Liver Metabolism 4: Lipid Metabolism #2 Flashcards
What si the building block molecule to synthesis FAs?
Acetyl CoA from citrate from the TCA cycle
What tissues can synthesize FAs de novo?
Hepatocytes (vast majority of it >80%)
Mammillary glands
Adipose tissues
Where in the mitochondria does FA synthesis in hepatocytes occur?
Cytosol
How does acetyl CoA produced in the mitochondria allowed to be transported across the cytosol?
1) Oxaloacetate + Acetyl CoA -> citrate
- uses citrate synthase as enzyme
2) citrate is able to cross mitochondria membrane and is then lysed into OAA+ acetyl CoA again in the cytosol
- uses ATP citrate lyase as enzyme
When do high levels of citrate present in hepatocytes?
In high energy concentration
- high levels of ATP and NADH and low levels of ADP
in high energy concentrations, turns off isocitrate enzymes in TCA and causes citrate to build up in mitochondria. Citrate build up = FA synthesis
What is the relationship between citrate and acetyl CoA carboxylase enzyme?
acetyl CoA carboxylase enzyme is topically inactive in the cytosol UNLESS high levels of CITRATE are present.
- in which case that are activated and acetyl CoA in cytoplasm is converted into malonyl CoA
What does malonyl-CoA help regulate?
Its presence in the cytosol inhibits CPT 1 and 2 receptors required for LCFA degradation
there is no point in degrading and synthesis of FAs at the same time
What are the 4 broad steps of FA synthesis?
1) condensation
2) reduction #1
3) dehydration
4) reduction #2
How does palmitoyl CoA cause feedback inhibition?
It’s presence in the cytosol turns off acetyl CoA carboxylase enzymes
How does insulin affect FA synthesis?
Activates acetyl CoA carboxylase regardless of current feedback present
- override command
How does AMP-activated protein protein kinase affect FA synthesis?
Is a protein kinase that is only activated in the presence of AMP
- low energy levels only
When activated, allosterically inhibits Acetyl-CoA carboxylase enzymes regardless of current conditions in cytosol
- override command
Why does lipid synthesis occur when large carbohydrate meals are consumed?
Because in hepatocytes only, the synthesis of TAGs and FAs can be done via glucose/carbohydrate molecules
- “cross-talk”
What is the reducing equivalent Molecule used in FA synthesis?
NADPH
Is produced in the Pentose pathway shunt and conversion of OAA to malate
the conservation of OAA to malate and malate to pyruvate via malic enzyme is ONLY found in hepatocytes
Hepatic steatosis
“Fatty liver disease (also NAFLD)
Overaccumulation of lipid droplets on the liver usually due to deficency in MTTP or over consumption of fats
Causes:
- too much TAG synthesis and exceeds ability of liver to produce VLDL molecules
- aging
- alcoholism
- some drugs
- obesity
- sedentary lifestyle
chronically leads to steatohepatitis (fatty liver with fibrosis) and activates stellate (ITO cells) to produce more fibrosis and eventually cirrhosis/end liver disease
is reversible UNTIL steatohepatitis is reached
hepatic steatosis is a risk factor for diabetes/atherosclerosis/cardiovascular diseases
Why cant liver use ketone bodies for fuel?
Liver doesnt have thiophorase enzymes
What is the rate limiting enzyme in ketogenesis?
HMG-CoA synthase
What is the rate limiting enzyme for FA synthesis
Acetyl CoA carboxylase
How is cholesterol and acetone produced differently, but with the same rate limiting enzyme and similar steps to cholesterol synthesis?
Cholesterol = is done inside the cytosol
Acetone = is done inside the mitochondria
What are the ketone bodies produced in ketogenesis?
Acetoacetate and B-hydroxybutryate
*these are both the two physiological ketone bodies that can be used for energy
acetoacetate spontaneously degrade EPO acetone which is not physiological ketone body
Diabetic ketoacidosis
In untreated diabetes (especially type 1)
Causes increased ketone body production and leads to damage to biological processes**
What are the major factors for FA synthesis and degradation?
Synthesis = after carb heavy meal and high insulin levels
Degradation = in starvation and low insulin levels
What is the common presentation with all Fatty acid oxidation disorders
Hypoketosis
- very low levels of acetyl CoA since cant use Fatty acids as fuel
Hypoglycemia
- can only use glucose as fuel
