Role of Protein Kinase C in the Regulation of Hepatic Flow and Metabolism in the Perfused rat liver

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Protein Kinase C (PKC) has been suggested to be involved in the regulation of hepatic flow and metabolism. The effects of PKC modulation on hepatic flow and carbohydrate metabolism were studied in the rat liver, which was isolated from fed or fasted rats, and perfused through the portal vein at a constant pressure of 12 kPa. Phorbol 12-myristate 13-acetate (PMA) and 4beta-phorbol didecanoate, active phorbol esters for PKC,decreased the hepatic flow and oxygen consumption, and increased net lactate production. PMA enhanced net glucose production in fed rats. 4alpha-phorbol didecanoate, an inactive phorbol ester for PKC,had negligible influences on the hepatic flow and oxygen consumption. The effects of PMA was augmented by the increases in calcium and glucose concentrations in the medium. The effects of PMA were attenuated by ative PKC inhibitors (staurosporine and H-7) but not by an inactive PKC inhibitor (HA-1004). Pretreatment of rats with gadolinium chloride, an incativator of Kupffer cells also inhibitted the effects of PMA.These results suggest that PKC,particularly in Kupffer cells, has an important role in the regulation of hepatic flow and metabolism, and that effects of PKC activation is modified by the portal glucose and calcium concentrations.Volatile anesthetics, isoflurane and halothane, attenuated the PMA-induced alterations in hepatic flow, oxygen consumption, and lactate production.