The 2-series prostaglandins suppress VLDL secretion in an inflammatory condition-dependent manner in primary rat hepatocytes Silvia Pérez, Patricia Aspichueta, Begoña Ochoa ⁎ , Yolanda Chico Department of Physiology, University of the Basque Country Medical School, P.O. Box 699, 48080-Bilbao, Spain Received 14 June 2005; received in revised form 13 January 2006; accepted 7 February 2006 Available online 3 March 2006 Abstract In the liver, prostaglandins (PG) generated mainly by activated non-parenchymal cells can modulate the parenchymal cell function during homeostasis and inflammation. Whether prostaglandins regulate the hepatocyte VLDL assembling/secretor phenotype in both conditions remains unresolved. We sought to determine whether and how PGE 2 , PGD 2 , and PGF 2α (5 and 50 μM) have a role in VLDL secretion regulation in resting and interleukin-6 (IL-6) stimulated rat hepatocytes. Prostaglandins led to comparable, concentration-dependent reductions in the secretion of VLDL apoB and lipids by resting, 24 h-cultured cells. Moreover, each apoB copy recruited less of each lipid class, correlating with reduced particle size, lipogenesis and cholesterogenesis, and impaired cellular triacylglycerol recycling. Triacylglycerol output reduction occurred early, as the transient PGD 2 - and PGF 2α -promoted apoB mRNA decreases. IL-6 markedly increased the apoB mRNA expression and the secretion of its protein in triacylglycerol-poor VLDL. The latter was uniquely blunted by PGE 2 , which unaffected basal or IL-6-activated apoB gene expression. Collectively, our findings show inflammation condition-based roles for 2-series-prostaglandins in VLDL secretion modulation. Whereas in non- stimulated hepatocytes, they all inhibited VLDL-apoB output, interfered with lipid provision for lipoprotein assembly and may be regarded as pro- steatotic, the anti-inflammatory PGE 2 antagonized the IL-6-promoted VLDL secretion contributing in restoring liver homeostasis. © 2006 Elsevier B.V. All rights reserved. Keywords: Triacylglycerol secretion; Cholesteryl ester metabolism; Hepatocyte gene expression; VLDL secretion; Acute-phase reaction control 1. Introduction After various insults, such as inflammation, trauma and infection, a cascade of reactions occurs in the host collectively known as the acute-phase response (APR). The APR is triggered and sustained by pro-inflammatory cyto- kines produced by the monocyte/macrophage system and by Kupffer cells in the liver. The interleukin (IL)-6 is the major inducer of acute-phase protein (APP) gene expression in hepatocytes [1,2]. For the APR to be resolved, it is essential that the stimulation of target parenchymal liver cells ceases and that their biosynthetic profile and metabolic activity return to normal. Acting through paracrine mechanisms, the prostanoids that are massively produced by liver sinusoidal cells under conditions of inflammation modulate the hepato- cyte function. Prostaglandin (PG) D 2 followed by PGE 2 and PGF 2α are the three major products of arachidonic acid- cyclooxygenase in activated endothelial and Kupffer cells in culture [3]. From among them, PGE 2 has been implicated in the attenuation of the IL-6-induced hepatocyte APR via the Gs-coupled prostaglandin receptor subtypes EP2 and EP4 [4]. These receptors are poorly expressed in resting hepatocytes in the normal liver, but abound on IL-6-activated hepatocyte membranes [5,6]. Profound alterations in lipid and lipoprotein metabolism are associated with the APR [7–9]. Septic hypertriglyceridemia is mainly caused by the accumulation of VLDL particles in the plasma [10] due to many changes in their metabolism, including increased secretion by the liver [11] and defective peripheral clearance of triacylglycerol (TAG)-rich lipoproteins (for a recent review, see [9]). Many of the alterations occurring during the APR can be simulated by cytokines, in vivo and in vitro. For example, administration of IL-6 to rodents results in hyper- triglyceridemia, stimulation of adipose tissue lipolysis and fatty Biochimica et Biophysica Acta 1761 (2006) 160 – 171 http://www.elsevier.com/locate/bba ⁎ Corresponding author. Fax: +34 946015662. E-mail address: begona.ochoa@ehu.es (B. Ochoa). 1388-1981/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2006.02.003