The influence of the inflammatory mediators interleukin 1β (IL1β) and tumour necrosis factor α (TNFα) on the glucagon-induced expression of phosphoenolpyruvate carboxykinase (PCK) and on glucose formation via gluconeogenesis was investigated in cultured rat hepatocytes. Gene expression was monitored by determination of mRNA levels and of enzyme activity. Glucose formation was estimated with newly synthesized radioactive glucose derived from a radiolabelled lactate precursor. Glucagon (0.1 or 1 nM) induced PCK mRNA transiently to a maximum 2 h after its application. In the presence of recombinant human (rh) IL1β or rhTNFα the increase in PCK mRNA levels was totally inhibited at 0.1 nM glucagon, whereas at 1 nM glucagon the maximal increase was inhibited by only 25%. Glucagon (0.1 or 1 nM) induced PCK activity to a maximum after 4 h (4-fold and 6-fold over prestimulatory activity respectively). In the presence of rhIL1β or rhTNFα the maximal increase was inhibited by approx. 50%. Addition of rhIL1β or rhTNFα 2 h after glucagon, at the maximal glucagon-induced PCK mRNA levels, accelerated the decay of PCK mRNA. Glucagon (0.1 or 1 nM) increased glucose formation from lactate by 1.3-fold and 1.7-fold respectively over unstimulated rates. In the presence of rhIL1β or rhTNFα this increase in glucose formation was inhibited by 60–90%. At 0.1 nM, glucagon doubled the intracellular cAMP concentration. This increase was prevented by rhIL1β or rhTNFα. At 1 nM, glucagon increased cAMP concentrations by 10-fold. In the presence of rhIL1β or rhTNFα this increase was inhibited by 70%. From the results it is suggested that rhIL1β and rhTNFα prevented glucagon-stimulated PCK gene expression and gluconeogenesis at least in part by inhibition of the glucagon-stimulated increase in cAMP concentrations.
Impairment by interleukin 1β and tumour necrosis factor α of the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis in cultured rat hepatocytes
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Bruno CHRIST, Annegret NATH; Impairment by interleukin 1β and tumour necrosis factor α of the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis in cultured rat hepatocytes. Biochem J 15 November 1996; 320 (1): 161–166. doi: https://doi.org/10.1042/bj3200161
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