The endoplasmic reticulum as a potential therapeutic target in nonalcoholic fatty liver disease

Abstract

The endoplasmic reticulum (ER) has emerged as a key to understanding the development and consequences of hepatic fat accumulation in nonalcoholic fatty liver disease (NAFLD). An essential function of this organelle is the proper assembly of proteins that are destined for intracellular organelles and the cell surface. Recent evidence suggests that chemical chaperones that enhance the functional capacity of the ER improve liver function in obesity and NAFLD. These chaperones may therefore provide a novel potential therapeutic strategy in NAFLD.

Figure 1. Simplified illustration of three proximal stress sensors, and putative targets involved in the unfolded protein response

In mammals, stress in the endoplasmic reticulum (ER) is sensed and the unfolded protein response (UPR) is activated by three ER transmembrane proteins: PERK (RNA-dependent protein kinase-like ER eukaryotic initiation factor-2α kinase), ATF6 (activating transcription factor 6), and IRE1 (inositol-requiring ER-to-nucleus signaling protein 1). Activation, as a result of UPR initiation, leads to increased translation and expression of ATF4 (activating transcription factor 4) through phosphorylation of eIF2α (eukaryotic initiation factor 2α). ATF6 is transported to the Golgi, where it is cleaved into a 50-kDa fragment, which then migrates to the nucleus and activates target genes. IRE1 activation leads to splicing of XBP1 (X-box-binding protein-1) and subsequent transcription of molecular chaperones [eg, GRP78 (78-kDa glucose-regulated protein)]. ATF3 activating transcription factor 3, CHOP CCAAT/enhancer binding homologous protein, EDEM ER degradation-enhancing α-mannosidase, GADD34 growth arrest and DNA damage-inducible transcript 34, GRP94 94-kDa glucose-regulated protein. (Reproduced with permission from Elsevier and Gentile CL, Pagliassotti MJ: The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem (2008) 19(9):567-576 © 2008 Elsevier.)