Lecture 2 - fatty acid oxidation inhibition Flashcards

1
Q

What are the types of mitochondrial toxicity?

A

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

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2
Q

How does inhibition of mitochondrial beta-oxidation occur?

A

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

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3
Q

What are examples of inhibitors of B-oxidation?

A

Amiodarone, Benzbromaron, Buprenorphine, Tolcapone, Valproate

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4
Q

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

A

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

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5
Q

What are important enzymes involved in mitochondrial FA metabolism?

A

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

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6
Q

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

A

treatments for DT2 and they inhibit gluconeogensis and reduce glucose production

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7
Q

What is fatty liver of pregnancy?

A

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

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8
Q

What are the diffential diagnosis of microvesicular steatosis?

A

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

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9
Q

How does tolcapone affect hepatic FA metabolism?

A

decreased the activity of long-acyl-CoA dehydrogenase

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10
Q

how does COMT inhibitors effect triglyceride export?

A

reduction of ApoB100 mRNA expression

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11
Q

How does valproate affect liver toxicity?

A

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

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