Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice

Abstract

The endoplasmic reticulum (ER) chaperone protein glucose-regulated protein 78 (GRP78)/binding immunoglobulin protein is a master regulator of ER homeostasis and stress responses, which have been implicated in the pathogenesis of metabolic disorders. By applying the locus of X-over P1-cyclization recombination strategy, we generated mice with liver-specific GRP78 loss. Our studies using this novel mouse model revealed that liver GRP78 was required for neonatal survival, and a loss of GRP78 in the adult liver greater than 50% caused an ER stress response and dilation of the ER compartment, which was accompanied by the onset of apoptosis. This suggested the critical involvement of GRP78 in maintaining hepatocyte ER homeostasis and viability. Furthermore, these mice exhibited elevations of serum alanine aminotransferase and fat accumulation in the liver, and they were sensitized to a variety of acute and chronic hepatic disorders by alcohol, a high-fat diet, drugs, and toxins. These disorders were alleviated by the simultaneous administration of the molecular chaperone 4-phenylbutyrate. A microarray analysis and a two-dimensional protein profile revealed major perturbations of unfolded protein response targets, common enzymes/factors in lipogenesis, and new factors possibly contributing to liver steatosis or fibrosis under ER stress (e.g., major urinary proteins in the liver, fatty acid binding proteins, adipose differentiation-related protein, cysteine-rich with epidermal growth factor-like domains 2, nuclear protein 1, and growth differentiation factor 15). Our findings underscore the importance of GRP78 in managing the physiological client protein load and suppressing apoptosis in hepatocytes, and they support the pathological role of ER stress in the evolution of fatty liver disease under adverse conditions (i.e., drugs, diet, toxins, and alcohol).