SUN-106 Loss of Coordination in the Expression of Hepatic Lipase and Endoplasmic Reticulum Stress Genes in Steatosis

Abstract

The retention of cellular homeostasis is essential for the efficient execution of all biological processes which is reflected to the coordinated expression of genes that belong to same transcriptional networks. During pathology, homeostasis is abolished and cells read just their transcriptional program in a manner according to which several transcripts are being up- or down-regulated. Conventionally, genes exhibiting the highest overexpression or downregulation are considered as the most relevant for disease development. Despite this aberrant expression, coordination of individual genes and certain transcriptional networks is likely retained unless this disturbance of concerted expression is linked to disease development. To test this hypothesis we used induced hepatic steatosis as a model that was inflicted in outbred deer mice (Peromyscus) by high fat/sucrose diet. Our transcriptional analysis focused on genes associated with the unfolded protein response (UPR), lipophagy (ATG5, ATG14 and LAMP1) and lipid metabolism (lipoprotein lipase (LPL), hepatic lipase (HL) or trafficking (low density lipoprotein receptor, LDLR). qPCR studies showed that long-term administration of high-fat diet caused overexpression of all targets tested regardless of the onset of steatosis, suggesting that activation of gene expression was induced by the diet and not by the disease. However, when the coordination with the UPR was analyzed, it was discovered that HL was the only target gene exhibiting coordination with the UPR genes in all liver specimens except those that had evidence of hepatic steatosis. Subsequent studies involving cultured rat hepatocytes showed that during ER stress the expression of HL is suppressed by a manner that involves the PERK arm of the UPR and specifically by CHOP. This effect is likely mediated by the transcription factor HNF4 that is an established activator of HL. These findings illustrate the power of coordination analysis by using genetically diverse disease models. Furthermore, they challenge conventional views on the impact of specific genes in disease and suggest that besides abundance, the maintenance of coordination between transcriptional networks may be equally or even more important for disease development.