Week 5 Flashcards
1
Q
Lipoproteins
- Definition
- Where do lipids come from? Where do they originate?
- function
- synthesized
A
- large macromolecule complexes of protein and lipids that help in transport of lipids
- Can be dietary or synthesized
- can carry dietary lipids from intestine via blood to different target organs for different functions (use or storage)
- Synthesized (endogenous): made in liver, converts excess carbohydrates carbons to fatty acid (FA) and cholesterol will change the FA to triglycerides and transpose them to the lipoprotein so that they can be taken to different tissues for utilization and storage
2
Q
different kinds of lipoproteins?
A
- chylomicron
- VLDL
- LDL
- HDL
3
Q
Chylomicron
- size/density…why?
- What do they do?
- Identifying apoproteins
- Where are they from?
- maturation
- trading with HDL
- what do they turn into?
A
- lowest density and highest particle size; have higher tri-glyceride content and low protien contest
- Carry dietary lipids absorbed in intestine to different parts of the body abundant in them to different tissues (muscles and adipose, etc.) for usage/storage.
- ApoB48, C2, E
- intestines the chylomicron will first be released into lymphatics and get put into systemic circulation as they mature
- While traveling they gain other apo-lipo proteins ( C2 and E from HDL) in the blood making them mature chylomicrons
- After they have distributed tri-acyl glycerols they become remnant chylomicrons which then goes back to the liver and uses apoE for cytoplasmic uptake into hepatocyte and whatever cholesterol it has left will be reused or dumped in bile.
4
Q
VLDL
- size/density
- apoproteins
- what does it carry?
- where is it produced? carries?
- fate?
- IDL
A
- slightly more dense than chylomicron and is slightly smaller in particle size than chylomicron
- ApoE, ApoB100, and Apo C2
- cholesterol and triglycerides but different from chylomicrons because they are endogenous meaning that the liver makes them–also carries cholesterol esters
- in the liver and carries endogenous fats like tri-glyceride, cholesterol, and cholesterol esters that are synthesized from carbohydrate carbons
- Once they drop off some of the cholesterol and majority of tri-glyceride to the tissue for usage and storage it becomes more dense making it IDL (15% protein, 85% lipid)
- Distributes the remnant triglycerides to other tissues making it an LDL
5
Q
LDL
- what does it have?
- What are cholesterol esters?
- made from?
- apoproteins
- how does it function
A
- High in cholesterol and cholesterol esters, low in triglycerides
- Cholesterol esterified to FA molecules; it is preferred transport form of cholesterol
- IDL which is made from VLDL
- gives up APOC2 and APO E–which are recylced; remains with ApoB100 ONLY
- usually does not go back to liver and is mostly absorbed by receptor mediated mechanisms in different cells who need cholesterol. Since it does not usually go back to liver and it can be taken up by other cells using LDLR
6
Q
HDL
- density and size
- What do they do? Why is it good?
- name of process
A
□ Highest density because it has high amount of protein and smaller size
- It distributes lots of apo-proteins and helps with maturation of other lipoprotein, but also takes excess cholesterol (from peripheral cells, foam cells for example) and triglycerides (from chylomicron) back to liver for usage/elimination
- reverse transport of cholesterol
7
Q
What happens with high fat diet?
A
- chylomicron levels will rise because the fat you’re getting is coming from diet; eventually some cholesterol and triacylglycerols will come back via the chylomicron remnants and may be packaged into VLDL, so VLDL and and LDL might rise later on
8
Q
similarity between Apo B 48 and 100
A
- ApoB 48 is made in enterocytes, is truncated version of the entire peptide (only 48% of normal peptide), because when it gets transcribed it goes through RNA editing so a stop codon is introduced abruptly, making shorter version of protein
- ApoB 100 is made from same gene and made in hepatocyte; will be full version of the gene (w/o any RNA editing)
9
Q
If a cell can make cholesterol when would it want to get cholesterol from LDL?
A
- When there is low intra-cellular levels of cholesterol– for example, if you are on a statin which inhibits biosynthesis of cholesterol then the cell will begin to have intercellular crisis for cholesterol and that acts as stimulus for increased production of LDLR which will go to the surface and bind LDL
10
Q
What does LDLR recognize on LDL in order to have it bind?
A
It will recognize the ApoB100, which also helps the LDL fit into the LDLR
11
Q
familial hypercholesterolemia
- locus heterogeneity
- cause and explanation
A
- so two mutations on very different genes having similar effects.
- defective receptor: receptor is unable to make it into membrane or is ineffective at binding LDL so LDL will accumulate in blood because it cannot be taken into the cell leading to a high cholesterol level
- Other mutation is on the ApoB100 portion on the LDL, so even though the receptor works just fine LDL is unable to bind because it cannot be recognized/ is having a hard time fitting into the receptor– this means that LDL cannot be taken in, which causes build up of LDL which leads to hypercholesterolemia
12
Q
Link high levels of LDL to CV diseases
A
- high amount of LDL in the blood there is high chances of LDL being trapped to vessel wall and when they get trapped they are exposed to reactive oxygen which will then modify apoB proteins on the surface and the lipids so this oxidized LDL looks very foreign (does not look endogenous) which will induce immune reaction which will cause monocytes to be attracted to the area, they will differentiate into macrophages. The macrophages will then bind to the foreign looking oxidized LDL and when it phagocytoses it the macrophage is turned into a lipid loaded foam cell. When foam cells accumulate they will become calcified which will induce inflammation which can damage surrounding cells in the vessel and the accumulation of calcified foam cells are the entero-sclerotic plaques which will reduce the circumference of the artery/blood vessel which makes patient prone to cardiovascular disease such as an MI (myocardial infarction)
13
Q
Reverse transport of cholesterol
- LCAT
A
- HDL will distribute its apoproteins and collect cholesterol from peripheral cells (such as foam cells or VLDL) and then comes back to liver and dumps the cholesterol and forms cholesterol ester for usage or elimination
- Lecithin–cholesterol acyltransferase: helps esterify the cholesterol picked up by the HDL by binding it to a fatty acid and then packing it to the center; Once this happens the HDL is considered mature
14
Q
Fat Storage
- when?
- high hormone
- effect of insulin
- coenzyme
- what happens?
A
- Fed state
- Insulin will have role to play in the storage of the fat in order to bring everything back to homeostasis
- activates lipoprotein lipase through dephosphorylation which is in the membrane of different cells (adipose tissue or muscle cells) and this facilitates storage of dietary fats
- apoc2 will further activate lipoprotein lipase and it will begin to break TG into glycerol and Fatty acids.
- Glycerol goes into liver and goes into glycolysis while fatty acids gets into the peripheral cell where it would be stored or used
15
Q
Fat mobilization
- when?
- hormone?
- how do they work?
A
- Fasted state
- Glucagon; Epinephrine and cortisol may also be high during this time
- Glucagon and epinephrine will bind to g protein coupled receptors which increases adenyl cyclase which causes increase in cAMP (secondary messenger) will phosphorylate and activate PKA, PKA will phosphorylate and activate hormone sensitive lipase (the most important hormone present in the adipocytes for lipolysis), hormone sensitive lipase will then break down the tri-glyceride into fatty acids and glycerol and then release them out into the blood to be dispersed to tissues
16
Q
Palmitic acid
- what is it?
- Why is it special?
- where does it get its carbons?
A
- 16 carbon fatty acid chain
- Primary fatty acid that is made in liver– liver will first synthesize Palmitic acid and if it needs a different kind of acid (steric acid or malic acid) it will modify palmitic acid
- producing 14 carbons from malonyl CoA and adding one acetyl coA making it a 16 carbon chain; Each reaction with malonyl CoA adds 2 carbons–so 7*2=14
17
Q
How can we link Palmitic acid, cholesterol, and acetyl CoA
A
- Need acetyl CoA to make cholesterol and fatty acid
- When FA breaks down it breaks into acetyl CoA
18
Q
Where does Acetyl CoA come from suring fatty acid synthesis?
A
- From glucose carbons or from ketogenic AA (lysine and leucine)
- Their carbon structure will break down directly into acetyl CoA
19
Q
Fatty Acid synthesis first step
- rate limiting enzyme
- co-enzyme
- regulation in fed state vs fasting state
- allosteric activator
- citrate shuttle
- negative allosteric
A
- Acetyl CoA carboxylase carboxylates acetyl CoA to malonyl CoA by adding a carboxyl group
- All carboxylation are done by by Vit B
- In fed state it is activated by insulin through dephosphorylation (in adipose and liver)
- In fasting state it will be inactivated by glucagon phosphorylating it
- Allo act.: High amount of citrate in the cell it will upregulate Acetyl CoA carboxylase because high citrate means there is a lot of energy in the cell because you have high amount of glucose carbons causing high amount of acetyl CoA which forms a lot of citrate and if that stays there it will inhibit citrate synthase which will stop TCA
- Citrate shuttle: Since acetyl CoA cannot get out of mitochondria it is converted in TCA to citrate gets out of mito through transporter goes back into oxaloacetate and acetyl CoA and then that acetyl CoA will be turned into Malonyl CoA
- High amount of palmitic acid in liver already will down regulate Acetyl CoA carboxylase
20
Q
Fatty acid synthesis
- where does it happen?
- type of reaction
- what does it require? and what do each of those require?
- enzymes
- number of cycles– palmitic acid
A
- Made by liver and adipose tissue
- multi-reaction step: involves condensation, reduction, dehydration, reduction
- requires several reaction cycles, Each cycle has 4 different types of reactions in it
- Condensation enzyme is a synthase, Reduction enzymes is a reductase, Dehydration enzyme is a dehydrotase, And then one more reductase
- depends on the chain length of the fatty acid; Palmitic acid is 7 cycles
21
Q
Enzyme complex responsible for all the enzymes needed to produce fatty acid?
- number of domains
- what helps it?
A
○ FAS: fatty acid synthase complex
- has 7 domains and each has an active site with its own separate enzyme
- Also uses acyl carrier proteins help to shuttle intermediates from one domain to the next
22
Q
First reaction cycle of FA synthesis
- what happens?
- and then?
A
- Condenses acetyl Coa (2 carbons) and a malonyl CoA (2 carbons) making 4 carbon intermediate
- Thereafter, every cycle adds one malonyl CoA to intermediate making it grow by 2 carbons until it achieves 16 carbon chain
23
Q
Commonality between cholesterol and fatty acid synthesis?
A
- Coming from acteyl CoA
- Predominately made in the liver and steroid hormone synthesizing cells– but all nucleated cells can make it
24
Q
Process of cholesterol synthesis
- what comes together? what enzyme is used?
- what are the intermediates and what do they lead to?
A
- Acetyl CoA and Acetoacetyl CoA (ketone) condense together to form HMG-CoA (Hydroxy methyl gluteral co enzyme A) the next step leads to formation of mevalonate by HMG-CoA reductase which is the rate limiting enzyme
- From mevalonate we make a lot of pyrophosphate intermediates which helps to make a lot of other things that the cells uses (so there are important). From the pyrophosphate intermediate we get a squalene which goes to lanosterol and then cholesterol
25
Q
Pyrophophates
- name some
- what are they?
- where are they used?
- what can they make? what happens with statin?
- what cells suffer the most?
- Isopentenyl pyrophosphate importance
A
- isopentenyl/geranyl/farnesyl)
- They are cell signaling molecules
- Used in osteoclasts to form ruffle border and in ETC
- help in making co-enzyme Q so if cholesterol biosynthesis is inhibited by statin you will have decrease in Co Q– which will affect ETC and ATP production
- Cells that suffer the most are muscles–this is what causes muscle cramping/pain with statins
- help to activate intracellular cell signaling- like RO RAS by activating hydrophobic group to cell molecules
26
Q
Regulation of HMG CoA reductase
- what is it?
- hormonal regulation; fed vs fasting
- intracellular regulation; high vs low cholesterol
A
- HMG CoA reductase is the rate-limiting enzyme.
- Hormonal Regulation: In the fed state, insulin will activate phosphatases which will dephosphorylate HMG CoA and turn it on, causing an upregulation of cholesterol biosynthesis; In the fasted state (high levels of glucagon), there will be high amounts of intracellular AMP. High amounts of AMP will activate AMP-dependent protein kinase–> phosphorylate HMG CoA—> turn off/inactivate HMG CoA reductase –> downregulation of cholesterol biosynthesis
- High amounts of intracellular cholesterol/sterols–> turns on expression of proteases–> proteolytically cleave HMG CoA—> reduce levels of HMG CoA in the cells, downregulate cholesterol synthesis;
- Cholesterol deficient–> upregulate LDL receptors to allow for more cholesterol in the cell AND to up upregulate cholesterol biosynthesis, cholesterol dissociates from SCAP within the ER membrane–> cholesterol can’t keep SCAP and SREBP in the ER membrane anymore–> will move from the ER to the Golgi membrane–> the N-terminal end will get cleaved off and released into the cytoplasm–> N-terminal end is a transcription factor–> goes into the nucleus and bind the steroid response element (the promotor of HMG CoA reductase)–> upregulates HMG CoA reductase production–> upregulates cholesterol biosynthesis within the cell
27
Q
Oxidation of Fats
- occurs
- how does size effect?
A
- in the mitochondria
- Short (<6 C) and medium (6-12) fatty acids enter the mitochondria right away but long-chain fatty acids (13-24 carbons) are shuttled in through the Carnitine shuttle. Very long-chain fatty acids (>24 carbons) have to go to a peroxisome first to undergo partial oxidation to become a long-chain
28
Q
location of catbolic vs anabolic processes
- why?
A
○ The majority of anabolic processes occur in the cytoplasm and the majority of catabolic processes occur in the mitochondria.
- Because catabolic processes produce energy and the mitochondria is the powerhouse of the cell…
29
Q
Oxidation of Fats Pathway
A
- start at the carboxyl terminal end rather than the methyl terminal end
- Coenzyme A is added to the Fatty Acid by AcylCoA synthetase (requires 2 ATP for each fatty acid to be activated) forming Fatty-Acyl Coenzyme A (FACoA); this enters the mitochondria
- Once it is in the intermembrane space,FACoA swaps its’ CoA for carnitine by the enzyme CPT1 (carnitine palmitoyltransferase I).
which is then transported into the matrix by Carnitine-Acylcarnitine translocase ( will bring FA-carnitine in and take pre-carnitine out of the matrix.) - CPTII (carnitine palmitoyltransferase II) in the inner mitochondrial membrane swaps the carnitine out for CoA activating the fatty acid and it enters Beta oxidation
30
Q
Carnetine
A
- (made endogenously in the kidney or obtained exogenously through diet of animal-based foods)
- The body would prefer to obtain carnitine from the diet rather than having to make it itself because it requires a lot of energy and makes very little product (Carnitine) compared to the amount of substrate required.
31
Q
- Will newly synthesized FAs be simultaneously oxidized
- regulatory mechanism
A
- No because if the cell is synthesizing and degrading at the same time, it will use up all of its’ ATP and end up dying
- Conversion of Acetyl CoA to Malonyl CoA in the cytoplasm by Acetyl CoA carboxylase–> increases concentration of Malonyl CoA–> inhibits CPT1–> Carnitine can’t be attached–> FA can’t enter the mitochondria–> can’t undergo oxidation while synthesis is occuring
32
Q
CPT1 deficiency
- what is happening
- effects? kidney, liver
- ketones
- neuro sxs
A
- Is not swapping CoA for carnitine, allowing for buildup of free carnitine in the blood.
- kidneys try to get rid of some of it, resulting in carnitine in the urine and High acylted FAs
- Glycogenolysis is likely happening but the liver will run out of glycogen at some point. We should have back up from gluconeogenesis but there are low amounts of fatty acids being burned resulting in low amounts of acetyl CoA and ketones and since Acetyl CoA is an activator of pyruvate carboxylase which is the first enzyme of gluconeogenesis (Pyruvate to Oxaloacetate) gluconeogenesis can’t start and glucose levels start dropping
- Because fat is not burning , there will be low amounts of Acetyl CoA which usually forms ketones
- neurologic symptoms down the line because the brain can only use glucose and ketones as an energy source and both of these will eventually be low!
33
Q
CPT2 deficiency
- what is it?
- kidney?
A
- present as high levels of carnitine in the mitochondria that may eventually come out into the blood but would be acylated carnitine (not free carnitine).
- kidney unable to filter out acylated carnitine because it is too big so its not in the urine.
34
Q
primary carnitine deficiency
A
transport that reabsorbs carnitine in the kidneys are defective so the patient can’t keep carnitine in the blood and loses all the carnitine in the urine
35
Q
cycles of oxidation
- how does it occur? what does it release? ex?
- do the math for palmitic acid
- products of cycle
- types of reactions
- where do products go?
A
- each cycle will release 2 carbons in the form of acetyl CoA. (So when you burn a palmitic acid (16 carbon fatty acid), you will get 8 acetyl CoA)
- 7 cycles of oxidation each release 1 acetyl CoA (2 carbons each)–> (7x1=7 )–> 7 acetyl CoA (14 carbons total); And the last 2 carbons at the methyl terminal end will be left as the final acetyl CoA. (totaling 8 acetyl CoA, accounting for each of the 16 carbons)
- produce 1 NADH and 1 FADH2
- Starts with dehydrogenation with the enzyme Acyl CoA dehydrogenase (known as CADs), then hydrogenation step, Third is another dehydrogenation step, and finally in the last reaction, coenzyme A will come in which will lead to produciton of Acetyl CoA which will come out as a product of each cycle along with an NADH and FADH2
- Acetyl CoA will go into the TCA cycle to make more NADH and FADH2 and the NADH and FADH2 produced here will go directly into the ETC cycle to make ATP
36
Q
Acyl CoA dehydrogenase
- types
A
- SCAD= Acyl CoA Dehydrogenase for short-chain fatty acids
- MCAD= for medium-chain fatty acid
- LCAD= for long-chain fatty acid
- VLCAD= for very long-chain fatty acid
37
Q
Deficiency of MCAD
A
common genetic disorder which will lead to decreased oxidation of medium-chain fatty acids in the liver–> accumulation of FAs in the liver–> increase triglyceride produciton–> increase VLDL–> fat accumulation in hepatocytes–> fatty liver
38
Q
Types of fats
- from the ocean?
A
- Saturated, Unsaturated, Transfats
- DHA
39
Q
Saturated Fats
- Chemical structure
- Physical state
- Physiologic state
- Endogenous
- major effects on health–length
A
- No double bonds, fully saturated with hydrogen, Will be stiff, flat chain that can stack up on one another
- solid at room temperature
- More susceptible to oxidation to make energy
- Made in the body endogenously as palmitic acid
- increase cardiovascular risk(not fully elucidated), can raise LDL cholesterol
- when looking at the health effects of saturated fats, it really depends on what length of saturated fat because medium-chain fatty acids can aid in weight loss and improve cardiovascular function.
40
Q
Chain Length
- source of short
- source of medium– best place to get them–how can they help?
- source of long chain in diet– effect on metabolism
- source of very-long-chains
A
- microbiota including acetate, propionate, and butyrate also some in dairy
- Coconut oil and dairy products (goat milk)– Coconut oil is the place to go for highest content of medium chain triglycerides (over 50%)– may be helpful for weight loss and other metabolic effects
- Saturated: Meat, dairy, and palm oil; Unsaturated: Olive oil, soybean, Flax oil; long chains depend upon the carnitine shuttle which expends a lot of energy (2ATP)
- C26 (cerotic acid) –there are some genetic conditions where the body can’t break it down
41
Q
Vegetable oil and fats
A
- All of the vegetable oils can give us a combination of different fatty acids in different amounts
- olive oil: oleic (omega 9)
- soybea: linoleic (omega 6)
- flax oil: α-linolenic (omega 3)
42
Q
Monounsaturated Fats
- Chemical Structure?
- Physical State?
- Physiologic Functions
- Effects on Health?
- sources
A
- One double bond located at the 9th position (omega-9s)
- Liquid but can get a little cloudy/thick if you put them in the fridge
- can be incorporated in the membrane and can be used for energy
- can reduce LDL
- olive oil, nuts, as well as avocados
43
Q
Polyunsaturated Fats
- Chemical Structure
- omega 3 vs 6 structure
- Physical State
- Physiologic Functions
- Effects on health
A
- Multiple double bonds (at least 2)
- location of the first double bond in relation to the omega end determines whether it is omega-3 or omega-6
- Liquid at room temperature
- These help contribute to membrane flexibility and are also precursors for eicosanoids (inflammatory products such as prostaglandins)
- lower risk of cardio vascular disease and death in general
44
Q
Essential Fats:
- which ones?
- why?
- common food sources for 6?
- sources of 3
- ratio of inflammation
A
- omega 6 and omega 3
- because we don’t make them in the body and must get them in the diet.
- Sunflower oil (vegetable oil), chicken (in small amounts)
- found in Flax seeds, chia seeds, hemp seeds, walnuts (probably the highest source for nuts)
- 16 omega 6s to 1 omega 3
45
Q
Linoleic acid
- precursor of?
- skin
- inflammation
A
- omega 6 fatty acid and serves as an arachidonic acid precursor which will be converted into prostaglandins and leukotrienes which are inflammatory
- A complex forms with linoleic acid to make skin impermeable to water
- Linoleic acid is also a neuronal fat precursor
