Lipoproteins, eicosanoids, xenobiotics Flashcards
1
Q
What are lipoproteins?
A
Non-covalent complexes of lipid and protein to carry lipid through the bloodstream.
2
Q
What is the structure of lipoproteins?
A
Sphere with proteins, cholesterol, phospholipids on the surface. Non-polar lipids on the inside. Increase in density is mostly due to the composition of protein.
3
Q
What emulsifies dietary fats?
A
Bile salts
4
Q
What do intestinal enzymes break down?
A
Dietary triglycerides, cholesterol esters, phospholipids
5
Q
What are the four intestinal enzymes?
A
Pancreatic lipase, colipase, cholesterol esterase, phospholipase
6
Q
What does pancreatic lipase do?
A
Cleaves ester bonds in dietary triglycerides
7
Q
What does colipase do?
A
Helps pancreatic lipase attach to micelles
8
Q
What does cholesterol esterase do?
A
Hydrolyzes cholesterol esters
9
Q
What does phospholipase do?
A
Breaks down phospholipids
10
Q
What are transferred across the intestinal mucosa?
A
Cholesterol and fatty acids
11
Q
What happens after cholesterol and fatty acids go across the intestinal mucosa?
A
Triglycerides are reformed and cholesterol is esterified with fatty acids. Chlomicrons are then formed in the ER of the small intestine where we absorb fat.
12
Q
What does APOB48 bring into the small intestine?
A
Microsomal Triglyceride Transfer Protein which brings in triglycerides, fatty acids, and cholesterol
13
Q
Where do chylomicrons go?
A
Lymphatic circulation and then to bloodstream
14
Q
What activates capillary lipoprotein lipase?
A
Apoprotein C-II in chylomicrons
15
Q
What does lipoprotein lipase on chylomicron triglycerides release?
A
Fatty acids. Free fatty acids then enter cells throughout the body via capillary beds.
16
Q
What organ degrades chylomicron remnants?
A
Liver
17
Q
What are the four lipoproteins?
A
Chylomicrons, VLDL, LDL, HDL
18
Q
Where are chylomicrons synthesized?
A
In the intestinal epithelium after a meal. Not present in normal fasting plasma.
19
Q
What is the main role of chylomicrons?
A
It is the principal carrier of dietary lipids and fat-soluble vitamins to tissues
20
Q
What apoproteins are in chylomicrons?
A
B-48, C-II, A-I, E
21
Q
Where are VLDLs made?
A
In the liver
22
Q
What is the main role of VLDL?
A
Main carrier of endogenous triglycerides to tissues
23
Q
What apoproteins are in VLDL?
A
B-100, C-II, E
24
Q
Where are LDLs made?
A
In circulation from VLDL
25
What is the main role of LDL?
Main transporter of cholesterol to tissues
26
What apoproteins are in LDL?
B-100
27
What is the main role of HDL?
Takes cholesterol from tissues to liver. It also distributes cholesterol to LDL, IDL, VLDL
28
What apoproteins are in HDL?
A-I, A-II
29
What does A-I do?
Activates LCAT and binds HDL receptor (Also in chylomicrons).
30
What does B-48 do?
Forms chylomicrons
31
What does B-100 do?
Binds LDL receptor (in VLDL and LDL)
32
What does C-II do?
Activates lipoprotein lipase (in chylomicrons and VLDL)
33
What does apoprotein E do?
Recognizes LDL receptor
34
What does cholesterol ester transfer protein (CETP) do?
Reverse cholesterol transport
35
What does lipoprotein lipase do?
Delipidates VLDL and chylomicrons at the capillary surface
36
Outline the exogenous lipid cycle of lipoprotein metabolism
Dietary lipid goes into intestines, Apo48 Chylomicrons are made and its remnants goes to to the liver while its triglycerides go to other tissues. The liver transports free cholesterol and bile salts back to the intestines.
37
Outline the endogenous lipid cycle
VLDL is made in the liver. VLDL makes IDL and TG. IDL makes LDL. TG and LDL go to other tissues. Cholesterol from other tissues gets extracted by HDL and brought to the liver or back to the lipoproteins.
38
What is an LDL receptor and where is it found?
A glycoprotein found on the surface of all cells
39
What do LDL receptors bind to?
Lipoproteins containing ApoB and ApoE and breaks them down inside its cell
40
What determines LDL receptor numbers?
Cholesterol; receptors increase with insufficient cholesterol, decrease with sufficient cholesterol
41
What happens when there's a defective Apoprotein B?
Elevated serum cholesterol
42
What are essential fatty acids? What are they precursors to?
PUFAs called omega-6 linoleic acid (18:2) and omega-3 alpha-linolenic acid (18:3); eicosanoids
43
What are eicosanoids and what do they do?
20-C fatty acid derivatives and have physiological effects over body functions that can be manipulated depending on the fatty acid composition of the diet. They act as local signaling molecules made by many cell types.
44
What's a healthy ratio of linoleic to alpha-linolenic acid?
4:1 or less
45
What cell types make the 4 different eicosanoids?
Many tissues - Prostaglandins (PG)
Macrophage, neutrophils, monocytes - leukotrienes (LT)
Endothelium - prostacyclins
Platelets - thromboxanes (TX)
46
What do prostaglandins do?
Contracts smooth muscle, lowers blood pressure, regulation of gastric secretions, body temp, platelet aggregation, controls inflammation, vascular permeability
47
What do leukotrienes do?
Chemotaxis (help RBCs move), cell-to-cell adhesions
48
What does prostacyclin do to counteract thromboxanes?
Anti-aggregation of cells, vasodilation, lowers blood pressure
49
What do thromboxanes do?
Aggregation of cells, vasoconstriction, increases blood pressure
50
What is the parent structure of prostaglandins?
Prostanoic acid
51
At what carbon are the double bonds that prostaglandin can have?
5,6 (cis) and 13, 14 (trans) and 17, 18 (cis); PGA1 indicates one double bond.
52
What is the parent structure of leukotrienes?
Hydroperoxyeicosatetraenoic acid (HPETEs)
53
What amino acid complex does LTC4 have?
Glutathione (glu-cys-gly)
54
What are the most highly characterized eicosanoids (PGs, TXs, LTs) derived from?
Arachidonic acid, an omega-6 fatty acid
55
How is arachidonic acid metabolized?
An AA inserted into the C-2 of membrane phospholipid is released via 2 systems: phospholipase A2 and calcium converting phosphatidylcholine to arachidonic acid in the cytosol is the major one; phospholipase C converting phosphatidylinositol bisphosphate to arachidonic acid is the minor one.
56
What enzymes are involved in synthesis of PGs, TXs, LTs from arachidonic acid?
Cyclooxygenases (COX) - initiates conversion to PGs, TXs
Lipoxygenase (LOX) - conversion to HPETEs to make LTs or lipoxins (LX); AKA cyclooxygenase system, "cyclic pathway", "linear pathway"
57
How are eicosanoids inactivated?
When hydroxyl at C15 is oxidized to a ketone
58
How do you modify arachidonic acid release?
By making a protein (lipocortin) that inhibits phospholipase A2 to have an anti-inflammatory response.
NSAIDs - aspirin (irreversible) and ibuprofen (reversible) inhibit cyclooxygenase
59
What three major types of omega-3 fatty acids are in our diet?
Alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)
60
Why is AA inefficiently synthesized from linoleic acid? This is the same reason why ALA converted to EPA and DHA is limited in the body.
C5 and C6 desaturases are slow enzymes
61
Who are the competitors for placement in membrane phospholipids?
ALA and linoleic acid; ALA + Linoleic compete with arachidonic acid
62
What effect does omega-3 PUFAs have on the body?
Anti-inflammatory, anti-fever, and anti-pain (exact opposite of omega-6 PUFAs) by displacing arachidonic acid from cell membranes
63
What fatty acid competes with AA insertion into carbon 2 of an eicosanoid precursor?
DGLA and GLA
64
What mechanism makes specialized lipid pro-resolving mediators for inflammation?
Transcellular interactions between cells that involve transfer of biosynthetic intermediates
65
What are some actions of specialized pro-resolving lipid mediators?
Blocks prostaglandins, leukotrienes, cytokines, and PMNs and eosinophils. Recruits nonphlogistic monocytes and stimulates microbial defenses.
66
What are the main routes of xenobiotic elimination?
Bile salt secretion and renal excretion
67
What are the two major enzymes that phase II metabolism of xenobiotics uses?
GST for glutathionation and UGT for N- or O-glucuronidation
68
What are some endogenous sources of reactive oxygen species?
Enzymes (COX, LOX, CYP450, Xanthine oxidase), phagocytic respiratory burst, ETC
69
What are some exogenous sources of reactive oxygen species?
UV radiation, drugs, air pollutants
70
What two things can happen in free radical damage to PUFA?
1. Decomposition to bifunctional aldehydes and/or alpha, beta-unsaturated aldehydes which can form adducts or crosslink other biomolecules.
2. Reaction with sulfhydryl groups on enzymes.
71
What is the first line of defense against ROS? What tissue location is this in?
Antioxidant enzymes in liver, kidney, adrenals: glutathione peroxidase, superoxide dismutase (SOD), catalase
72
What is the second line of defense against ROS?
Exogenous vitamins E + beta-carotene +vitamin C
| Other free radical scavengers like uric acid
73
What is in the cytosol SOD? Mitochondria SOD?
Cytosol - Cu2+--Zn2+
| Mitochondria - Mn2+
74
Where is glutathione peroxidase found in the cell?
Cytosol and mitochondria
75
Where is catalase found in the cell?
Peroxisomes
76
Where can you find vitamin E in the cell?
Cell membrane, lysosomes, SER, and nucleus
77
Where can you find vitamin C in the cell?
Lysosomes and cytoplasm
78
Where can you find beta-carotene in the cell?
Lysosomes, membrane, SER
79
Where can you find glutathione peroxidase in the cell?
Cytoplasm, mitochondria
80
Where can you find SOD in the cell?
Mitochondria, cytoplasm
81
Where and how is vitamin C absorbed?
In the distal small intestine via sodium dependent ascorbate transporter (SVCT1). Other cells use SVCT2 or GLUT1/3.
82
What does vitamin C do for us?
Ascorbate is a primary antioxidant that neutralizes radical O and N, peroxides, superoxides. Ascorbic acid loses electron to have ascorbate radical which is very stable (semidehydroascorbate).
83
How is regeneration of the reduced form of Vitamin C done?
Uses reducing agents (NADH or GSH) and one of the enzymes, dehydroascorbate reductase, thioredoxin reductase, or NADH reductase)
84
What can dehydroascorbate be converted to if it is not reduced in time?
Diketogulonic acid or oxalic acid (poorly water-soluble so it forms crystals in kidneys)
85
What does vitamin E consist of (2 things)? Where does it accumulate in the cell and what type of cell?
Tocopherols and tocotrienols; membranes and lipoproteins
86
What tissues are alpha-tocopherol most abundant? Where is it selectively extracted?
Skin and muscle; in the liver
87
What does vitamin E do?
Terminates membrane lipid oxidation through single electron transfers, forming a stable tocopherol species
88
What does the redox cycle use to regenerate reduced vitamin E?
Reduced vitamin C, when vitamin E gets exposed to vitamin C on membrane surface
89
What does the thiol cycle do?
Resets radical scavengers to their reduced forms
90
What is uric acid made from in the body?
Purine metabolism
91
What does urate do?
Scavenges single oxygen, OH radicals, peroxyl radicals, and traps them in the plasma; it binds transition metals that may initiate LDL oxidation
92
Urate is reduced by...
Vitamin C. But it cannot reduce alpha-tocopherol like vitamin C
93
What are the exogenous antioxidants?
Vitamin C + E, phytochemicals
94
What are the endogenous antioxidants?
Uric acid, coenzyme Q
95
What are the pro-oxidants?
NO, reactive N-O species (RNOS), UV rays, pollutants
96
Where are CoQ enzymes in the cell?
Inner mitochondrial membrane, ER, golgi, peroxisomes
97
Which cell membranes are CoQ in?
ALL cells
98
What does CoQ do?
1. Electron carrier in respiratory chain
2. An effective lipid-soluble antioxidant, prevents oxidation of lipids, proteins, and DNA
3. Protects LDL from oxidation
4. Can regenerate reduced vitamin E
5. Anti-inflammatory effects by influencing gene expression
6. Stimulates release of NO
7. CoQ in tissue may increase with oxidative stress conditions
99
Where are phytochemicals come from?
Plants
100
What are the four types of phytochemicals?
Terpenoids, shikimates, polyketides, alkaloids
101
What are the derivatives of shikimates phytochemical?
Flavanoids, stilbenes (resveratrol), and coumarins (Warfarin)
102
What gives a compound a greater anti-oxidant capacity?
Increased number of hydroxyl groups
103
What is an example of a a phytochemical phenolic acid analog?
Curcumin; gives the yellow collor in turmeric
104
What does curcumin do to be anti-inflammatory?
Inhibits phospholipase A2, COX2, 5-LOX; increases GSH levels to increase activity of phase II enzyme
105
What is an example of a phytochemical polyphenol flavonoid category? What is an example of a flavone?
Flavones is one variation with 3 rings which it can occur free or conjugated to a sugar to be water-soluble; Quercetin is a flavone mostly found as a glycoside
106
What foods are quercetin found in?
Brassica vegetables, red onions, apples, berries, capers
107
What can quercetin do as an antioxidant?
Donate electrons to ROS and chelate ROS-producing metal ions; induces cancer cell apoptosis; conjugates have lower activity than parent compound
108
What happens when antioxidants like vitamin E, C, CoQ and quercetin are at high doses in the body?
They become cytotoxic, increasing oxidative stress. Become pro-oxidant ROS.
109
How do RBCs maintain their membranes?
NADPH and ATP from glycolysis
110
What does NADPH do to glutathione?
Reduces it to GSH form and therefore removes ROS by converting H2O2 to H20.
111
What is the purpose of ROS as a normal process in the body?
Create cross-linked hemoglobins (Heinz bodies)
112
What are the three nitric oxide synthase isoforms?
eNOS (endothelial), nNOS (neural), iNOS (inducible)
113
What residue does nitric oxide synthase target?
Aromatic residues of thiols (RSH)
114
NO diffuses through...
Membranes
115
What does iNOS do?
Produces toxic levels of NO
116
What is the amino acid pool?
Abstract way of saying the availability, distribution, and uses of AAs
117
Intracellular AA concentrations are higher than extracellular. T or F?
True
118
What 4 things can AAs from the diet be used for in the cell?
Proteins, N-containing compounds, Nitrogen (Urea to urine), Carbon (CO2 and water)
119
What two things are secreted in the stomach?
HCl from parietal cells; pepsinogen from chief cells (autocatalytic)
120
What pancreatic enzymes are there?
Enteropeptidase (in brush border, initiates cascade) activates
trypsinogen,
which is converted to trypsin,
which activates other peptidases,
which include endopeptidase in the intestines such as chymotrypsin, elastase, carboxypeptidases
121
What enzymes are in the intestines?
Aminopeptidases, dipeptidases in brush border and intracellular peptidases for small absorbed peptides
122
How do AAs get into brush border cells?
Na+-AA cotransporter when Na+ is low inside brush border cells. Low intracellular Na+ is maintained by Na+/K+ active transporter. AA use facilitated transporter to export themselves.
123
What are two AA absorption disorders in the intestines and kidneys?
Cystinuria (renal) and Hartnup's (intestinal) disease
124
What hormones influence protein degradation and which way?
Insulin decreases degradation, increases protein synthesis
| Glucocorticoids and thyroid hormones increase degradation
125
What are determinants of protein turnover rate?
Proteases - uses ATP to break down protein by lysosomes, apoptosis, metalloproteinases in ECM, serine proteases for digesting and blood clotting, breaks down ubiquitin-tagged proteins
Oxidation of AA by free radicals
Denaturation leading to lysosomal destruction
N-terminal residues and PEST sequences turns protein over quicker
Ubiquitination - labels cytosolic protein for destruction
126
Which end of the protein determines it's half-life?
N-terminal; N-end rule
127
What's the metabolic flow of AA nitrogen?
transamination, deamination, urea formation
128
What is transamination? What enzymes and cofactors are involved?
Transfer of amino group from amino acid to an alph-keto acid; aminotransferases (ALT + AST); Pyridoxal phosphate (B6)
129
What enzymes, cofactors, and allosteric regulators are involved in oxidative deamination of amino acids?
Glutamate dehydrogenase takes glutamate to alpha-ketoglutarate; NAD+ or NADP+; ADP (+) and GTP (-)
130
What animal secretes ammonia directly?
Fish
131
What animal secretes urea directly?
Humans
132
What animal secretes uric acid directly?
Birds
133
Which organ releases amino acids during fasting? Which amino acids are the main nitrogen carriers? What type of AA is a key energy source for skeletal muscle during fasting?
Skeletal muscle; Alanine + Glutamine; Branched-chain AA like Leucine, Isoleucine, Valine
134
What amino acid is the primary fuel for kidneys in normal and fasting conditions? What molecules are used by the renal medulla and cortex respectively?
Glutamine: it is a source of ammonia to buffer acid H+; glucose is used in renal medulla, lactate used by cortex
135
What amino acid is the primary fuel source for the gut?
Glutamine; nitrogens from gut are transferred to liver for detox
136
What can the gut oxidize besides glutamine? Does the gut use fats and glucose for their primary energy?
Aspartate and BCAA; no, fats and glucose transferred to liver
137
What kind of fatty-acids can colon cells use?
Short-chain FAs produced by bacteria in the gut
138
Which eicosanoids are "cyclic" and which are "linear"?
PGs and TXs are cyclic (5/6-ringed); LTs are linear with open chain + 3-5 dbs
