then exocytosis from enterocytes into lymphatics
- enter bloodstream via ductus thoracicus
Which extracellular lipases are responsible for breakdown of ingested TAGs in the GI tract.
mainly partial hydrolyzation, by
- lingual + gastric lipase: approx. 15%, hydrolyze sn-3 esters
- pancreatic lipase: main lipase, hydryolzes sn-1 and -3 esters
- pancreatic carboxylesterase: also able to hydrolyze CEs, PLs and MAGs
- phospholipase A: hydrolyzes PLs
⇒ β-MAGs and FAs formed, approx. 25% completely hydrolyzed → glycerol
How does pancreatic lipase work?
hydrolyzation of sn-1, -3 ester bonds
BUT: requires colipase
- pro-colipase cleaved by trypsin to active colipase
- associates w/ pancreatic lipase, p_revents the inhibitory effect of bile salts_ on the lipase
How is the intestinal lipid content absorbed in the body?
Differentiate.
- long chain FAs and MAGs: diffuse into intestinal epithelium
- short + medium chain FAs, glycerol directly taken up into portal vein
- cholesterol + sterols: competitively transported into intestinal epithelium via NPC1-like1
- bile salts remain in intestines, reabsorbed in ileum to enter enterohepatic circulation
Inhibitor of Niemann-Pick C1-like protein 1?
Consequence?
ezitimibe
⇒ no free C/sterols absorbed into intestinal mucosa
How are TAGs resynthesized in the intestinal epithelium?
enter the epithelium either as:
- 2-MAG (72%) → monoacylglycerol pathway
- 1-MAG (6%) → monoacylglycerol or phosphatidic acid pathway
- glycerol (22%) → either enter phosphatidic acid pathway or go directly via portal vein to liver
NOTE: 2-MAG can be isomerized to 1-MAG
What is glyceroneogenesis?
Where does it happen?
shortened version of gluconeogenesis
pyruvate → glycerol-3P for TAG synthesis
⇒ controls blood lipid levels
in liver and adipose tissue
Describe the pathway of glyceroneogensis.
Which enzyme is unique to this pathway?
Reaction.
- gluconeogenesis until DHAP formed
-
glycerol 3P-dehydrogenase
* *DHAP + NADH → glycerol-3P + NAD+**
⇒ can now be used for TAG synthesis
Which enzyme catalyzes the rate-limiting step of glyceroneogenesis?
since gluconeogenesis and glyceroneogenesis use the same pathway, PEPCK also catalyzes the rate-limiting step here
What controls glyceroneogenesis in liver and adipose tissue.
How?
activity of PEPCK is
mainly controlled by glucocorticoids on level of gene expression:
- induce PEPCK in liver → ↑ glyceroneogenesis → ↑ TAGs synthesized + released into blood stream
- repress PEPCK in adipose tissue → ↓ glyceroneogenesis → no TAGs synthesized (would be stored) → FFAs released into blood stream
⇒ glucocorticoids signal stress, hence we need energy, causing high TAG, FFA levels
What is the function of chylomicrons?
Describe their assembly.
transport ingested TAGs via lymph into blood stream to extrahepatic tissues
-
apo B48 (synthesized in rER) incorporated by triglyceride transfer protein into particles w/ TAG
(forming the core of the whole thing) - C and PLs (synthesized in the sER), and apo AI added (makes sense b/c this forms the layer around the core)
- transported to Golgi to add carbohydrate residues
- released from enterocyte by exocytosis into lymphatics
What happens with chylomicrons once they entered the lymph?
- receive apo E, CII, CIII from HDL
- apo CII activates lipoprotein lipase, loose most of TAG content
- returns cholesterol, apo AI, CII, CIII to HDL → remnant chylomicron
- binds via apo E to LDL-R on liver, internalized
What are the contents of chylomicron remnants?
only apo B48, E,
10-30% of initial TAG content
Where can lipoprotein lipase be found?
Function?
What happens with its products?
located on endothelium of extrahep. tissues
TAGs from chylomicrons/VLDL → G + FAs
- FAs absorbed by extrahep. tissue
- G reabsorbed by liver + phosphorylated for new TAG synthesis
On which tissues can specialized lipoprotein lipases be found?
on heart and lactating mammary gland
much higher affinity for TAGs
→ redirection of TAGs from extrahepatic tissues to heart/lactating mammary gland to provide TAGs for energy generation/milk production
Which apoproteins activate, resp. inhibit lipoprotein lipase?
- activators: apo CII
- inhibitors: apo AII, CIII
Which factor alters the expression of lipoprotein lipase?
How and where?
insulin
→ enhances synthesis + transport to luminal surface
of lipoprotein lipase in adipocytes
What is the function of hepatic lipase?
similar to lipoprotein lipase, cleaves TAGs, but
only uses content of
- HDL2 → forming HDL3
- VLDL remnant → forming IDL
What is the function of VLDL?
Describe their assembly.
synthesized in liver to transport TAGs to extrahepatic tissues when more fats/carbs ingested than used
- apo B100 (synthesized on polyribosomes) translocated by microsomal triglyceride transfer protein to ER
- lipidated w/ PLs, cholesterol and TAGs by MTP → VLDL2
- transported to Golgi in COPII vesicles
- fusion w/ TAG-rich lipid droplets → VLDL1
- secreted into blood stream
List some factors that incr. the secretion of VLDL.
-
fed state
- presence of high conc. of insulin, low conc. of glucagon
- diets high in fructose, sucrose
- high levels of circulating FFAs
- ingestion of ethanol
How does insulin affect VLDL assembly?
- inhibits apo B100 synthesis
- inhibiting conversion of VLDL2 to VLDL1 in Golgi
What does ARF-1 do?
ADP-ribosylation factor 1
blocks phospholipase D → no conversion of phosphatidic acid to PLs (required for VLDL assembly)
What happens with VLDL once it entered the blood stream?
similar to processing of chylomicrons
- receives CE, apo E, CI - CIII from HDL
- apo CII activates lipoprotein lipase, loose most of TAG content
- return apo CI - CIII to HDL → remnant VLDL
-
either:
- binds via LDL-R to liver, internalized
- IDL formed
VLDL receive <span>C</span>holesterol<span>E</span>sters, apo <u>C</u> (I-III), <u>E</u>
What are the contents of remnant VLDL?
only apo B100, E
PLs, C/CEs
10-30% of TAGs left
How is IDL formed?
from remnant VLDL
- interacts w/ hepatic lipase → more TAGs lost
- loses apo E to HDL → LDL formed
Which receptor is responsible for the binding of the chylomicron and VLDL remnants to the liver?
LDL (apo-B100, E) receptor: binds all types of lipoproteins
Describe the structure of LDL.
Function?
transport of cholesterol + cholesterolesters
to extrahepatic tissues, there
- incorporated into membrane, or
- used for sterol/bile acid synthesis
contains only apo B100 after being formed by IDL
What causes familial hypercholesterolemia?
Consequences?
deficiency of LDL (apo B100, E) receptor
→ ↑ blood cholesterol level → premature atherosclerosis
Describe how LDL is taken up into the cell.
- LDL binds to LDL (apo B100, E) receptor in coated pits
- coated vesicles (clathrin) are formed
- fuse w/ early endosome → diffusion of receptor from LDL due to low pH
- receptor translocated back to cell surface
- LDL apoB100 degraded in lysosomes
⇒ all cholesterol leaves as free cholesterol into cytoplasm
What is the function of HDL?
Where is it synthesized?
List the different types.
transport of cholesterol in form of cholesterolesters from extrahepatic tissues to liver
= reverse cholesterol transport
synthesized in liver & intestine
- (nascent, discoidal) pre-β HDL
- HDL3
- HDL2
Explain reverse cholesterol transport:
HDL formation → transfer of cholesterol from extrahepatic tissue to HDL
- synthesis of nascent HDL
- PTLP transfers further phospholipids to HDL
- apo AI binds + activates LCAT → cholesterolesters formed → distension to HDL3
- ABCA1 and ABCG1 on extrahep. tissue transfer cholesterol to HDL3
cf. own cards
Describe the synthesis of nascent HDL.
lipid-poor apo AI synthesized in liver/intestinal mucosa, receives cholesterol + phospholipids from ABCA1
→ discoidal nascent HDL
Describe the function of ABCA1 (and ABCG1).
Where can they be found?
ATP binding cassette transporters
→ require ATP
-
ABCA 1: in liver, extrahepatic tissues
binds phospholipids + cholesterol to apo AI -
ABCG 1: in extrahepatic tissues
transports cholesterol across the membrane to HDL
What is the function of LCAT?
Reaction.
lecithin:cholesterol acyltransferase
sitting on HDL, converting new cholesterol to cholesterolesters
cholesterol + lecithin
↓
cholesterolesters + lysolecithin
Which apoproteins are activators of LCAT?
apo AI, CI, D
LCAT, … CI, AI, D
What is the function of PTLP?
phospholipid transfer protein
transfers phospholipids from chylomicrons/VLDL to nascent HDL
Explain reverse cholesterol transport:
HDL3 → transfer of cholesterol to liver
- cholesterol transferred from extrahep. tissue conv. to CE by action of LCAT
- transfer of phospholipids, apo CI, III, E from chylomicrons/VLDL to HDL3 → HDL2
-
then either:
- taken up into liver
- exchange w/ VLDL via CETP
Which substances does HDL receive after uptake of further cholesterol from extraheptic tissues?
Consequence?
phospholipids, apo CI, III, E
(+ further conversion of cholesterol → CE by LCAT)
→ HDL2 formed
What is the function of CETP?
cholesterolester transferprotein
cholesterolesters from HDL2 exchanged w/ TAGs from VLDL
How are the contents of HDL taken up into the liver?
Differentiate.
SR-B1 = scavenger receptor-B1
takes up cholesterolesters → nascent HDL, HDL3 is formed
hepatic lipase
degrades TAGs of HDL2 after exchange via CTEP → HDL3
direct uptake of HDL2 via apo E receptors
What is the function of SR-1B?
uptake of cholesterolesters from HDL to liver/steroidogenic tissues after binding of apo A1
⇒ reverse cholesterol transport
