Pharmacological ER stress promotes hepatic lipogenesis and lipid droplet formation

Endoplasmic Reticulum (ER) stress refers to a condition of accumulation of unfolded or misfolded proteins in the ER lumen. A variety of biochemical stimuli or pathophysiologic conditions can directly or indirectly induce ER stress, leading to activation of an ER-originated adaptive signaling response called Unfolded Protein Response (UPR). Recent studies demonstrated that ER stress and UPR signaling are critically involved in the initiation and progression of many diseases, such as metabolic disease, cardiovascular disease, neurodegenerative disease, and cancer. In this study, we show that ER stress induced by pharmacologic reagents, including tunicamycin (TM) and thapsigargin (Tg), promotes hepatic lipogenesis and lipid droplet formation. Using quantitative gene expression analysis, we identified 3 groups of key lipogenic regulators or enzymes that are inducible by pharmacological ER stress in a human hepatoma cell line Huh-7. These ER stress-inducible lipogenic factors include: 1) lipogenic trans-activators including CCAAT/ enhancer binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coacti-vator 1-alpha (PGC1α), and Liver X receptor alpha (LXRα); 2) components of lipid droplets including fat-specific protein 27 (FSP27), adipose differentiation related protein (ADRP), fat-inducing transcript 2 (FIT2), and adipocyte lipid-binding protein (AP2); 3) key enzymes involved in de novo lipogenesis including acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase-1 (SCD1). Supporting the role of pharmacologic ER stress in up-regulating de novo lipogenesis, TM or Tg treatment significantly increased accumulation of cytosolic lipid droplet formation in the hepatocytes. Moreover, we showed that forced expression of an activated form of X-box binding protein 1 (XBP1), a potent UPR trans-activator, can dramatically increase expression of PPARγ and C/EBPα in Huh-7 cells. The identification of ER stress-inducible lipogenic regulators provides important insights into the molecular basis by which acute ER stress promotes de novo lipogenesis. In summary, the findings from this study have important implication in understanding the link between ER stress and metabolic disease.