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Effects of Alanine on Gluconeogenesis in Isolated Rat Hepatocytes^1,2,3,

Department of Physiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616

The effect of alanine on pyruvate kinase was investigated in isolated rat hepatocytes. Alanine at concentrations of 2, 5 or 10 mM increased glucose production by 73% during the first 30 minutes of incubation of hepatocytes with 9 mM lactate and 1 mM pyruvate. After 30 minutes, the rate was not affected by the addition of alanine. A dose-response study showed that maximal stimulation of gluconeogenesis was achieved with 0.5 mM alanine. Using a method that measured recycling of phosphoenolpyruvate the pyruvate, it was found that in either fed or starved rats, alanine significantly decreased the percentage of phosphoenolpyruvate recycling when lactate was the substrate. However, no significant change in recycling was noted when either pyruvate or lactate-pyruvate was the glucose precursor. This study suggests that in intact liver cells, alanine has an inhibitory effect on pyruvate kinase. However, the inhibition is not of sufficient magnitude to completely account for the increase in glucose production when lactate is the substrate. It is hypothesized that alanine may have other effects on gluconeogenesis in addition to that of inhibiting pyruvate kinase.

KEY WORDS: • alanine • pyruvate kinase • gluconeogenesis

¹ Supported in part by U.S. Public Health Service Grant No. AM04732. F.M.D. was a recipient of fellowships from the Regents of the University of California and the California Foundation for Biochemical Research.

² From a dissertation submitted by F.M.D. to the Graduate School, University of California, Davis, in partial fulfillment of the requirements for the Ph.D. degree.

³ Preliminary reports of this work have been presented at the annual meetings of the Federation of American Societies for Experimental Biology. Dong, F. M. & Freedland, R. A. (1976) Functional inhibition of pyruvate kinase by alanine in isolated rat hepatocytes. Fed. Proc. 35, 537 (abs. #1822); and (1977) Recycling through pyruvate kinase in isolated rat hepatocytes. Fed Proc. 36, 1173 (abs. #4768).

⁴ Present address: Department of Biochemistry SJ-70, University of Washington, Seattle, WA 98195.

⁵ To whom reprint requests should be sent.

Manuscript received 10 March 1980.