Identification of betaine as an osmolyte in rat liver macrophages (Kupffer cells)

Background & Aims: Anisosmotic cell volume changes were identified recently as a critical factor in the regulation of eicosanoid formation in stimulated liver macrophages (Kupffer cells). Therefore, the aim of this study was to investigate whether osmolytes are involved in the control of Kupffer cell function. Methods: Cultured rat liver macrophages (Kupffer cells) were studied with respect to their functional adaptation to hyperosmotic environments. Results: Hyperosmotic exposure of lipopolysaccharide-stimulated Kupffer cells led to sevenfold stimulation of prostaglandin E(2) formation caused by a strong induction of cyclooxygenase 2. Hyperosmotic exposure was accompanied by approximately a 10-fold increase of Na+-dependent betaine uptake and betaine transporter-messenger RNA levels. Conversely, hypoosmotic exposure decreased betaine uptake and stimulated betaine release from Kupffer cells and the perfused rat liver. Addition of betaine (1 mmol/L) to hyperosmotically exposed Kupffer cells abolished the strong induction of cyclooxygenase 2 and the increase of prostaglandin E(2) formation. Conclusions: This study identifies the use of an osmolyte strategy in liver macrophages. Betaine serves as an osmolyte in Kupffer cells, whose transport is induced in response to increases of ambient osmolarity. Regulation of this transporter as well as betaine availability may represent a novel regulatory site for Kupffer cell function.