Lipoproteins Flashcards
1
Q
What are the three pathways of lipoprotein transport?
A
Exogenous
Endogenous
Reverse cholesterol transport
2
Q
What is a lipoprotein?
A
a particle for transporting lipids
3
Q
Where are lipoproteins made?
A
in the liver and intestine
4
Q
What are the types of lipoproteins and where are they made?
A
Chylomicron (intestine)
LDL, IDL (liver)
VLDL, HDL (liver, also little from intestine)
5
Q
What is the composition of a lipoprotein?
A
non-polar lipids within: TGs, cholesteryl ester
polar lipids on the outside: phospholipids, free cholesterol, apoproteins
6
Q
What is does an apoprotein do?
A
plays role in assembly, secretion, metabolism, and clearance, associated with lipoproteins
7
Q
What are the major apoproteins in lipoprotein metabolism?
A
B; A-I; A-IV; C-II; E
8
Q
What does ApoB do?
A
48 and 100 are packaged with chylomicrons and VLDLs respectively
9
Q
What’s the difference between ApoB-48 and ApoB-100?
A
48 is shorter because it lacks the LDL binding sequence; associated with chylomicrons and intestinal cells; 100 associated with VLDL and hepatocytes
10
Q
What are the 2 main roles of ApoA-I?
A
HDL apoprotein component, and cofactor for LCAT
11
Q
What is LCAT?
A
Lecithin:cholesterol transferase; functions to pick up and esterify free cholesterol for internalization to the lipoprotein core
12
Q
What is ApoA-IV?
A
produced in intestine and bound to chylomicrons; functions to activate LCAT and a bunch of other things as well; also the only apoprotein that also exists as free protein in blood plasma
13
Q
What is the main role of ApoC-II?
A
to bind and activate LPL for uptake of TGs; located in chylomicrons, VLDL, and HDL
14
Q
What does ApoE do?
A
it’s the ligand in remnant chylomicrons for hepatic LDL receptors, along with ApoB-100
15
Q
What is the name of the enzyme complex that edits ApoB mRNA?
A
ApoB EC 1
16
Q
What kind of post-transcriptional modifications does the ApoB mRNA undergo?
A
to make ApoB-100: nothing
to make ApoB-48: one base is changed to make an earlier stop codon
17
Q
What does LPL do and where is it located?
A
it hydrolyzes the TGs within lipoproteins that have ApoC-II; located in capillary endothelial cells
18
Q
What does HL do and where is it located?
A
hepatic lipase will play a role in remnant lipoprotein uptake to the liver, independent of LDL receptors, as it’s located on proteoglycans on hepatocytes
19
Q
What does LCAT do and where is it located?
A
it esterifies free cholesterol for internalization to HDL in the reverse cholesterol transport path; located in HDL
20
Q
What does ETP do and where is it located?
A
ester transfer proteins catalyze exchange of lipids between LDL and HDL; located there
21
Q
What does the ABC class of proteins do and where are they located?
A
they mediate the lipid efflux from peripheral cells to HDL for return to liver, as well as help form nascent HDLs
22
Q
What’s the difference between ABC proteins A1 and G1?
A
A1 works with more nascent HDLs and G1 works with more mature HDLs
23
Q
What does HMG-CoA reductase do, and where is it located?
A
it’s the rate-limiting enzyme in cholesterol synthesis
24
Q
What does ACAT do, and where is it located?
A
catalyzes the conversion of free cholesterol to cholesterylester within cells for storage
25
What is the function of the LDL receptor and where is it located?
binds ApoB-100 and ApoE (less affinity) for hepatic uptake of LDLs and remnant lipoproteins; located in liver cells
26
What does a defect in the LDL receptor cause?
familial hypercholesterolemia, HLD; atherogenic
27
What is LRP?
LDL Receptor Related Protein: functions in hepatic uptake of remnant lipoproteins
28
What is SR-B1?
scavenger receptor B1; mediates hepatic uptake of cholesteryl ester from HDLs
29
What is the final step in the HDL/reverse cholesterol transport pathway?
uptake of HDL into the liver, as mediated by SR-B1
30
What are the overall steps of lipoprotein trafficking, starting from the liver?
VLDL secreted; gives away TGs to peripheral tissue; remnant becomes IDL then LDL; LDL remnant reuptaken by the liver's LDL receptors
31
What are the overall steps of lipoprotein trafficking, starting from the intestine?
chylomicron secreted; gives away TGs to peripheral tissue; remnant reuptaken by the liver by
32
What are the overall steps of the reverse cholesterol transport system?
HDL secreted from the liver or gut with no contents; picks up free cholesterol from peripheral tissues; esterifies/internalizes it with LCAT; SR-B1 transports it into the liver
33
How does a cholesterol get from intestine to liver?
HDL or chylomicron
34
How does a cholesterol get from liver to peripheral tissue?
VLDL
35
How does a cholesterol get from adipocyte to the liver?
HDL
36
What does a defect in the LDL receptor cause?
familial hypercholesterolemia, HLD; atherogenic
37
What is LRP?
LDL Receptor Related Protein: functions in hepatic uptake of remnant lipoproteins
38
What is MTP (microsomal triglyceride transfer protein)?
a heterodimeric protein in the ER membrane that lipidates ApoB (large subunit does) so it can be added to the TG to make the primordial chylomicron; functions to lipidate proteins using lipids from ER memebrane
39
What is the final step in the HDL/reverse cholesterol transport pathway?
uptake of HDL into the liver, as mediated by SR-B1
40
What are the overall steps of lipoprotein trafficking, starting from the liver?
VLDL secreted; gives away TGs to peripheral tissue; remnant becomes IDL then LDL; LDL remnant reuptaken by the liver?
41
When are phospholipids removed from the chylomicron/lipoprotein?
whenever they become excessive after the lipoprotein gives away its content
42
What are the overall steps of the reverse cholesterol transport system?
HDL secreted from the liver or gut with no contents; picks up free cholesterol from peripheral tissues; esterifies/internalizes it with LCAT; SR-B1 transports it into the liver
43
What regulates the amount of ApoB in lipoproteins?
MTP - because if MTP doesn't lipidate it then the ApoB gets degraded
44
How does a cholesterol get from liver to peripheral tissue?
VLDL
45
How does a cholesterol get from adipocyte to the liver?
HDL
46
How are TGs from the diet processed to get to the circulation?
take up into enterocyte as FA and MAG; reassembled into TG in ER, packaged with ApoB-48 and A-IV; buds off and travels to golgi independent of MTs as a primordial chylomicron; in golgi gets more proteins added; buds off and secreted into circulation as chylomicron
47
What proteins are in the ER to reassemble the FA and MAG?
MGAT and DGAT
48
What is MTP?
a protein in the ER membrane that helps add ApoB to the TG to make the primordial chylomicron
49
By what process does a chylomicron pick up Apo E and C-II?
transfer from HDL particles it encounters in circulation
50
When is ApoB-48 removed from the lipoprotein?
never
51
when are phospholipids removed from the chylomicron/lipoprotein?
whenever they become excessive after the lipoprotein gives away its content
52
What subunit of MTP has solubility responsibility?
the protein disulfide isomerase; maintains solubulity of the large subunit
53
What regulates the amount of ApoB in lipoproteins?
MTP - because if MTP doesn't lipidate it then the ApoB gets degraded
54
What does CETP do and where is it located?
it catalyzes the exchange of TGs and cholesteryl ester from VLDL to HDL; located in plasma
55
How does cholesterol get into the plasma circulation?
effluxed from cells via ABC protein transporters
56
How do LDL remnants, TGs, and cholesterol get into the liver?
via LDL receptors, hepatic TG lipase, and SR-B1 (for HDL path) respectively
57
What does SREBP do and where is it located?
sterol response element-binding protein senses and regulates the amount of cholesterol in a cell by activating SCAP, which (when active) is a TF for LDL receptor gene; located in ER membrane
58
How do statins work?
they are HMG CoA Reductase inhibitors which inhibits cholesterol synthesis, and SCAP activators, which upregulates LDL receptors
59
Why does high LDL lead to atherosclerosis?
oxidized LDL damages the endothelium of vessels which allows macrophages to get up under the epithelial cells and cause plaques
60
How can LDL be indirectly measured?
total cholesterol minus HDL minus TG/5
61
What is monogenic vs. polygenic?
mongenic means a disorder has one genetic basis, whereas polygenic is lots of genetic factors
62
What defect causes familial hypercholesterolemia, and what is the phenotype?
defect in the LDL receptor; see HCL or mixed HLD
63
What forms the fibrous cap of a plaque?
macrophages, T cells, smooth-muscle cells, and matrix (collagen)
64
What defect causes familial dysbetalipoproteinemia, and what is the phenotype?
homozygous E2/E2 isoform has defective binding of remnants to the LDL receptor; see mixed HLD; most rare
65
For atherosclerosis, are risk factors independent or cumulative, and what are some example risk factors?
cumulative: they include age, gender, smoking, obesity, diabetes, high LDL (from diet), etc.
66
How are plaques formed?
damaged endothelium=adhesions, attract monocytes; monocytes engulf LDL-->macrophages; secrete substance to inflame and build up plaque
67
What is the major damager of endothelium?
LDL, especially oxidized LDL
68
What are the different names for the monocytes?
monocyte, macrophage, foam cell
69
What do macrophages secrete and what is their role in plaque formation?
cytokines, cause inflammation and smooth muscle release of collagen
70
How do macrophages uptake LDL and how is this regulated?
via the scavenger receptor; it's not regulated
71
What is the substance forming a plaque?
fibrous cap outside; lipid pool inside; macrophages if cracked
72
What is in the lipid pool of a plaque?
foam cells, cholesterol esters, necrotic cells, and cholesterol crystals
73
What forms the fibrous cap of a plaque?
macrophages, T cells, smooth-muscle cells, and matrix (collagen)
74
What happens when a plaque cracks?
more macrophages come to repair it and secrete metalloproteinases which cause platelet aggregation; leading to thrombus which could form an embolus and cause MI
75
How does aspirin help with atherosclerosis?
Reduces platelet aggregation so if plaque forms it's less likely to thrombose
76
Why are statins so useful?
they activate SCAP which up regulates LDL receptors; they also have vasodilatory and anti-inflammatory effects
77
Name three main functions of cholesterol.
1. component of membranes
2. precursor to bile acids
3. precursor to steroids
4. precursor to Vitamin D
78
What are the main sources of cholesterol to the body?
gallbladder (produced in liver); turnover of gut epithelial cells; diet (smallest contributor)
79
How is cholesterol absorbed?
From the diet: bile micellates; absorbed via NPC1L1 transporter to enterocyte
80
What is ABCG 5/8 and what does it do?
it's a cholesterol transporter involved in the efflux of cholesterol from the enterocyte
81
What is the fate of plant sterols in the diet and why?
they are excluded from enterocytes, pass because??
82
What is the fate of cholesterol that is returned to the gut or not absorbed?
packaged into chylomicrons
83
What does the drug ezetimibe do?
inhibits the NPC1L1 transporter, which takes up cholesterol in the first place
84
What is the cholesterol uptake pathway and how it it regulated?
NPC1L1 transporter will take in cholesterol; ABCG5/8 will spit it back out;if not spit back out it is packaged into chylomicrons and secreted
85
Where is the ABCG transporter located and how does it function?
microvillus membrane of the enterocyte; functions as heterodimer
86
What is the effect of increasing plant sterols in the diet?
they will out-compete the cholesterol for a place in the micelle and taken up first, displacing the cholesterol
87
Describe the cholesterol biosynthesis pathway.
start with acetyl-CoA (source of 27 Cs); RLS = HMG CoA reductase; major intermediates are acetoacetyl-CoA, HMG CoA, and squalene
88
Describe the action of HMG CoA reductase.
reduces acetoacetyl-CoA to HMG CoA, transfers electrons to NADPH (reaction requires 16mol NADPH)
89
What is the committed step in cholesterol biosynthesis?
the reduction of acetoacetyl-CoA to HMG CoA, catalyzed by HMG CoA reductase
90
What is the product of cholesterol biosynthesis?
mevalonate
91
What regulates HMG CoA reductase?
HMG CoA; free cholesterol; insulin/glucagon; TH/cortisol; SREBP; statins
92
How does a cell know when cholesterol levels are low?
SCAP senses it and will send SREBP to be activated to ultimately upregulate the LDL receptors
93
What is the hepatic effect of high levels of bile?
inhibition of cholesterol biosynthesis
94
What's an LXR?
liver x receptor; they are nuclear receptors activated by oxysterols, heterodimerize with RXR, and increase transcription of many genes; can also autoregulate
95
What happens when an LXR is inhibited or knocked out?
so many things, both desired (like lowering cholesterol synthesis) and undesired (like harmful things)
96
What is Smith-Lemli-Opitz syndrome?
delta-7 enzyme deficiency; causes high levels of toxic cholesterol intermediates, and low levels of cholesterol that also present as structural defects
97
How to treat SMith-Lemli-Opitz syndrome?
high cholesterol diet helps some, and statins to inhibit intracellular synthesis, but neither cross BBB
98
How are bile acids made?
synthesized from cholesterol in the liver and transported to the gallbladder for storage
99
Where are bile acids secreted to?
the duodenum
100
Where are bile acids absorbed from?
the ileum (distal intestine)
101
What regulated bile acid synthesis?
FXR - farnesoid X receptor; this downregulates transcription of CYP 7A1 which is the RLS in bile acid synthesis
102
How do bile acids get back to the liver?
absorbed via active transport in the ileum and travel via portal venous system
103
What is the precursor of steroids?
cholesterol
104
Where are glucocorticoids made?
adrenal cortex
105
What regulates the release of glucocorticoids?
ACTH
106
What are the effects of glucocorticoids?
gluconeogenesis to store glycogen; protein catabolism; anti-inflammatory; inhibit leukocyte migration; promote sodium retention
107
What are glucocorticoids used for therapeutically, and what is a potential side effect?
given for arthritis and possibly cause hyperglycemia
108
Where is testosterone made?
Leydig cells of testes
109
What regulates sex hormone production?
testosterone: pituitary release of LH
estrogen: FSH
110
Where is estrogen made?
ovarian granulosa cells
111
What does testosterone and estrogen each induce?
testosterone--differentiation of spermatogonia
| estrogen--femininization
112
What are mineralcorticoids?
made in adrenal cortex, regulate urinary secretions and absorptions; ex: aldosterone which acts in kidney to retain water
113
What are the steps leading up to aldosterone secretion?
drop in BP causes renin release from justoaglomerular apparatus; renin activates angiotensin I to II; which tells adrenal cortex to release aldosterone
114
What is congenital adrenal hyperplasia?
defect in steroidigenic enzymes so cortisol/aldosterone aren't produced; increased ACTH causes lots of 17-hydroxyprogesterone, converted to testosterone, masculinization of female infants
115
Where does vitamin D come from?
synthesized in skin with sunlight; diet; made from cholesterol
116
What are the major metabolic steps in vitamin D synthesis?
1. hydroxylation
| 2. conversion to 1,25-dihydroxycholecalciferol
117
What are the steps of hydroxylation of vitamin D?
becomes C-25 in liver, then C-1 in kidney; end up as 1,25-dihydroxycholecalciferol
118
How does the active form of vitamin D work?
nuclear vit D receptor (VDR); activates genes such as calbindin which helps with intestinal absorption of calcium
119
What does calbindin do and why is it significant?
it helps with intestinal absorption of calcium and recruits stem cells from bone to provide Ca/Phos balance for mineralization
120
How is vitamin D synthesis regulated?
regulated tightly in the kidney--induced by PTH; regulated loosely in the liver; inhibited by fibroblast growth factor 23 from osteocytes
121
What does PTH depend on?
secreted at low serum calcium levels, some serum phosphorous levels
122
What are some causes of vitamin D deficiency?
lack of sunlight or liver/kidney disease (can't activate it so it might as well not be there)
123
How does liver disease cause vitamin D deficiency?
liver can't make adequate amount of bile, so fat-soluble vitamins (d included) can't be absorbed
124
What are some clinical signs of vitamin D deficiency?
weak bones, swollen extremity joints, rachitic rosary ribs
125
What is ezetimibe and how does it function?
it inhibits NPC1L1, which would uptake dietary cholesterol
126
How does fat and cholesterol get out of the enterocyte?
chylomicrons
127
Atypical retinitis pigmentosa and neurologic degeneration, related to defective MTP, is secondary to...
vitamin E deficiency, because it's a fat soluble vitamin and the fat can't leave the enterocyte when the MTP doesn't work to make the chylomicrons
128
How does obesity/insulin resistance relate to high LDL?
insulin resistance causes adipocytes to release FFAs which go to liver put into VLDL, exchanged with HDL, HL acts and causes ApoB1 to dissociate and get cleared, so less HDL
129
Where do small dense LDL particles come from?
in NAFLD the CETP is very active, VLDL-->LDL, then as it gives off its TGs it becomes a SD LDL
130
What is CRP?
an acute phase reactant induced in liver by IL-1 and IL-6; index of inflammation and predictor for heart attack/stroke; lowered by statins
