Dual proteotoxic stress accelerates liver injury via activation of p62‐Nrf2

Abstract

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein‐secretory organ. For example, aggregation of mutated alpha1‐antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs‐PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs‐PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62‐containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin‐2. p62 build‐up led to activation of the p62–Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62–Nrf2 axis. In humans, the PiZ variant was over‐represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15–85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Alpha-1 antitrypsin deficiency: A re-surfacing adult liver disorder

“…32 Finally, the mouse model was instrumental to investigate the role of cofactors in the modulation of liver disease. In that respect, overexpression of hepatitis B surface protein, as seen in individuals with chronic hepatitis B infection, was found to aggravate liver injury, fibrosis, and the frequency of hepatocellular carcinoma in Pi*Z mice, 33 while the mild iron accumulation seen in homeostatic iron regulator (Hfe) gene knockout animals did not have a significant effect. 34 Notably, administration of the nonsteroidal anti-inflammatory drug indomethacin increased liver damage via activation of the IL-6-STAT-3 pathway in Pi*Z mice.…”

Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression

“…Serum proteins are produced in the ER before being secreted into the bloodstream through the Golgi apparatus. A large network of chaperones, foldases, and cofactors, such as the calnexin–calreticulin system and binding immunoglobulin protein, are responsible for facilitating protein folding and quality control in the ER 29,30 …”

“…A large network of chaperones, foldases, and cofactors, such as the calnexin-calreticulin system and binding immunoglobulin protein, are responsible for facilitating protein folding and quality control in the ER. [29,30] Accumulation of abnormal proteins leads to ER stress, which engages the "unfolded protein response". Irreversible ER stress results in the apoptosis of damaged cells through various mechanisms.…”

Anti‑inflammation treatment for protection of hepatocytes and amelioration of hepatic fibrosis in rats

“…The deregulation of autophagy has been associated with several liver diseases and its regulation has been recognized as a potential novel treatment strategy (39). However, the results of studies investigating the effects of autophagy on liver fibrosis or cirrhosis are contradictory (40)(41)(42)(43)(44). A number of studies have suggested that autophagy prevents the development of liver fibrosis (41,44).…”

“…A number of studies have suggested that autophagy prevents the development of liver fibrosis (41,44). On the other hand, other studies have demonstrated that autophagy promotes the progression of hepatic fibrosis (42,43). The aforementioned studies suggested that autophagy could regulate multiple biological processes that affect the onset hepatic fibrosis.…”