Hepatic role in pH regulation: role of the intercellular glutamine cycle

Hepatic urea formation removes bicarbonate (not CO2), arising from the breakdown of the α-carboxylates of amino acids, in amounts stoichiometric with NH4+. Excess NH4+ is transported via the bloodstream to the kidney in the form of glutamine, there to be degrated by renal glutaminase and excreted via the tubules. By intricate intercellular compartmentation in the liver of a more periportal localization of urea synthesis and glutaminase, the regulation of hepatic glutaminase provides a major point of pH control in the organism. In acidosis, both these processes are shut off, decreasing bicarbonate removal, favoring hepatic glutamine formation by the perivenously located glutamine synthetase, and causing increased renal excreation of NH4+ instead of urea. The converse holds in alkalosis. Thus, a hepatic intercellular glutamine cycle between periportal and perivenous cells of the lobule serves a regulatory function in the pH homeostasis of the organism.