You have been studying a cell line derived from a muscle tumor and comparing its activities, with respect to the effects of high levels of fatty acids on glucose oxidation, to those of normal skeletal muscle cells from the same individual. You find that exposing the normal cells to high levels of free fatty acids results in impaired levels of glucose oxidation. These results are expected based upon the interactions of the glucose-fatty acid cycle. However, the tumor-derived cells do not exhibit reduced glycolysis in the presence of high levels of free fatty acids. Which of the following best explains these observations?

Question

Quizplus · Accepted Answer

The tumor cells likely have a mutant form of PFK1 that is insensitive to allosteric inhibition by citrate, allowing glycolysis to continue even in the presence of high levels of fatty acids, which normally would inhibit glycolysis in normal cells. According to the glucose-fatty acid cycle, these 2 fuel sources reciprocally antagonize the utilization of each other. In other words, glucose oxidation can restrict fatty acid metabolism and fatty acid oxidation leads to reduced utilization of glucose. There are 2 major mechanisms by which fatty acid oxidation can restrict the flow of glucose through glycolysis. High levels of fat oxidation lead to generation of acetyl-CoA in excess of the cells' ability to fully oxidize it in the TCA cycle. Some of this acetyl-CoA is converted to citrate via the citrate synthase reaction of the TCA cycle, but the citrate cannot be further oxidized, so it is transported to the cytosol where it allosterically inhibits the PFK1 reaction. In addition, the acetyl-CoA allosterically activates pyruvate dehydrogenase complex (PDHc) kinases that, when activated, phosphorylate the PDHc. Phosporylated PDHc is less capable of oxidizing acetyl-CoA and leads to increased levels of pyruvate in the cytosol. The increased pyruvate restricts the ability of pyruvate kinase to oxidize phosphoenolpyruvate, resulting in reduced flow through glycolysis.

You Have Been Studying a Cell Line Derived from a Muscle