Hepatic Na(+)-dicarboxylate cotransport: identification, characterization, and acinar localization

Area of Science:

• Hepatology
• Molecular Transport
• Biochemistry

Background:

• Rat liver perfusion studies suggest alpha-ketoglutarate (KG) and dicarboxylate transport exhibit acinar heterogeneity, predominantly in the perivenous region.
• The isolated perfused liver model has limitations in distinguishing intra-acinar differences in solute transport and metabolism.

Purpose of the Study:

• To investigate the driving forces and acinar localization of alpha-ketoglutarate (KG) transport.
• To differentiate KG transport mechanisms from potential indirect effects of ion gradients or cotransport.

Main Methods:

• Utilized rat basolateral liver plasma membrane vesicles (blLPMV) from control, carbon tetrachloride (CCl4)-treated (perivenous toxin), and allyl alcohol (AA)-treated (periportal toxin) rats.
• Assessed [14C]KG uptake under various ion gradients (Na+, K+, H+) and in the presence of ionophores (gramicidin, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone).
• Evaluated cis-inhibition of KG uptake by other organic anions and amino acids.

Main Results:

• KG uptake into blLPMV was significantly stimulated by an inwardly directed Na+ gradient, independent of other cation gradients or diffusion potentials.
• KG transport was confirmed as electrogenic, involving the net transfer of positive charge.
• Uptake was cis-inhibited by tricarboxylic acid cycle intermediates (succinate, fumarate, malate, citrate) but not by oxalate, malonate, glutamate, or taurocholate.

Conclusions:

• Rat liver basolateral membrane transport of alpha-ketoglutarate is primarily mediated by a Na+-dependent, electrogenic carrier system.
• The findings support the acinar heterogeneity of KG transport, with a predominant localization in the perivenous region of the liver acinus.