Regulation of hepatic carbohydrate metabolism by FFA and acetyl-CoA: Sequential feedback inhibition

Abstract

In recent years experiments in slices, perfused liver and in the whole animal demonstrated that liver carbohydrate metabolism can be controlled by free fatty acids (FFA). Our investigations suggest that FFA and acetyl-CoA might provide regulation of the rate and direction of opposing pathways of hepatic glycolysis and gluconeogenesis by controlling the activity of key enzyme systems. Long and short chain FFA were observed to selectively inhibit the key enzymes of glucose catabolism, glucokinase, hexokinase, phosphofructokinase and pyruvate kinase. The long chain FFA were inhibitors two magnitudes stronger than octanoate. The FFA were also able to inhibit lactate production in a fortified supernatant fluid system. Acetyl-CoA inhibited hepatic glucokinase and pyruvate kinase but did not affect liver hexokinase, phosphofructokinase, lactate dehydrogenase, glucose-6-phosphatase or fructose-1, 6-diphosphatase. The inhibition of glucokinase and pyruvate kinase was dependent on the dose and preincubation time with acetyl-CoA. The acetyl-CoA is the end product of the degradation of FFA which in turn is an end product of glucose catabolism; therefore, the inhibition of the three key glycolytic enzymes by FFA and the subsequent reinforcement of the inhibition of glucokinase and pyruvate kinase may be called sequential feedback inhibition. The regulatory role of phosphoenol-pyruvate, NADH, ATP, alanine and oxaloacetate in the control of hepatic carbohydrate metabolism is discussed.