Dysregulated expression of proteins associated with ER stress, autophagy and apoptosis in tissues from nonalcoholic fatty liver disease

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.

Unfolded Protein Response Sensors in Hepatic Lipid Metabolism and Nonalcoholic Fatty Liver Disease

“…106 In addition to enhanced CHOP expression, human NASH was found to be associated with decreased expression of adaptive proteins and ER chaperones suggesting preferential activation of the proapoptotic UPR in advanced stages of NAFLD. 107 Another study, however, found that human NASH is associated with the induction of adaptive proteins but not CHOP or other proapoptotic proteins. 40 Furthermore, there have been conflicting reports on the effect of Chop deletion on the development of murine steatohepatitis.…”

Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease

“…Normalization of ER stress markers correlated with weight loss and reduced hepatic lipid content after bariatric surgery (54). Furthermore, activation of the UPR was observed in the livers of obese patients with NASH as well as in mice fed a methionine-cholinedeficient diet (MCDD) exhibiting NASH features without obesity (55)(56)(57)(58). A direct activation of the IRE1α-XBP1 branch was observed in vivo during the development of insulin resistance in the liver (59).…”

Taurine alleviates endoplasmic reticulum stress in the chondrocytes from patients with osteoarthritis

“…Perturbations of intracellular calcium homeostasis cause the accumulation of misfolded and/or unfolded proteins in the ER, leading to a state known as ER stress. ER stress has been reported to be involved in ischemia reperfusion, diabetes mellitus, liver disease, kidney disease and neuro-degenerative disease [13,[21][22][23][24]. In addition, a large number of studies have proved that ER stress is also associated with chondrocyte death by apoptosis in vivo and in vitro [6,14].…”