Week 6: Ethanol Metabolism

Question 1

Where is ethanol metabolized?

Answer 1

Hepatocytes of the liver

Question 2

Ethanol metabolism pathway

Answer 2

Ethanol -simple diffusion-> cytoplasm

Ethanol + NAD+ -Alcohol Dehydrogenase-> Acetaldehyde + NADH

Acetaldehyde –> matrix of mitochondria

Acetaldehyde + NAD+ -Acetaldehyde Dehydrogenase-> Acetate + NADH

Acetate has 2 fates

• Liver can use for energy if it needs
• Can be transported into the blood to extrahepatic tissues

Acetate + CoASH + ATP -Acetyl CoA Synthetase-> Acetyl-CoA + ADP

Acetyl-CoA + Oxaloacetate -TCA Cycle->

Question 3

Biochemistry of ethanol hepatotoxicity

Answer 3

Acetaldehyde is very reactive and bind to anything indiscriminately and disturb their functions causing hepatotoxicity

Question 4

Genetic notes of ethanol metabolism

Answer 4

Acetaldehyde dehydrogenase mutations decreasing or eliminating its activity, will have an increase in [Acetaldehyde]

• These individuals have no reported cases of alcoholism because acetaldehyde causes hangovers
• Acetaldehyde -CTZ center in the brain-> Nausea/Vomiting

Acetaldehyde dehydrogenase Gain of function has a lower [Acetaldehyde] so this has a higher risk of alcoholism because they don’t get the nausea and vomiting because they process acetaldehyde much more quickly

Question 5

Ethanol metabolism in the Fed state

Answer 5

in the liver:

GLUT 2 activity from fed state

glucose -glycolysis-> pyruvate

ethanol + NAD+ -alcohol dehydrogenase-> Acetaldehyde + NADH

This contributes to {NADH] in the cytoplasm along with the metabolism of glucose

(*In the Mitochondria*)Acetaldehyde + NAD+ -Acetaldehyde dehydrogenase-> Acetate + NADH

Contributes to the NADH levels in the mitochondria in the fed state

The NADH from glucose metabolism also needs to be transported to the mitochondria to the ETC

Normally, NADH is transported by reducing DHAP -DH enzyme-> G3P + FAD+ –> FADH2 + DHAP

FADH2 then goes to ETC

However, when ethanol is added, [NADH] increases in the cytoplasm because the FADH2 system is getting backed up from the additional NADH in the cytoplasm which can inhibit glycolysis and shift pyruvate from entering the mitochondria and pyruvate will be converted to lactate to regenerate NAD+ to keep glycolysis going

Lactate can enter the blood and cause lactic acidosis in extreme cases

The ethanol NADH in the mitochondria goes to the ETC inhibits DH enzymes in the TCA cycle so Acetyl-CoA + Oxaloacetate –> Citrate -> isocitrate but isocitrate DH is inhibited by high [NADH] causing aconitase to reverse and build up citrate

Citrate then gets displaced into the cytoplasm

Citrate in cytoplasm -citrate lyase-> Acetyl CoA and Oxaloacetate back in the mitochondria

Acetyl-CoA -Acetyl-CoA Carboxylase-> Malonyl CoA (activated by insulin signaling)

Malonyl CoA –> FA synthesis

FAs -> Triglyceride synthesis

HAve excess of G3P from fed state not being oxidized from energy overload from ethanol

So G3P -> Glycerol for the backbone of the triglycerides

Triglycerides are packaged into VLDL and sent out into the blood

If substantial amounts of ethanol is drank, more and more substrates get put into FA synthesis for instance

If the TG synthesis pathway is saturated, Triglycerides won’t be packaged into VLDL and can lead to Alcoholic Fatty Liver Disease

Question 6

Ethanol Metabolism in the fasting state

Answer 6

Glucagon signaling

No glucose coming in and glycolysis is inhbiited

Ethanol is still metabolized by alcohol dehydrogenase making acetaldehyde and NADH

Acetaldehyde enters mitochondria and is processed by acetaldehyde DH resulting in acetate and NADH

Acetate can be used by the liver or extrahepatic tissues such as skeletal muscle

Liver:

Acetate -Acetyl-CoA synthetase-> Acetyl-CoA

β-oxidation FA -> Acetyl-CoA

So now 2 sources of Acetyl-CoA dramatically increasing its concentration

Acetyl-CoA inhibits further production of Acetyl-CoA from pyruvate by pyruvate DH

Acetyl-CoA activates Pyruvate Carboxylase converting pyruvate into oxaloacetate

Oxaloacetate -malate DH-> Malate

Malate -gluconeogenesis-> glucose

Problem is we are limited by pyruvate, although we have a lot of NADH being made from ethanol, transport shuttle is slowed from high [Acetyl-CoA] keeping NADH levels high in the mitochondria, so NADH in cytosol builds up and ends up

Converting pyruvate -> lactate to regenerate NAD+ and can cause lactic acidosis

so now pyruvate is being taken out of the gluconeogenic pathway so this reduces the amount of glucose being made in the liver leading to hypoglycemia

In the matrix of the mitochondria:

β oxidation and Ethanol abundance of Acetyl-CoA so this induces ketone synthesis which will lead to keto-acidosis which is additive to lactic acidosis dropping the pH of the blood

Ethanol is overloading the system and will have backups of certain substrates and can lead to toxic accumulation of normal molecules

Question 7

toxic accumulation of normal molecules in the fed state

Answer 7

FAs and TGs leading to Fatty liver and Lactate

Question 8

toxic accumulation of normal molecules in the fasting state

Answer 8

Lactate and Ketones which lead to ketones earlier in the fasting state and leading to ketoacidosis and reducing glucose from gluconeogenesis by removing pyruvate pushing it to lactate

Question 9

In the fasting state where is the pyruvate coming from

Answer 9

Amino Acids from skeletal muscle and performing a lot of transamination reactions in the form of alanine and to generate pyruvate