Abstract 1567: Visceral Obesity Caused by Overexpressing SREBP-1c in Liver
Sterol regulatory element binding protein (SREBP)-1c is a key transcription factor that mediates the gene regulatory effects of hormones, cytokines, metabolites as lipids or glucose as well as cholesterol. The systemic impact of this central regulator of lipid metabolism in vivo was analyzed in transgenic mouse models expressing the N-terminal transcriptional active domain of SREBP-1c tissue specifically in liver and adipose tissue, respectively. Animals were kept under standardized conditions with regular chow until the age of 24 weeks. Macroscopic examinations revealed that overexpression of SREBP-1c in adipose tissue results in a complete loss of adipose tissue, i.e. features of lipodstropy with parallel development of massive fatty livers. In contrast, liverspecific overexpression of SREBP-1c results in massively increased amount of visceral adipose tissue featuring a fatty liver with hepatic lipid accumulation. Both models have elevated serum lipid parameters and signs of insulin resistance. Following liver resection histological and gene expression studies were performed (Mouse 430 2.0, (Affymetrix); 2-fold regulation (p=0.01) (Genespring, Agilent)). In the lipodystrophic mice genes for lipid peroxidation, transport and degradation of oxidized lipids being essential in neutralization of oxidative metabolic products, e.g. ATP-transporter as ABCA1, are differentially regulated in the liver indicating both, increased anabolism and catabolism of lipids. In contrast to that, in the fatty liver model genes for lipid and energy-metabolism like mitochondrial NADH-dehydrogenase, aldehyd-dehydrogenases next to various sterol carrier proteins or cytochrome subunits were regulated indicating increased lipid anabolism but reduced catabolism. These mouse models allow the elucidation of the pathogenetic role of the transcription factor SREBP-1c, but also the investigation of different pathophysiological mechanisms of lipid accumulation in liver and their implications for metabolism.