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MTC Block 2: Post Quiz Material > 4- Triglyceride Metabolism and Ketogenesis > Flashcards

4- Triglyceride Metabolism and Ketogenesis Flashcards

1
Q

triglycerides

A
  • storage fats/stored energy (provide more than half energy requirements of liver, heart, and resting skeletal muscle)
  • major energy reserve in body
  • composed of 3 fatty acids, each with an ester linkage to a single glycerol

-highly concentrated stores of metabolic energy cause they are reduced and dehydrated (stored free of water, so less weight than carb/protein) and yield 9kcal/g of energy instead of 4kcal/g by carb/protein (TG are more reduced)

simple= same fatty acid in all 3 positions

most naturally occurring ones have different fatty acids on the glycerol

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2
Q

adipocytes

A
  • specialized fat cells that store TG
  • found under skin and in abdominal cavity/mammary glands
  • store neutral lipids as lipid droplets
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3
Q

long term vs. short term energy

A

short-term: glucose and glycogen, fast delivery

long-term (months): fats like TG, slow delivery

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4
Q

Peripheral tissues need to gain access to fatty acid energy reserve stored in adipocytes… how do they do this?

A

3 steps
1. TG must be mobilized (degraded to fatty acids/glycerol, then released from adipose tissue and transported to energy requiring tissues)

  1. Inside tissues they must be activated and transported into mitochondria where enyzmes of B-oxidation reside
  2. fatty acids must be broken down (oxidized into acetyl-CoA, which can be further processed in the TCA cycle)
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5
Q

How do we get the fat into our usable system?

A
  1. from diet
  2. mobilized stored fat in adipocytes
  3. convert excess dietary carbs to fats for export to other tissues in liver
  • most fats are ingested in form of TG which is degraded to fatty acids for adorption across intestinal epithelim
  • TG are not very soluble so they need bile salts with them which are released into the small intestine after a fatty meal
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6
Q

bile salts

A
  • biological detergent (forming mixed micelles to help emulsify fat)
  • allows pancreatic lipases to break it up

amphipathic lipid made in liver and stored in gall bladder which is released into the small intestine after a fatty meal

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7
Q

steatorrhea

A
  • inadequate production of bile salts
  • lipid malabsorption (typically comes with liver disease/damage)
  • large amounts of fats are excreted in the feces
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8
Q

Dietary fatty acids absorbed in small intestine (discuss mechanism)

A

fats ingested in diet

  1. bile salts emulsify dietary fat in small intestine (forming mixed micelles)
  2. Intestinal lipases degrade triacylglycerols
  3. fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols
  4. triacylglycerols are incorporated, with cholesterol and apolipoproteins, into chylomicrons
  5. chylomicrons move though the lymphatic system and bloodstream to tissues
  6. lipoprotein lipase, activated by apoC-II in the capillary, converts triacylglycerols to fatty acids and glycerol
  7. fatty acids are oxidized as fuel or reesterified for storage
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9
Q

chylomicrons

A
  • largest lipoproteins
  • released into lymph the blood and bind to lipoprotein lipases (primarily at adipose tissue and muscle), where it is then hydrolyzed into free fatty acids and glycerol for transport into tissues

triglyceride-rich spherical particles also function in the transport of fat-soluble vitamins, cholesterol, and steroid hormones

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10
Q

what happens to chylomicron remnants

A

-smaller remnants that get taken to the liver…

taken up by liver by endocytosis

  • TG can be oxidized to provide energy or precursors for the synthesis of ketone bodies
  • if diet has more FA then needed, then TG is packaged into very low density lipoproteins (VLDL) for transport in blood to adipose tissue (for storage as lipid droplets within adipocytes)
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11
Q

lipolysis

A

mobilization of stored fatty acids

  • stimulated by glucagon
  • inhibited by insulin
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12
Q

lipid droplet and perilipins

A
  1. Lipid Droplet
    core: sterol esters and TG
    outer layer: monolayer of phospholipids
  2. Perilipins
    coat lipid droplets to prevent untimely lipid mobilization .
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13
Q

Steps taken when glucagon is released (need metabolic energy)

A
  1. Epinephrine/glucagon, secreted in response to low blood glucose levels, activate adenylyl cyclase in the adipocyte plasma membrane to produce cAMP
  2. PKA phosphorylates perilipin A and hormone sensitive lipase
  3. RATE LIMITING STEP. Phosphorylated perilipin causes hormone sensitive lipase in the cytosol to move to the lipid droplet where it can begin hydrolyzing TG to free fatty acids and glycerol.
  4. free fatty acids pass from the adipocyte into the blood to bind to albumin (10 FA/monomer) to increase their solubility
  5. Bound fatty acids are carried to tissues (e.g. skeletal muscle, heart, renal cortex) via the bloodstream.
  6. Fatty acids dissociate from albumin and are moved by plasma membrane transporters into cells to serve as fuel.
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14
Q

what happens to glycerol when TG is broken down?

A

-adipocytes dont have glycerol kinase so glycerol is released to go back to the liver

glycerol (glycerol kinase) L-glycerol-3-phosphate (glycerol 3-phosphate dehydrogenase) dihydroxyacetone (triose phosphate isomerase) D-glyceraldehyde 3-phosphate

-which can then go into glycolysis

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15
Q

why do type II (insulin-independent) diabetics frequently exhibit hypertriglyceridemia?

A

partly due to aberrant regulation of hormone-sensitive lipase

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16
Q

degradation of fats

A

fats are degraded into fatty acids and glycerol in cytoplasm

BUT enzyme that does B-oxidation is in the mitochondrial matrix

  • free fatty acids taken up by energy-requiring tissues must fist be activated before they can enter this intracellular organelle
  • fatty acids with chain lengths of 14 or more carbons cannot pass directly though the mitochondrial membrane so they first go through the carnitine shuttle (3 rxns)
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17
Q

Carnitine Shuttle

A

fatty acids with carbons chains of 14 or more go through this shuttle to get into the mitochondrial matrix so they can be degraded by B-oxidation

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18
Q

Carnitine Shuttle (3 steps)

A
  1. Esterfication to CoA
    - enzyme: acyl-CoA synthetase (2 step rxn)
    - occurs in cytosolic side of outer mitochondrial membrane
    - uses 2 ATP

Activated long-chain fatty acids are transported across inner mitochondrial membrane….

  1. Transesterification to carnitine…
    - enzyme: carnitine acyltransferase I (CPT1)
    - attaches acyl group of CoA to carnitine

….followed by transport (RATE LIMITING STEP FOR B-OXIDATION)

  • fatty acyl-carnitine enter maxtrix by facilitated diffusion
  • channel: acyl -carnitine/carnitine transporter OR Carnitine/acylcarnitine translocase (CT) that spans inner mitochondrial membrane

-Malonyl CoA inhibits CPT1 isoform in liver and prevents futile cycling in liver

  1. Transesterfication back to CoA
    - enzyme: carnitine acyltransferase II (CPT II)
    - occurs on inside of inner mitochondrial membrane
    - fatty acyl-CoA and carnitine are released into the matrix, carnitine then reenters the intermembrane space via CT
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19
Q

two separate pools of CoA and fatty acyl-CoA

A
  1. Mitochondrial CoA: used in the oxidative degradation of pyruvate (pyruvate dehydrogenase complex reaction), fatty acids and some amino acids. Mitochondrial fatty acyl-CoA is the substrate for β-oxidation
  2. Cytosolic CoA: used in membrane lipid/fatty acid biosynthesis. whereas the cytosolic fatty acyl-CoA is used for membrane lipid synthesis or it can be linked to carnitine and moved into the matrix for oxidation and ATP production.
20
Q

carnitine

A

helps move fatty acyl CoA back to mitochondrial matrix

21
Q

sources of carnitine

A

-obtained from diet (meat)

  • synthesized by lys and met in liver and kidney BUT NOT SKELETAL MUSCLE OR HEART
  • heart and skeletal muscle are completely dependent on carnitine from hepatocytes and diet
22
Q

diseases from deficiencies of individual components of the carnitine cycle

A

result in impaired utilization of long-chain fatty acids for energy production and accumulation of toxic amounts of free fatty acids

CPT1 def in liver: impairs liver from synthesizing glucose during a fast, leads to hypoglycemia

CPT2 def: occurs primarily in cardiac and skeletal muscle, where symptoms range from cardiomyopathy to muscle weakness

23
Q

B-oxidation overview

A
  • fatty acid degradation
  • one pass through removes 2 carbons so you need 7 rounds to oxidize 1 molecule of palmitoyl-CoA to 8 acetyl-CoA
  • once this occurs then acetyl-CoA is formed and goes into the TCA cycle

or

FADH2 and NADH are formed and go to ETC

ACETYL-COA IS THE MAIN PRODUCT

24
Q

B-oxidation steps (detailed)

A
  1. Dehydrogenation of fatty acyl-CoA
    -acyl-CoA dehydrogenase
    -produces FADH2
    Palmitoyl-CoA —> trans-delta2-enoyl-CoA
  2. hydration of the trans double bond
  3. second dehydrogenation
  4. Thiolytic cleavage
    - releases molecule of acetyl-CoA and acyl-CoA that is shortened by two carbons
  • NOTE: all enzymes in B-oxidation are specific to chain length like acyl-CoA dehydrogenase
  • there is an inner mitochondrial membrane-bound trifunctional protein that contains all three long chain enzymes
25
Acyl-CoA Dehydrogenase
Palmitoyl-CoA to trans-delta2-enoyl-CoA -VLCAD: recognizes very long chain fatty acids (>22 carbons) - bound to inner mitochondrial membrane all others are in the matrix - also a "long" one here - MCAD: medium chain (6-12 carbons) -SCAD: short chain (<6 carbons)
26
MCAD deficiency
most common defect. fat accumulation in liver, hypoglycemia (tissues only rely on glucose instead of also fatty acids), vomiting, lethargy, coma after fasting for 12 hours or more pts with this just need to eat high carb diets and not fast
27
B-oxidation intermediates and only enzyme we need to know
1. Palmitoyl-CoA acyl-CoA dehydrogenase (forms FADH2) 2. trans-delta2-enoyl-CoA 3. L-B-Hydroxy-acyl-CoA 4. B-ketoacyl-CoA 5. (C14) Acyl-CoA (aka myristoyl-CoA)
28
B-oxidation pathway for unsaturated fatty acids
- unsaturated FA needs to be in trans configuration for enoyl-CoA hydratase to act on it - so you need an isomerase to convert cis to trans or a reductase to convert the double bond into single bonds either way enoyl-CoA hydratase can act on it and it can go through B-oxidation the way saturated FA do
29
odd-chain fatty acid B-oxidation
-everything happens normally BUT at the end it leads to a 5C substrate that gets cleaved to acetyl-CoA (2C) and a 3C molecule called propinoyl-CoA propinoyl-CoA will enter a different pathway and will form succinyl-CoA - enzymes used in this pathway 1. propionyl-CoA carboxylase 2. methylmalonyl-CoA epimerase 3. methyl-malonyl-CoA mutase *note: these enzymes use adenosylcobalamin (Vitamin B12) as a coenzyme
30
propinoic acidemia (PA)
Deficiencies in propionyl-CoA carboxylase, biotin transport -early neonatal period with progressive encephalopathy -propionic acid builds up in the bloodstream -damages the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking
31
methylmalonic acidemia (MA)
Deficiencies in methylmalonyl- CoA mutase, and adenosylcobalamin synthesis - early neonatal period with progressive encephalopathy. - severe nutritional deficiency of vitamin B12 - buildup of unused methylmalonyl-CoA - diagnosis is often used as an indicator of vitamin B12 deficiency in serum.
32
a-oxidation
- metabolism of brached chain fatty acids | - occurs in peroxisome with Phytanic acid (a ton of it in dairy products and ruminant animal fat)
33
Refsum's disease
- genetic deficiency of peroxisomal enzyme in a-oxidation of phytanic acid - build up of phytanic acid in tissues and sera - shortening of 4th toe - they should restrict dairy and meat intake
34
Zellweger syndrome
-unable to make peroxisomes so you lack all a-oxidation and very long chain fatty acid B-oxidation (which is also done in peroxisome) - like hexacosoanoic acid (26:0)
35
X-linked adrenoleukodystrophy (XALD)
- fail to oxidize very long chain fatty acids (too much hexacosanoic acid- 26:0) - lack of functional transporter for them to get into the peroxisome - affects young boys with loss of vision, behavioral disturbances, and early death - mixture of oleic acid and erucic acid (olive oil and rapeseed oil) reduces levels of VLCFAs
36
Regulation of Fatty acid oxidation
1. 3-step carnitine shuttle (movement of fatty acyl groups from cytosol to mitochondrial matrix) is rate limiting step 2. Malonyl-CoA inhibits carnitine acyltransferase I (to inhibit fatty acid oxidation when liver has enough glucose) 3. B-oxidation enzymes - B-hydroxyacyl-CoA dehydrogenase is inhibited with increased NADH - high acetyl-CoA inhibits thiolase 4. during fasting AMPK is activated and phosphorylates acetyl-CoA carboxylase and lowers malonyl-CoA (allows B-oxidation to replenish supply of ATP)
37
in liver, fatty acyl-CoA formed in cytosol has 2 fates
1. B-oxidation in mitochondria | 2. conversion into TG and phospholipids in the cytosol
38
Ketogenesis
- occurs in liver (mitochondrial matrix) - Acetyl-Co is converted by three steps into ketone bodies 1. acetone - exhaled out 2. B-hydroxybutyrate 3. acetoacetate - these two can be transported to tissues and converted to acetyl-CoA for TCA cycle (skeletal, heart, and renal cortex mainly)
39
ketogenesis extra info
- depends on oxaloacetate for formation of citrate - oxaloacetate becomes limiting if carbs are unavailabe (fasting/starving) so then oxaloacetate is used to form glucose by gluconeogenic pathway - this makes acetyl-CoA to be diverted into ketogenesis
40
Ketogenesis pathway
All dependent on NADH/NAD+ ratio (too much NAD+ and it wont happen) 2 acetyl-CoA become acetoacetyl-CoA using B-ketothiolase then a series of reactions to get to 1. acetone 2. B-hydroxybutyrate 3. acetoacetate (forms 1 and 2)
41
Diabetic ketoacidosis
- when too much acetone is formed through ketogenesis - increased amounts of acetone in blood can cause "acetone breath" - excessive accumulation of ketone bodies in blood (20mM instead of .2-5mM)
42
Ketogenesis does NOT occur in the liver
- ketone body activation is done by 3-ketoacyl-CoA transferase which is not in the liver - ketone bodies are water-soluble so they can travel in the blood - brain can adapt to using ketone bodies - alternate source of fuel
43
when is ketogenesis used
- hardly if you have a normal diet | - if you are starving then you do ketogenesis so the brain can use up all the glucose before any other body parts
44
increase in acetyl-CoA ... whats the effect on ketone body formation?
accelerates formation of ketone bodies beyond capacity of extrahepatic tissues to oxidize them (resulting in acidosis or ketosis)
45
Anabolism of fatty acids
- requires acetyl-CoA and malonyl-CoA - requires reducing power from NADPH - takes place in cytosol in animals
46
Catabolism of fatty acids
- produces acetyl-CoA - produces reducing power (NADH) - takes place in the mitochondria

MTC Block 2: Post Quiz Material (7 decks)

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