Lipoproteins, Cholesterol, integration Flashcards
What is Orlistat and Olestra?
Orlistat = Lipase inhibitor
Olstra = Artificial fat/food additive
*Prevent breakdown of dietary fats for absorption in the small intestin → fats stay in the digestive tract → Steatorrhea (diarrhea)
What is the general structure of lipoproteins?
Lipoproteins are the circulating lipid carriers
- Hydrophobic/neutral lipid core → cholesterylester, triglyceride
- Monolayer Amphipatic coat → free cholesterol, phospholipids, phosphatidylcholine
- At least 1 Apolipoprotein (acts as dock or cofactor)
What are the different lipoproteins in order of density?
- Chylomicrons (least dense)
- Very-low density lipoprotein (VLDL)
- Intermediate density lipoprotein (IDL)
- Low density lipoprotein (LDL)
- High density lipoprotein (HDL)
*Filled with triacylglycerol makes them larger in size, but lower density (more proteins = more density)
What is the structure of the different lipoproteins?
Chylomicrons → Filled with triglycerides, Apo B-48, Apo-C, Apo E, Apo-A-1
Chylomicrons remnants → Apo B-48, Apo-E
VLDL → Filled with triglycerides, Apo B-100, Apo-E, Apo-C
IDL → same as VLDL but less triglycerides (from VLDL)
LDL → mostly Cholesterol esther in core, Apo-B100 (from IDL + interaction with HL)
HDL → Apo-A1
FINISH
What is the purpose/generatilites of the exogenous vs endogenous pathway of Lipoprotein metabolism?
Exogenous:
- Dependent on dietary intake
- Gives to muscle and adipose tissue if immediate needs
- Small intestine → Chylomicrons formed in small intestine → {capillaries of muscle and adipose tissues} → Chylomicrons remnants → Liver
- Done (no more chylomicrons in circulation ~2-3h post-meal)
- Bring lipids from Small intestine → Liver
Exogenous:
- Brings lipids from Liver → Peripheral tissues
- Independent of dietary intakes
- Liver → VLDL → {capillaries of muscle and adipose tissues} → IDL → Tissue
What is the role of lipoprotein lipase (LPL)?
- Binds to chylomicrons + is activated by cofactor Apo-C II
- It will uptake triacylglycerols in the chylomicrons → hydrolyze them to be uptaken by capillaries
*Apo-C III inhibits LPL for balance
Chylomicrons remnants after going through capillaries don’t have Apo-C anymore as it stays bound to LPL
In the exogenous pathway, how to chylomicron remnants interact with the liver?
LDLreceptor → Apo-E
LRP → Apo-B 48
What is the difference between Apo-B 100 and Apo-B 48?
Apo-B 100 = 100% length of the protein → synthesized by liver (VLDL)
Apo-B 48 = 48% length of the protein → synthesized by small intestine (Chylomicrons)
What is HL?
Hepatic Lipase: Causes IDL → LDL (releases triacylglycerol to the liver?)
How is cholesterol uptaken by tissues?
- Uptake don via LDL-receptor which binds to Apo-B 100 → clathrin-coated pit → vesicle (endocytosis)
- Fusion of the vesicle with endosome → acidification → lyses the membrane (2ndary lysosome)
- Apo-B amino acids are released + Cholesterol makes Cholesteryl ester droplets or is brought to ER for membrane usage
What is the importance of HDL?
How are the made?
*Reverse Cholesterol Transport (Tissues → Liver)
1. ABCA-1 → efflux lipids onto Apo-A1 to form preHDL
2. Disk-shaped preHDL detaches from ABCA-1 (conformational change)
3. LCAT esterifies cholesterol → (disk-shape → ball-shape) → maturation to HDL3
4. CETP → CE and TG transfer between HDL3 and VLDL
5. Ultimately forms mature HDL2 → has right epitope (Apo-A1) to bind SRB1
6. HDL2 delivers CE and TG to liver → when emptied (Apo-A1 is unlipidated) → change in conformation → undocking of unlipidated Apo-A1 → goes back to tissue to binds ABCA-1
*ABCA-1 = Floppase → Uses ATP to move protein inside → outside
*Esterification of cholesterol = addition of FA from PC to make cholesterol completely neutral)
*CETP = Cholesteryl ester transfer protein
What is the rate-limiting step of Reverse Cholesterol Transport?
HDL bringing Cholesterol from tissues → Liver
Rate-limiting step = ABCA-1
What characteristic of Apo-A1 allows it to bind specific receptors needed to bring cholesterol from tissues to the liver in HDL?
Unlipidated A1 → Strong affinity for ABCA-1 (tissues), no affinity for SRB1 (Liver)
Lipidated A1 → Strong affinity for SRB1 (Liver), no affinity for ABCA-1 (detaches when starts being lipidated)
*Conformational changes
What is the effect of an increase in ACAT
Acyl-coenzyme A:cholesterol transferase (ACAT) → catalyzes formation of cholesterol esters inside ER → stored into cholesterol droplets
*In macrophages
It limits HDL-mediated cholesterol uptake
What is CETP?
CETP = Cholesteryl Ester Transfer Protein
Tube shape with hydrophobic interior → allows transfer between HDL3 and VLDL
- Cholesteryl Ester (CE): HDL3 → VLDL
- TG: VLDL → HDL3
*Down concentration gradient
End product = HDL2 → right epitope (APO-A1) to bind SRB1 in the liver
What is Cholesterol used for in the liver?
- Formation of Bile salts for bile
- Formation of VLDL
What is the rate limiting step of bile synthesis?
Cholesterol → 7a hydrocholesterol
*For synthesis of Bile salts
Enzyme = Cyp7a1 (hydroxylase)
What are the names of the 2 bile salts?
Both synthesized from cholesterol:
- Glycocholate (Glycine)
- Taurocholate (Taurine)
What is considered as good and bad cholesterol?
Good cholesterol → HDL (removes excess cholesterol from tissues)
Bad cholesterol → LDL (carries cholesterol from liver to tissues) → when too much in capillaries, accumulates and forms plaques → Antheosclerosis
What is Antherosclerosis?
Build up of fat and cholesterol in arterial walls
When overabundance of LDL → infiltrate the arterial wall → macrophages engulf the extra LDL → undergo apoptosis → build a plaque narrowing the blood vessels (increasing blood pressure)
Eventually, if the blood can’t pass, O2 can’t get to muscles → causes heart attack or stroke (brain)
What is the effect of a deficiency in LDLR?
Too much LDL accumulation in circulation → high cardiovascular disease risk
What is the effect of a deficiency in ABCA-1
*Floppase → make HDL
ABCA-1 deficiency → too little HDL → high cardiovascular disease risk because can’t bring cholesterol back from tissues to liver so accumulates
Which of the following can cause Hyper-Chylomicronemia?
- Lipoprotein Lipase deficiency
- ApoC-III mutations
- Apo E deficiency
- ABCA1 mutations
- ApoA-I deficiency
Lipoprotein Lipase deficiency
Apo E deficiency
*ApoC-III mutations → inhibitor of LPL → Gain of function mutation could increase chylomicron concentration
*ABCA1 and ApoA-I are related to HDL metabolism → not related
Abnormally high [LDL] in plasma can be caused by L-O-F of which of the following?
- LDLr
- ApoB-100
- ABCA1
- Lipoprotein Lipase
- Pancreatic Lipase
LDLreceptor and ApoB-100 (receptor and ligand)
Low HDL concentrations may result from mutation in which of the following?
- LDLr
- LPL
- LCAT
- ABCA1
- ApoA-I
LCAT, ABCA1, ApoA-I
Which food provides a dietary source of “good” cholesterol?
NONE specifically, its all about quantities
HDL = good cholesterol
LDL = bad cholesterol
What is the starting block of the synthesis of cholesterol?
Acetyl-CoA → Cholesterol (through the Mevalonate Pathway)
*One-way pathway, Cholesterol can’t broken down to Acetyl-CoA
What are the general/important steps of the Mevalonate Pathway?
Mevalonate Pathway = Acetyl-CoA → Cholesterol
- Acetyl-CoA → {release CoA and attach to another Acetyl-CoA} → Acetoacetyl-CoA
- Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA
*Up to here same steps as ketogenesis - RATE LIMITING STEP: HMG-CoA reductase
HMG-CoA → {consume 2x NADPH, release CoA-SH} → Mevalonate - From Mevalonate → Farnesyl pyrophosphate
Consumption of lots of ATP - Farnesyl pyrophosphate → Squalene (consumes NADHP)
Multiple Steps → Cholesterol
What is consumed in the synthesis of Cholesterol?
Acetyl-CoA → Cholesterol consumes 36 ATP + 16 NADPH/cholesterol
*that’s why the pathway doesn’t reverse, it takes too much energy to make (we don’t degrade cholesterol, its precious!!)
What is the rate-limiting step of the synthesis of cholesterol?
HMG-CoA reductase
What is another use of Farnesyl pyrophosphate? (An intermediate of the Mevalonate Pathway)
It is also a lipid anchor → inserted in the bilayer lipid membrane and makes a thioether linkage between Cysteine and prenyl group → PRENYLATION
How is cholesterol homeostasis maintained at the level of the whole body?
Cholesterol pool ~ 100g
Dietay intakes ~ 300mg/d
Synthesis from the liver ~ 700mg/d
Bile acids secretion ~ 500mg/d
Biliary cholesterol ~ 500mg/d
→ NET BALANCE if you don’t eat too much
How is homeostasis of cholesterol maintained at the cellular level?
- LDL uptaken trough LDLr on cell surface
Cholesterol is used or not
- pre-HDL is effluxed through ABCA1
Which 2 factors are responsible for regulation of HMG-CoA reductase?
- Energy state of the cell
Low energy state (high [AMP]/[ATP]) activates AMPK → phosphorylates HMG-CoA reductase to inactivate it
Back in high energy state → protein phosphatase will dephosphorylate it to reactivate it → promote synthesis of cholesterol
(Because cholesterol synthesis takes up so much energy) - Gene regulation (sensing [cholesterol])
How does transcriptional control regulate cholesterol synthesis?
SREBP = Sterol-response element binding protein → TF for gene like HMG-CoA reductase and LDLreceptor
- Has a regulatory head bound to scap and bHLH head which can bind DNA
In high cholesterol state:
Cholesterol in ER membrane allows Insig to bind to Scap-SREBP
In low cholesterol state:
1. Scap is not reatined to the ER membrane → transports SREBP to the Golgi
2. Proteolytic processing of SREBP by S1P and S2P
3. bHLH head is cut (by S2P) → goes to the nucleus → activates transcription of target genes → promote cholesterol synthesis
→ Increase in HMG-CoA reductase levels
→ Increase in LDL-receptor levels (more LDL uptake)
How can cholesterol synthesis be pharmacologically regulated?
HMG-CoA reductase inhibitors
Ex: Statins
How do statins work?
Statins are a class of HMG-CoA reductase inhibitors (drugs that regulate cholesterol synthesis)
By inhibiting HMG-CoA reductase, cells are lower in cholesterol → they can uptake more cholesterol from LDL (increase LDL receptor transcription) → more clearance of LDL in the blood
What is the main function of cholesteryl esters?
Which enzyme are involved in synthesis of cholesteryl esters?
Storage of cholesterol in lipid droplets
ACAT: Cholesterol → Cholesterol ester
- inside cells (lipid droplets, VLDL)
- ACAT = Acyl-CoA:Cholesterol Acyltransferase
LCAT: Cholesterol + PC (Lecithine) → Cholesterol ester + Lysolecithin
- in Plasma (HDL)
- Lecithine:Cholesterol Acyltransferase
Which organs are lipid droplets found in?
What are the differences?
Adipocytes → store large amounts of TG in huge 1x lipid droples/cell
Liver → smaller lipid droplets, much more transient buffer reservoir of esterified FA and esterified cholesterol
What are the different Sterol derivatives?
- Cholesteryl Ester
- Bile salts
- Hormones
- Vitamin D
Where does synthesis of steroid hormones from cholesteol occur in the body?
In adrenal glands
*Cholesterol can’t be degraded, but we can modify it!
Other example is VitD important for bone development
What organs does HDL deliver cholesterol to? For what usage?
Liver → bile acids
Adrenal glands → steroid hormones
Skin → Vitamin D
What type of fuel storage is found in the brain and the heart?
What is their prefered fuel
NO fuel reserves in the brain and the heart → need constant supply
- Brain prefers Glucose
- Heart muscles prefer Fatty Acids
After a meal, at rest, what is the orders of pathways activated in the muscles?
- Glycogen synthesis
VERY minor/not efficient:
2. FA synthesis
3. TG synthesis
4. Storage in very few lipid droplets
After a meal, at rest, what is the orders of pathways activated in the liver?
- Glycogen synthesis
- FA sythesis
- TG synthesis
- Storage in lipid droplets + VLDL secretion
After a meal, at rest, what is the orders of pathways activated in the brain and heart?
TCA cycle + OxPhos
- No fuel storage
- Always working
After a meal, at rest, what is the orders of pathways activated in adipose tissue?
- FA synthesis
- TG synthesis
- Storage of lipid droplets
What are the fuel reserves in each organ/tissue?
Muscles → Glycogen + Protein
Liver → Glycogen + Triacylglycerols
Adipose Tissue → Triacylglycerols
Brain → None
Heart → None
What are the main energy pathways of the different organs/tissues?
Muscle → b-oxidation, glycolysis, proteolysis, CAC
Liver → Glycolysis, gluconeogenesis, b-oxidation, FA synthesis
Adipose tissue → b-oxidation, TG synthesis
Brain → Glycolysis, CAC
Heart → b-oxidation, CAC
During exercise/stress, what is the orders of pathways activated in the muscles?
- Anaerobic glycolysis → Produces Lactate → sent to Liver
- TCA + OxPhos
- Glycogen breakdown (stimulated by adrenaline)
*Glucose from liver is uptaken from circulation
FA are taken up from the blood:
4. Lipolysis of TG in lipid droplets
5. b-oxidation of FA → TCA + OxPhos
During exercise/stress, what is the orders of pathways activated in the liver, in the brain, in the heart and in adipose tissue?
Liver:
1. Glycogen breakdown
2. Lipolysis of TG in lipid droplets
3. FA export to blood
*Liver is taken up from circulation and changed back to glucose
Heart:
1. TCA cycle + OxPhos
Heart:
1. TCA cycle + OxPhos
Adipose Tissue: (nothing glucose related)
1. Lipolysis of TG in lipid droplets
2. FA export to blood
During starvation/prolonged exercise, what are the orders of pathways activated in the muscle, liver, in the brain, in the heart and in adipose tissue?
*For glucose only
*only change is the Liver starts making gluconeogenesis + ketogenesis
Muscle → nothing
Brain → unchanged TCA cycle + OxPhos
Heart → unchanged TCA cycle + OxPhos
Adipose Tissue → nothing (already breaking down)
Pancrease releases glucagon → Gluconeogenesis in the LIVER → Glucose → Heart + Brain (not muscles)
*Also Ketogenesis from FA
What are all the effects of low blood glucose?
- Glucagon secretion from pancrease
- Increased cAMP
- Increased phosphoryation of key enzymes:
- Phosphorylase b→a (increase Glycogen breakdown)
- Glycogen synthase a→b (decrease glycogen synthesis)
- PFK-2 → F2,6BPase (decrease glycolysis, increase gluconeogenesis)
- PK → Phosphorylated PK (decrease glycolysis, increase gluconeogenesis)
What is the effect of diabetes on metabolism (different tissues)
NO insulin release (or insulin hyporesponsiveness)
In muscle cells → less glucose uptake (no Glu4) → Proteolysis bc low glucose uptake
In adipose cells → less glucose uptake (no Glu4) → Lipolysis bc low glucose uptake
In Liver cells → Ketogenesis
*False impression of lower energy state:
- Ketogenesis
- More circulation of FA (more FA breakdown)
Anterosclerosis.
Select all that are true.
A) In familial Tangier Disease, [HDL-cholesterol] is above normal value in the blood
B) Accumulation of oxLDL in the arterial walls contribute to the narrowing of arteries
C) Decreased HDL levels pre-dispose patients to cardivascular diseases
D) Transiant elevation of chylomicrons in blood is associated with increased risk of cardiovascular disease
E) In familial hypercholesterolemia, [LDL-cholesterol] is above normal values in the blood
B) Accumulation of oxLDL in the arterial walls contribute to the narrowing of arteries
C) Decreased HDL levels pre-dispose patients to cardivascular diseases
E) In familial hypercholesterolemia, [LDL-cholesterol] is above normal values in the blood
