Adenovirus‐mediated hepatic syndecan‐1 overexpression induces hepatocyte proliferation and hyperlipidaemia in mice

Abstract

Heparan sulfate proteoglycans (HSPGs) have been involved in the regulation of cell growth, apoptosis and lipid metabolism in vitro; however, their functional role in vivo remains unknown. Here, we describe hepatic tissue and lipid metabolism changes after liver overexpression of syndecan-1 (SDC-1), the main hepatic HSPG, in mice induced by adenoviral gene transfer. SDC-1 overexpression was associated with marked hepatocyte proliferation, cell-isolated apoptosis and increased plasma alanine aminotransferase (ALT) levels. Additionally, SDC-1 liver overexpression significantly raised plasma cholesterol and triglyceride concentrations due to an increase in all lipoprotein particles, including the appearance of large and apolipoprotein (apo) E-enriched high-density lipoprotein (HDL) particles. Hepatic very low-density lipoprotein (VLDL) production was not affected by SDC-1 overexpression, suggesting a delayed plasma clearance of apo B lipoproteins as the underlying hyperlipidaemic mechanism. These pleotropic effects were qualitatively equivalent, even though less intense, in mice overexpressing a cytoplasmic C-terminal domain-deleted SDC-1. This is the first report in vivo of the biological effects induced by a specific HSPG in the liver, with potential implications in both regenerative biology and molecular lipidology.