Liver Cell Volume Regulation: Size Matters

Abstract

Liver cells are located in a critical anatomic site, with dual perfusion by both the portal and systemic circulations. Consequently, they are subject to unusually large changes in the concentrations of solutes such as amino acids, bile acids, and glucose between the fed and fasted states. Because these solutes are concentrated intracellularly, and osmolar gradients as low as ϳ1 mosm⅐L Ϫ1 are sufficient to induce transmembrane water movement, liver cell volume can increase by 5% to 10% in response to increased solute uptake. 1 These primary changes in volume are followed after a delay by compensatory increases in membrane ion permeability of 20-fold or more (Fig. 1), and the resulting shift toward net solute efflux represents a critical adaptive response that favors passive water movement and restoration of cell volume toward basal values. 2 Volume recovery is usually incomplete, however, and there is emerging evidence that the small residual differences from baseline, either positive or negative, act as a signal that directly influences a broad range of processes including kinase activation, gene expression, and membrane transport. 3 In this brief review, the emerging evidence supporting the presence of functional interactions between solute transport, intracellular metabolism, and cell volume is explored. Emphasis is placed on the role of ion channels and membrane transport in cell volume regulation, and the evolution of evidence that cell volume as a critical determinant of liver cell and organ function is summarized as well.

Calcium Mobilization Evoked by Hepatocellular Swelling Is Linked to Activation of Phospholipase Cγ

“…Coverslips were washed twice with TBS and rocked overnight at 4°C with PLC␥1 (Tyr-783) antibody and in selected studies with paxillin antibody. Coverslips were washed three times with TBS and rocked for 1 h at room temperature with Cy3-labeled donkey anti-rabbit Ig F(abЈ) 2 and/or Cy5-labeled donkey anti-mouse Ig F(abЈ) 2 (Jackson ImmunoResearch Laboratories). Coverslips were washed three times with TBS and then mounted on slides with Aqua Polymount (Polysciences).…”

“…For example, under physiological conditions, postprandial uptake of amino acids by hepatocytes results in significant swelling, with subsequent recovery of cell volume (1). Physiological recovery of cell volume requires the opening of plasma membrane K ϩ and Cl Ϫ channels with consequent fluid and electrolyte efflux (2). This process provides a safeguard against irreversible swelling, which, in pathological states, is manifested by ballooning degeneration of hepatocytes (3).…”

The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

“…Changes in liver cell hydration are important regulators of hepatic metabolism, gene expression, and transport across the plasma membrane through activation of osmosensing and osmosignaling pathways (1)(2)(3)(4)(5)(6). Hypoosmotic cell swelling involves integrin-dependent osmosensing and osmosignaling via Src kinase and mitogen-activated protein kinases (7,8), resulting in an inhibition of autophagic proteolysis and stimulation of bile acid excretion (7,8).…”

“…Apart from effects on metabolism and gene expression (1)(2)(3)(4)(5)(6), hyperosmotic hepatocyte shrinkage triggers a rapid translocation of intracellular CD95 to the plasma membrane, which is accompanied by DISC 1 formation and sensitizes hepatocytes toward CD95 ligand (CD95L)-induced apoptosis (9,10). Hyperosmotic membrane targeting and activation of CD95 involves rapid activation of the epidermal growth factor receptor (EGFR) and of c-Jun-N-terminal kinases (JNK) (10), an association of activated EGFR and CD95, and subsequent CD95 tyrosine phosphorylation by the EGFR tyrosine kinase activity.…”

Volume-sensitive Tyrosine Kinases Regulate Liver Cell Volume through Effects on Vesicular Trafficking and Membrane Na+ Permeability

“…First, small changes in liver cell volume have been shown to activate multiple signaling pathways in addition to tyrosine kinase (e.g. c-Jun NH 2 -terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and h-sgk) (5,6,22,40). For example, elevation of cytosolic [Ca 2ϩ ] is required for activation of both whole-cell and single NSC channel currents (5,22).…”