Lecture 2 - fatty acid oxidation inhibition

Question 1

What are the types of mitochondrial toxicity?

Answer 1

Inhibition of electron transport chain, uncoupling of oxidative phosphorylation, inhibition of mtDNA synthesis, opening of permeability transition pore and inhibiton of fatty acid oxidation

Question 2

How does inhibition of mitochondrial beta-oxidation occur?

Answer 2

Mostly achieved by structural analogues of fatty acids that compete at one of the enzymatic steps. This results in decrease in ATP production and accumulation of long-chain acyl-CoAs, FAs and triglycerides

Question 3

What are examples of inhibitors of B-oxidation?

Answer 3

Amiodarone, Benzbromaron, Buprenorphine, Tolcapone, Valproate

Question 4

How can you determine/measure B-oxidation and fat accumulation?

Answer 4

Measurement of palmitate, C-acetyl-CoA and Ketone bodies (hepatocytes) or CO2 (muscle cells).
determine triglycerides in cells and tissues using staining or saponification
determine carnitine derivatives in plasma and urine using LC-MS

Question 5

What are important enzymes involved in mitochondrial FA metabolism?

Answer 5

Acyl-CoA synthase, CPT1 (carnitine to acylcarnitine), translocase and CPT II

Question 6

Why were CPT II inhibitors developed and what do they do?

Answer 6

treatments for DT2 and they inhibit gluconeogensis and reduce glucose production

Question 7

What is fatty liver of pregnancy?

Answer 7

Disease occurring in final stages of pregnancy and occurs because FA metabolism intermediates are exported from child to mother which results in impairment of hepatic mitochondrial function of the mother

Question 8

What are the diffential diagnosis of microvesicular steatosis?

Answer 8

Metabolism diseases (fatty livers of pregnancy), Reye’s syndrome, Toxic liver injuries (occuring by drugs - valproate, amiodarone, tetracycline and toxicants/toxins)

Question 9

How does tolcapone affect hepatic FA metabolism?

Answer 9

decreased the activity of long-acyl-CoA dehydrogenase

Question 10

how does COMT inhibitors effect triglyceride export?

Answer 10

reduction of ApoB100 mRNA expression

Question 11

How does valproate affect liver toxicity?

Answer 11

Depletion of CoASH and carnitine. Has toxic metabolites that inhibit beta-oxidation and respiratory chain