Lectures 20-28 Flashcards
(148 cards)
1
Q
what are the sources of cholesterol?w
A
diet, and endogenous synthesis
2
Q
what cells are able to synthesize chol? what is the main organ for synthesis?
A
almost all cells (incl brain) can synth. liver is main location.
3
Q
what makes the cholesterol molecule polar?
A
the OH (hydroxy) group attached to one of the 6 membered rings
4
Q
what can happen to make cholesterol non-polar? what occurs when this happens?
A
the OH can be replaced by a long chain fatty acid. (ie, esterified). then can no longer go into lipid bilayer, and forms lipid droplets in macrophages
5
Q
what form is cholesterol transported in in plasma?
A
plasma cholesterol is in esterified form (less polar/more hydrophobic than usual). has to be transported in association with proteins.
6
Q
what are the 3 sources of liver cholesterol?
A
- dietary
- recycled from other tissues
- de novo synthesis
7
Q
what are the 3 routes by which cholesterol leaves the liver?
A
- via secretion in VLDL
- free cholesterol secreted in bile
- conversion to bile salts/acids
8
Q
what is the precursor to cholesterol synthesis? what pathway comes prior to chol synthesis?
A
Acetyl-CoA. same Acetyl-CoA pool that provides the precursors for fatty acids (ie citrate from TCA is abundant, so diffuses out of the mitochondria)
9
Q
where in the cell does de novo synthesis of cholesterol occur?
A
cytoplasm.
10
Q
what is the general process of making a cholesterol, starting with Acetyl-CoA and going up to Mevalonic Acid?
A
2 Acetyl CoA -> Acetoacetyl CoA -> HMG CoA -> Mevalonic Acid (using HMG CoA reductase to obtain Mevalonic Acid)
11
Q
what is the general process of making a cholesterol, starting with Mevalonic Acid and going up to cholesterol?
A
Mevalonic Acid (6C) -> Isopentenyl phrophosphate (IPP) (5C) -> 10C molec -> 15C molec -> Squalene (30C) -> Lanosterol (30C) -> cholesterol (27C)
12
Q
What controls the synthesis/activity of HMG CoA Reductase?
A
inhibited by statins, inhibited by cholesterol
13
Q
what is Smith-Lemli-Optiz syndrome (SLOS)?
A
genetic disorder, partial deficiency of 7-dehydroholesterol-7-reductase, involved in final step of chol synthesis. causes a variety of symptoms including retardation and phys abnormalities
14
Q
How does chol enter body cells?
A
using the LDL receptor pathway. all cells contain the LDL receptor. LDL binds to receptor, is taken into cell, fuses with lysosome, cholesterol ester is hydrolized into free cholesterol and fatty acids.
15
Q
how does cholesterol travel in the blood?
A
in LDL with protein (ApoB100).
16
Q
what happens to the ApoB100 when the LDL is taken into a cell?
A
degraded to amino acids.
17
Q
where does the free cholesterol go once in the cell? what effect does it have
A
moves to plasma membrane or to ER to regulate via SREPB pathway (regulates HMG Reductase and LDL Receptor genes). Also upregulates cholesterol storage enzyme ACAT1
18
Q
what is the main control point for cholesterol synthesis?
A
HMG-CoA reductase, step from HMG-CoA to Mevalonic Acid
19
Q
what controls expression of the HMG-CoA reductase gene? where does it bind?
A
a transcription factor, SREBP (sterol regulatory element binding protein). binds to the SRE located upstream of the HMG-CoA reductase gene
20
Q
where is SREPB usually located? what happens when it is cleaved?
A
on the ER membrane. once cleaved, travels to the nucleus, upregulates transcription of HMG-CoA reductase gene.
21
Q
what happens when cellular cholesterol levels are low?
A
SREBP travels to nucleus and upregulates transcription of HMG-CoA reductase gene.
22
Q
what inhibits activity of the SREBP?
A
cholesterol (meaning that there is sufficient cellular cholesterol, and the cell does not need to use HMG-CoA Reductase and make more).
23
Q
Activation of SREBP also activates what?
A
the LDL receptor gene so chol can be taken up by the cell
24
Q
HMG-CoA Reductase is also hormonally regulated. what is the effect of insulin? glucagon?
A
insulin upregulates expression of HMG-CoA Reductase. glucagon downregulates it. Makes sense: remember precursor of cholesterol is excess cytoplasmic Acetyl-CoA from TCA spillover
25
how do statin drugs inhibit HMG CoA Reductase? what do they do to plasma cholesterol levels?
they are competitive inhibitors and thereby reduce cellular cholesterol synthesis. due to less chol, SREBP levels increase and increase the transcription of HMG-CoA Reductase AND upregulate LDL receptor genes. therefore decrease plasma cholesterol by making it be taken into cells
26
what is ACAT?
key enzyme in cellular cholesterol storage in various cells. catalyzes cholesterol -> cholesterol ester (for cellular droplet storage)
27
what controls ACAT?
not SREBP (too slow, requires faster regulation). controlled by its own substrate (cholesterol). this is the first defense against high cholesterol levels
28
how is the synthesis of cholesterol and fatty acids primarily regulated?
at the gene/transcription level
29
when the free cholesterol increases in a cell, what happens to the LDL receptor levels?
they decline because the cell doesn't need to take up as much free chol.
30
when the free chol decreases in a cell, what happens to LDL receptor levels? what about HMG CoA Reductase levels?
LDL receptors increase to take in more circulating cholesterol. HMG CoA reductase is increasingly transcribed/translated in order to synthesize more chol de novo
31
how were SREBPs located experimentally?
based on their ability to bind to SREs
32
SREBP-1: what is it primarily involved with?
regulation of fatty acid synthesis
33
SREBP-2: what is it primarily involved with?
regulation of chol synthesis
34
what is unique about SREBP-2 as a tsn factor?
it is very large and is located in the ER.
35
how is SREBP-2 activated?
when there is insufficient cellular cholesterol, part of SCAP (touches SREBP normally) moves and SCAP changes shape. SREBP then drifts to Golgi where it is cleaved into a more normal-sized transcription factor and can diffuse into nucleus.
36
SREBP-1 clipping off from ER to go to nucleus is promoted by what?
insulin (sufficient insulin -> cleavage/activation of SREBP-1 -> Fatty acid synthesis/storage)
37
what genes are turned on by SREBP?
ACL, ACC, FAS
38
SREBP-1 generally mediates what?
insulin
39
if SREBP-1 mediates insulin, and SREBP-2 mediates cholesterol, then what mediates glucose?
CHREBP (carbohydrate response element binding protein)
40
how does CHREBP work?
similar to SREBPs: lives in cytosol, when high glucose levels, CHREBP is dephosphorylated, moves to nucleus, binds to DNA location (E-box), activates tsn.
41
what are required to translate Fatty Acid synthesis genes (FAS, ACC, ACL)?
both SRE and CHRE locations, activated by SREBP-1 and CHREBP
42
cholesterol is the obligatory precursor for biosynthesis of what 2 classes of molecules?
oxysterols and steroid hormones.
43
what do oxysterols do?
they have impt regulatory roles (via signal transduction) in cellular cholesterol homeostasis
44
what do steroid hormones do?
involved in regulatory processes in intermediary metabolism (more in endocrine course)
45
what are the 4 oxysterols we should be familiar with?
1. 7a-hydroxycholesterol
2. 24S-hydroxy cholesterol
3. 27-hydroxycholesterol
4. 25-hydroxycholesterol
46
what does 7a-hydroxycholesterol do?
first intermediate in the bile acid synthesis pathway. uses cholesterol as a substrate.
47
what does 24S-hydroxy cholesterol do?
most abundant oxysterol produced in the brain. the enzyme cholesterol 24S hydroxylase converts cholesterol to a more hydrophilic form to allow its release from the brain
48
what do 27-hydroxycholesterol and 25-hydroxycholesterol do?
impt in signaling/regulatory compounds
49
ACAT: regulated by SREBP?
No! regulated by its substrate (cholesterol)
50
the most impt rate-limiting step in the cholesterol biosynthetic pathway is:
conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase
51
what is the mutation in familial hypercholesterolemia?
mutation in the LDL receptor gene
52
what does ACAT do?
converts cholesterol (with OH hydroxy group) to cholesterol ester (with FA instead of OH). the esterified form can not go into the membrane and instead is stored as a lipid droplet in macrophages (foamy cells)
53
why does cholesterol travel with proteins?
it's insoluble - if it's free in the cell it will precipatate and can cause damage. so it travels in a complex with proteins.
54
What do NPC 1 and NPC 2 do?
they are involved with cholesterol trafficing within the cell -- allow cholesterol to move from lysosome to ER and complete endocytosis process
55
what happens to patients with NPC 1 and 2 deficiency?
Niemann-Pick Type C disease: progressive neurodegenerative disease. hepatic enlargement and slow dis-coordination, retardation.
56
where do the cholesterol molecs accumulate within the cell in NPC disease?
inside the lysosome
57
what is the difference between NPC 1 and NPC 2 proteins?
NPC1 is a membrane protein
NPC2 is a soluble protein
but both bind cholesterol very tightly and coordinate the movement of cholesterol within the cell (particularly, egress out of the lysosome)
58
if NPC1 and NPC2 are both absent, how does cholesterol move within the cell at all?
there are other pathways for cholesterol movement that are not NPC dependent: de novo synthesis and transport to the cytoplasm, and the cholesterol/cholesterol-ester cycle coordinated by ACAT
59
for NPA and NPB diseases, where is the mutation?
at the lysosomal sphingomyelinase (causes accumulation of sphingomyelin in the lysosome)
60
in NPC, do glycosphingolipids accumulate? sphingomyelin?
yes, but this is a secondary effect and only because cholesterol has a strong affinity for these. so when chol builds up, they build up as well.
61
what is the basic backbone structure for all sphingolipids?
ceramide (not glycerol)
62
what are gangliosides?
acidic glycolipids (aka glycosphingolipids) that are concentrated at the outer leaflets of plasma membranes. participate in signal transduction.
63
what is the backbone structure of glycolipids?
sphingosine/ceramide.
64
what is one requirement of glycolipids/glycosphingolipids?
need to be recycled/degraded continuously between membrane and cell. problem when a hydrolase for degradation is mutant: synthesis and degradation no longer balanced.
65
how do lipid storage diseases occur?
NL: the synthesis and degradation of glycosphingolipids/glycolipids/gangliosides is balanced, so the membrane is constantly renewed. if a specific hydrolase is mutated/missing, the synthesis will overtake the degradation and we have a lipid storage disease
66
lipid storage diseases are also called?
sphingolipidoses
67
Tay-Sachs is the result of mutation of what enzume?
beta-hexosaminidase A (Hex A)
68
what does Hex A do?
catalyzes ganglioside GM2 -> GM3
69
lack of Hex A causes what?
buildup of GM2
70
symptoms of Tay-Sachs?
macrocephaly, cherry red macular spot (due to buildup of lipids around it), progressive weakness, mental retardation
71
what disease involves defect in the enzyme beta-N-acetyl hexosaminidase A (Hex A)
Tay-Sachs
72
HDL: good chol or bad chol?
good chol
73
HDL is a lipoprotein that contains what?
apoA1/2, phospholipids (phosphatidyl choline), cholesterol, cholesterol esters
74
what is reverse cholesterol transport?
a metabolic process by which HDL removes excess cholesterol from peripheral tissues and transports it to liver for elimination or reutilization.
75
what reaction is catalyzed by LCAT?
phosphatidylcholine + cholesterol -> lysolecithin + cholesterol ester. most impt part is changing cholesterol to cholesterol ester
76
what organs produce the protein ApoA1?
liver, intestines
77
nascent HDL contains what?
ApoA1, apoE, apoC, cholesterol, phospholipids
78
what shape is nascent HDL?
discoid (like a disc)
79
what happens to transform nascent HDL into mature HDL?
LCAT enzyme converts cholesterol to cholesterol esters, and transforms HDL from disc shaped to spherical
80
what is the progression from nascent HDL to HDL3 to HDL2?
nascent HDL picks up cholesterol from peripheral tissues. HDL3 is the spherical result once cholesterol has become cholesterol esters (using LCAT). after receiving more cholesterol esters, becomes HDL2. Either HDL2 or HDL3 are recognized by SRB1 receptor in liver
81
what is the SRB1 receptor?
receptor in liver that binds HDL 2 or HDL3 in order to catabolize (breakdown)/reuse the cholesterol esters.
82
how do cholesterol and phospholipids from body cells enter into the HDL droplet?
via ABCA1 and ABCG1 transporters on peripheral tissue membrane
83
what is the problem in Tangier disease?
problem with ABCA1 genes. Leads to severe HDL deficiency. technically no problem with apoA1, apoC, apoE but these proteins degrade quickly without addition of chol/phospholipids so they appear to be low
84
what are symptoms of Tangier disease?
swollen/orange tonsils (from accumul of cholesterol esters in macrophages), lipid deposits in neuronal cells, smooth muscle cells, and fibroblasts. in blood, virtually no HDL, low LDL levels.
85
ABC transporters are a superfamily of proteins characterized by what? what do they do in general?
use ATP to transport substrates between different cellular compartments and to/from the cell.
86
what does ABCA1 do?
pushes phospholipids and cholesterol out of peripheral tissues and to apoA1 for inclusion in HDL droplets
87
what happens to ApoA1 if ABCA1 is defective?
it will degrade
88
what are RXR and LXR? where do they bind?
ligand-induced transcription factors. they bind to the Direct Repeat Response element (DR-4) upstream of the ABCA1 gene.
89
what is the ligand for RXR?
Retinoic acid
90
what is the ligand for LXR?
oxysterols
91
what are the differences between ABCA1 and ABCG1?
they are close homologs. ABCA1 regognizes apoA1 on nascent HDL and mediates the efflux of both phospholipids and cholesterol. ABCG1 recognizes HDL2/HDL3 and mediates the efflux of only cholesterol.
92
why would patients with Tangier disease have a buildup of cellular cholesterol esters?
if ABCA1 not available to kick cholesterol out of cell membranes, the cholesterol esters inside the cell (which are usually in equil with membrane chol due to ACAT1 activity) will build up.
93
what is the indirect pw by which humans can transfer cholesterol esters to liver?
via VLDL/LDL. using CETP (cholesterol ester transfer protein) - transfers cholesterol esters from HDL to VLDL, which then converts to LDL.
94
what are the 4 functions that bile salts/acids perform?
1. provide mechanism for cholesterol excretion (via feces)
2. emulsify to stabilize oil-water interface to allow action of lipases
3. detergent like actions, in order to take in hydrophobic nutrients (like fat-soluble vitamins)
4. regulate the expr of genes that synthesize the bile acids themselves
95
what happens to the ring structure of cholesterol in terms of being digested?
cannot be metabolized to CO2 and H2O: has to be eliminated via feces
96
how is it that bile acids are amphipathic?
they are sided: the hydroxyl groups are up and the methyl groups are down in relation to the plane
97
what is the rate-limiting step in bile acid synthesis?
cholesterol 7a-hydroxylase
98
what regulates the first step in bile acid synthesis (the cholesterol 7a-hydroxylase step)?
upregulated by cholesterol (a precursor), downregulated by cholic acid which is a bile acid (a product)
99
what are the 2 main bile acids?
cholic acid and chenodeoxycholic acid
100
bile acids have what happen to turn into bile salts?
they become conjugated to a molecule of either glycine or taurine.
101
what is the advantage of having bile salts rather than bile acids?
bile salts are stronger acids, and more effective detergents than bile acids.
102
what is the effect of bacteria in the intestine on bile salts?
they can remove the glycine or taurine and thereby regenerate the weaker bile acids
103
what happens once bile acids are secreted into the intestine?
enterohepatic circulation: they are efficiently reabsorbed (>95%) and returned to liver parenchyma. in intestine, they are unconjugated by bacteria back to bile acids. once in liver again, the glycine/taurine is added back on and they are now bile salts
104
what dietary change can increase your excretion of bile acids?
increasing dietary fiber. not very quick or effective though.
105
what causes gallstones?
usually caused by a decrease of bile salts in the bile, which may be due to ileal disease (less reabsorption of bile salts), obstruction of the bile duct, or hepatic dysfunction generally.
106
first step in digestion of lipids?
lingual lipase, in mouth.
107
short-chain triacylglycerols can be digested by what?
by lingual lipase, found in mouth. this is why mile fats are easy to digest: they are short and medium chain fats and do not require bile for digestion.
108
where does the process of emulsification of dietary lipids occur?
in duodenum. makes sense that it occurs before the bile salts meet the food (which occurs in the ileum)
109
what does emulsification accomplish?
increases the SA of the lipid droplets so that the digestive enzymes can act effectively
110
where to intestinal lipase enzymes sit in order to digest fats?
at the oil-water interface of emulsified fat droplets
111
besides lingual and gastric lipases, what else degrades ingested fats?
pancreatic enzymes: pancreatic lipase, pancreatic cholesterol ester hydrolase, and pancreatic phospholipase A2
112
what controls secretions of pancreatic enzymes?
hormones
113
Big picture: what emusifies digested fats? what breaks them down?
emulsify: bile salts
breakdown: pancreatic enzymes/lipases
114
once pancreatic lipases have cleaved ingested fats, how do they enter cells?
the free fatty acids, free cholesterol, and fat-soluble vitamins (ADEK) form mixed micelles. Micelles approach the brush border membrane of the enterocytes and hydrophilic lipids are absorbed.
115
how is it that micelles can be formed?
because free fatty acids, free cholesterol, bile salts are amphipathic. hydrophobic part stays in center of micelle.
116
once FFAs, free chol etc have entered mucosal cells, what happens?
converted back to activated form (FAs get CoA added, cholesterol is re-esterified). then repackaging to chylomicrons. they then go to lymphatic system, and find their way to ER of cells.
117
what is the structure of a chylomicron?
huge lipid droplets surrounded by a thin layer of phospholipids, free cholesterol, and apo-B48. contain TAGs and cholesterol esters, also the fat-soluble vitamins.
118
how are chylomicrons released from enterocytes?
via exocytosis into lymphatic vessels. they then enter the blood.
119
where does the packaging of chylomicrons occur?
in the ER of enterocytes
120
what happens if someone lacks MTTP?
rare disease called abetalipoproteinemia. cannot digest fat and fat-soluble vitamins.
121
what will plasma levels of chylomicrons, VLDL and LDL be for an individual with abetalipoproteinemia?
all low
122
what is the role of MTTP?
required for packaging of elements into chylomicron
123
what regulates the activity of 7a-hydroxylase?
cholesterol (activates) and cholic acid (inhibits)
124
Fat-soluble vitamins and cholesterol can be absorbed by intestinal enterocyte without further breakdown after ingestion: T or F?
T
125
Chylomicrons contain Apo-B48: T or F?
T
126
plasma lipoproteins are complexes with what materials?
spherical macromolecular complexes of lipids and proteins (apo-proteins)
127
what are the 4 types of lipoproteins as they circulate through the bloodstream?
chylomicrons, VLDL, LDL, HDL
128
what determines the density of the plasma lipoproteins?
the ratio of protein to lipid. higher protein amt = more dense
129
what is the lipid core of chylomicrons and VLDL?
TAGs
130
what is the lipid core of LDL and HDL?
cholesterol esters
131
what composes the shell of a plasma lipoprotein?
neutral lipid core surrounded by phospholipids, nonesterified (free) cholesterol, and apolipoproteins
132
why is HDL denser than chylomicrons?
higher ratio of surface proteins to inner lipids (lipids are far less dense)
133
what plasma lipoproteins contain the highest percentage of lipid and the smallest percentage of protein?
chylomicrons
134
what plasma lipoproteins have the longest half-lives in the blood?
HDL. chylomicrons have a very short half-life
135
what is the job of CETP?
(cholesterol ester transfer protein) picks up cholesterol ester from an HDL, and gives it to VLDL/HDL in exchange for TAG.
136
what is common about apolipoproteins E and C?
they are both found in VLDL and LDL.
137
what is the major apoprotein of chylomicrons? does it recognize the LDL receptor?
ApoB48. No.
138
What is the major apoprotein of VLDL and LDL? does it recognize the LDL receptor?
ApoB100. Yes.
139
What is the major apoprotein of HDL? what receptor does it recognize?
ApoA1. This is the one that gets chol and FAs from tissues via ABCA1 and ABCG1
140
Why is HDL the good kind of cholesterol?
Reverse Cholesterol Transfer: it takes cholesterol and PL from cells/tissues and delivers them to the liver and adrenal glands
141
what is the relationship between ApoA1 and LCAT?
both involved in HDL processing: ApoA1 activates LCAT
142
what is the role of MTTP?
loads up Apo48 with lipids in enterocytes to form a chylomicron
143
what is the process of forming a chylomicron in an enterocyte?
1. ApoB is translated by ribosome and protein made.
2. ApoB translocates across ER membrane
3. cholesterol, CE, phospholipids, TGs are gathered
4. MTTP attaches lipids to ApoB
5. chylomicron exocytosed to lymph/circulation
6. during exocytosis, picks up Apo C and Apo E
144
what does a chylomicron do once it leaves the enterocyte?
lymph -> circulation. drops off TAGs (recall lipoprotein lipase on capillary walls) which enter tissues as free fatty acids and are re-esterified for storage. glycerol backbone goes to liver. the chylomicron remnant binds to the chylomicron remnant receptor on liver and is endocytosed.
145
what is the importance of Apo E?
is the ligand for chylomicron remnant receptors in liver.
146
what is different between the VLDL pathway and the chylomicron pathway?
VLDL is degraded to produce IDL en route to LDL (recall chylomicron is degraded to chylomicron remnant). From VLDL, LDL is recognized by the LDL receptor in liver and other tissues. chylomicron delivers lipids to tissues and is then recognized by the chylomicron remnant receptor on liver.
147
how is a VLDL assembled?
same pathway as chylomicrons
148
what happens to VLDL as it circulates?
It is modified: TAG is degraded by lipoprotein lipase so it gets smaller/denser. Also, TAGs are transferred from VLDL to HDL, and CEs are transferred from HDL to VLDL. Accomplished via CETP (cholester ester transfer protein).
