Abstract
Nonalcoholic fatty liver disease (NAFLD) is categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) and has emerged as a risk factor for more critical clinical conditions. However, the underlying mechanisms of NAFLD pathogenesis are not fully understood. In this study, expression of proteins associated with endoplasmic reticulum (ER) stress, apoptosis and autophagy were analyzed in normal, NAFL and NASH human livers by western blotting. Levels of some ER stress-transducing transcription factors, including cleaved activating transcription factor 6, were higher in NASH than in the normal tissues. However, the expression of a majority of the ER chaperones and foldases analyzed, including glucose-regulated protein 78 and ER protein 44, was lower in NASH than in the normal tissues. Levels of apoptosis markers, such as cleaved poly (ADP-ribose) polymerase, were also lower in NASH tissues, in which expression of some B-cell lymphoma-2 family proteins was up- or down-regulated compared to the normal tissues. The level of the autophagy substrate p62 was not different in NASH and normal tissues, although some autophagy regulators were up- or down-regulated in the NASH tissues compared to the normal tissues. Levels of most of the proteins analyzed in NAFL tissues were either similar to those in one of the other two types, NASH and normal, or were somewhere in between. Together, these findings suggest that regulation of certain important tissues processes involved in protein quality control and cell survival were broadly compromised in the NAFLD tissues.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a pathological condition histologically categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) [1]
These findings suggest that regulation of certain important tissues processes involved in protein quality control and cell survival were broadly compromised in the NAFLD tissues
Enhanced expression of transcription factors associated with endoplasmic reticulum (ER) stress in NASH tissues Expression of three ER stress-responsive transcription factors was analyzed in NASH, NAFL and normal liver tissues by western blotting (Figure 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) is a pathological condition histologically categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) [1]. NAFLD can progress to cirrhosis and end-stage liver diseases such as hepatocellular carcinoma [2, 3]. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress, which triggers an adaptive response called the unfolded protein response (UPR) to restore ER homeostasis [4]. The UPR pathway is required to maintain hepatic lipid metabolism [5]. The UPR is coordinated primarily by three ER transmembrane stress transducers, protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol requiring enzyme 1 (IRE1). Prolonged ER stress leads to PERK signalingmediated upregulation of C/EBP homologous protein (CHOP), a pro-apoptotic transcription factor [6, 7]
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