Fatty Acid Oxidation And Ketogenesis Flashcards
Too many fatty acids in blood stream
Can be dangerous
So liver oxidizes them into acetyl CoA
From acetyl CoA —>
Make ketone bodies
Ketone bodies are only produced when
- Low insulin
2. A lot of fatty aid oxidation is going on
When
- Overnight fast
- Endurance exercise
- Stress (epi)
- Low carb diets (alternative fuel)
What triggers breakdown of TG and release of FA from adipose tissue?
Glucagon or epinephrine
Triacylglycerol —> glycerol + 3 fatty acids
Requires?
3 different lipases- each cut off one fatty acid
3 lipases required
- ATGL
- HS lipase
- MAG lipase
Process of cleaving off 3 fatty acids
In glucagon/epi signaling cascade cAMP activates PKA —> PKA phosphorylates perilipin to activate it —> perilipin restructures lipid droplet to make TG accessible —> perilipin also interacts with ATGL which cleaves off first FA (TAG —> DAG) —> PKA also activates HS lipase by phosphorylating it —> HS lipase cleaves off second FA (DAG —> MAG) —> MAP lipase cleaves off third fatty acid (MAG —> glycerol + 3 FA)
Long chain fatty acids
- Hydrophobic
- Can be toxic at high concentrations because hydrophobic interactions in proteins are disrupted
How are fatty acids transported to tissues?
Albumin
Albumin
- Can bind multiple FA b/c has hydrophobic pocket
- Delivers FA to lipid transfer protein at plasma membrane which brings FA into cell
Fatty acids must be degraded by removal of
2-C units
Fatty acid oxidation occurs in
Mitochondrira
- FA are transported in by lipid transfer protein after albumin delivers them
2-C unit is released as ________
Acetyl-CoA
NOT free acetate
Activation step of FA oxidation
- Only needs to happen once
Requires CoA (SH group) and ATP (make thioester bond)
Activation Step
Where?
Driven by?
Free fatty acid + HS-CoA + ATP —> Acyl-CoA + AMP + PPi
- Occurs at OMM
- Driven by hydrolysis of PPi
Activated fatty acids can?
Cross the OMM
Why have to add a CoA to free fatty acid?
Need to attach a carnitine molecule to the FA so that it can be transported across the IMM
Transport across IMM
Acyl-CoA + carnitine acyl-carnitine + HS-CoA
Enzyme: carnitine acyltransferase I
Attach carnitine to Activated FA —> CoA comes off and releases energy because break thioester bond
_______ carries acyl carnitine across IMM into matrix
Translocase
Carnitine acyltransferase II
Add CoA back to FA in the matrix —> acyl- CoA
What happens to carnitine after add CoA in matrix?
Recycle carnitine back out via translocase for use again
Beta-Oxidation Total Reaction
Palmitoyl CoA (16-C) + 7 FAD + 7 NAD+ + 7 H2O + 7 CoA —>
8 acetyl CoA + 7 FADH2 + 7 NADH + 7 H+
Summary of mechanism chemistry
Single bond —> double bond —> alcohol —> ketone
Step 1
Convert single bond between alpha and beta carbons to a double bond
- Oxidation / reduction
C-C oxidized to C=C
FAD is reduced to FADH2 —> 1.5 ATP
Step 2
Add water molecule to double bond —> double bond becomes an alcohol
Step 3
Convert alcohol into a ketone
-OH —> C=O
NAD+ reduced to NADH —> 2.5 ATP
Step 4
Acetyl CoA is split off and attach CoA to beta carbon of chain that has now been shortened by 2 carbons
Acetyl CoA goes through TCA cycle
C=(n-2) goes back and cycle is repeated 7 time
Get ____ ATP per cycle
14
Complete oxidation of 1 palmitic acid yields
108 total ATP
106 net ATP (2 used in activation step)
Large energy yield is due to
Highly reduced state of carbon in fatty acids
Complete oxidation of one glucose yields
80 ATP
Regulation of fatty acid oxidation is linked to
ETC and how rapidly NAD+ and FAD can be regenerated
Carnitine acyltransferase I regulation
Result:
Negative allosteric modifier: Malonyl CoA (made by acetyl CoA carboxylase in fed state)
Result: FA do not get into mitochondria in fed state
____ control rate of O2 consumption (rate of ETC)
ADP
High ADP = speed up ETC Low ADP (high ATP) = slow down ETC
Because ATP is utilized in gluconeogenesis…
ADP levels rise —> ETC speeds up —> FAD and NAD+ regenerated —> fatty acid oxidation increases
NADH and FADH2
Negative allosteric modifiers
Ketogenesis occurs in
Liver
What happens during ketogenesis
Ketone bodies are synthesized from acetyl CoA
—> generating an alternative fuel source to glucose
Advantages of ketone bodies (2)
- Water soluble
2. Reduces burden on liver to continue gluconeogenesis at a high rate
Every tissue except ____________ can use FA for energy
RBC and brain
Liver ________ ketone bodies but cannot ________
Liver synthesizes ketone bodies but cannot oxidize them because lack CoA transferase
Step 1 ketogenesis
Condense 2 acetyl CoA together —> acetoacetyl CoA + CoA
Step 2 ketogenesis
Acetoacetyl CoA + acetyl CoA + H2O —> HMG-CoA + CoA
If have insulin…HMG-CoA used by HMG-CoA reductase to make metholonate
If have no insulin…
Step 3 ketogenesis
HMG-CoA —> Acetoacetate + CoA
Step 4 ketogenesis
Depending on NAD+/NADH …
Form D-3-hydroxybutyrate or acetone
3 ketone bodies
Which predominates?
- Acetoacetate
- Acetone
- D-3-hydroxybutryrate (predominates)
Ketone bodies do not rise significantly in blood until
2-3 days of starvation
Advantage of ketone bodies
Glucose and muscle sparing
Reduces burden on liver for gluconeogenesis —> don’t have to breakdown as much muscle protein
Conditions that increase KB synthesis and oxidation
- Length of fasting (>3 days)
- Low carb diets
- Untreated type 1 diabetes
- Chronic alcoholism
Untreated Type 1 diabetes vs. Type 2 diabetes
Untreated type 1 diabetes leads to diabetic ketoacidosis
Type 2 diabetics do not show ketoacidosis
Chronic alcoholism leads to
Alcohol induced ketoacidosis
Oxidation of KB- step 1
D-3-hydroxybutyrate + NAD+ —> Acetoacetate + NADH + H+
Oxidation of KB- step 2
Acetoacetate + succinyl CoA —> acetoacetyl CoA + succinate
Succinyl CoA is from TCA cycle
Oxidation of KB- step 3
Acetoacetyl-CoA + CoA —> 2 acetyl CoA
Go into TCA cycle
Oxidation of KB can be done by
Most tissues - Requires mitochondria
Not RBC or liver
