A research scientist studying the metabolic pathways that contribute to obesity feeds experimental animals a high-carbohydrate, high-protein diet for a prolonged period. A sample of liver tissue is then obtained from the animals, and the activity of various enzymes involved in fatty acid metabolism is measured and recorded. It is determined that beta-oxidation of fatty acids is inhibited within these cells as a result of the diet. An increase in which of the following substances is most likely responsible for the observed effect?

Question

A research scientist studying the metabolic pathways that contribute to obesity feeds experimental animals a high-carbohydrate, high-protein diet for a prolonged period.  A sample of liver tissue is then obtained from the animals, and the activity of various enzymes involved in fatty acid metabolism is measured and recorded.  It is determined that beta-oxidation of fatty acids is inhibited within these cells as a result of the diet.  An increase in which of the following substances is most likely responsible for the observed effect?

Quizplus · Accepted Answer

In the well-fed state, the abundance of ATP in hepatocytes inhibits isocitrate dehydrogenase, leading to high levels of citrate in the mitochondria. Citrate is transferred to the cytosol via the citrate shuttle and cleaved by ATP citrate lyase to form acetyl-CoA. High citrate levels (in addition to elevated insulin caused by high carbohydrate intake) causes upregulation of Acetyl-CoA carboxylase. This cytosolic enzyme catalyzes the conversion of acetyl-CoA to malonyl-CoA in the rate-limiting step of de novo fatty acid synthesis. Fatty acid synthase then catalyzes the condensation of malonyl-CoA with acetyl-CoA to create a 4-carbon molecule that will undergo subsequent condensation reactions to form a 16-carbon fatty acid. Beta-oxidation of fatty acids takes place primarily within the mitochondrial matrix. Mitochondrial membranes are impermeable to fatty acids due to their negative charge, so a specialized membrane carrier (carnitine) must be used to shuttle them into the matrix. Malonyl-CoA inhibits carnitine acyltransferase, preventing the transfer of acyl groups into the mitochondria. This inhibitory action functions to prevent the breakdown of newly synthesized fatty acids. (Choice A) Ketone bodies (eg, acetoacetate) are a major source of fuel for muscle, brain, and cardiac tissue that are produced during times of starvation or fasting when oxaloacetate is in short supply and acetyl-CoA is in excess. (Choice B) Carnitine is an amino acid that is essential for the transport of fatty acids through the mitochondrial membrane. It is a necessary component of fatty acid oxidation. (Choice C) Citrate is an intermediate in the TCA cycle. It can be exported out of the mitochondrial matrix and into the cytosol, where it is broken down into acetyl-CoA for use in de novo fatty acid synthesis. (Choice E) NADPH is a reducing molecule necessary for the synthesis of fatty acids. In contrast, beta-oxidation of fats produces FADH₂ and NADH-reducing equivalents. Educational objective: Cytosolic acetyl-CoA carboxylase converts acetyl-CoA to malonyl-CoA during the rate-limiting step of de novo fatty acid synthesis. Malonyl-CoA also inhibits the action of mitochondrial carnitine acyltransferase, thereby inhibiting beta-oxidation of newly formed fatty acids. __________ References: Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. (http://www.ncbi.nlm.nih.gov/pubmed/22833869)

A Research Scientist Studying the Metabolic Pathways That Contribute to Obesity