Question

11. What would happen in a liver cell if citrate levels were high? Tell me what pathways would increase and which would decrease. Mention at least three key regulatory enzymes that would be affected as a result of this increase in acetyl-CoA. (10 pts)

Answer 1

Citrate is an important source of acetyl-CoA for making fatty acids. When the citrate concentration is high (as when the citric acid cycle is moving slowly or is stopped), it gets shuttled across the mitochondrial membrane into the cytoplasm and broken down by the enzyme citrate lyase to oxaloacetate and acetyl-CoA.

this acetyl-CoA is come from many pathways for citric acid cycle like pyruvate decarboxylation, beta oxidatipn of fatty acid, from ketone bodies or from amino acid metabolism. as the citrate concentration is higher in cell these pathways ultimate goes to slow down and anabolic pathway start. like gluconeogenesis (to form glycogen from glucose), fatty acid synthesis, ketone bodies, amino acid and cholesterol formation.

3 main enzyme which were affected by higher concentration of acetyl-CoA.

pyruvate dehydrogenase complex - Role of Acetyl-CoA in regulation Acetyl-CoA inhibits pyruvate dehydrogenase complex as a negative feedback mechanism. It also activates pyruvate carboxylase, which is used to push the equilibrium between glycolysis/gluconeogenesis slightly toward gluconeogenesis.

2. acetyl-CoA carboxylase - The regulation of fatty acid synthetase and acetyl-CoA carboxylase in adipose tissue is due to acetyl-CoA. Higher concentration of acetyl-CoA promote fatty acid syntheais by activation of fatty acid synthetase or acetyl-CoA carboxylase. acetyl-CoA carboxylase is required for formation of malonyl CoA from acetyl-CoA.

3. 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase - higher concentration of acetyl-CoA responsible for transportation of acetyl-CoA from mitochondria to cytosol and activate HMG-CoA reductase, a rate limiting enzyme for synthesis of cholesterol.