RETRACTED: Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy

Abstract

Background & Aims Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis. Methods Wild-type friendly virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signaling were examined. The role of autophagy was evaluated in ADH1-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without autophagy inducer rapamycin and lysosomal inhibitors. Results Chronic alcohol intake led to elevated AST, ALT, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides, hepatic fat deposition as evidenced by H&E and oil Red O staining, associated with disturbed fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, the effects of which were attenuated or ablated by ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100, 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, the effects of which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. Conclusions In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy.

FoxO1‐AMPK‐ULK1 Regulates Ethanol‐Induced Autophagy in Muscle by Enhanced ATG14 Association with the BECN1‐PIK3C3 Complex

“…On the other hand, the lysosomal inhibitor bafilomycin A1 did not modulate the effect of EtOH on LC3B-II or SQSTM1 (data not shown). While this result is in agreement with a report examining HepG2 cells and liver from chronic alcohol-fed mice (Guo et al, 2015), it is in contrast to previous studies in myocytes where there was an additive effect of EtOH and lysosomal inhibitors (Thapaliya et al, 2014, Luo, 2014). Although there is no clear explanation for this discrepancy, it may be due to differences in cell types and/or the inhibitors used in the respective studies.…”

NEFA‐induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non‐alcoholic steatohepatitis

“…37,38 However, Guo et al reported that the AST/ALT ratio was significantly increased in mice fed with 4% alcohol. 39 The discrepancies in the hepatic protein levels of COI-IV and the AST/ALT ratio between previous studies and our study could be due to differences in samples, the degree of hepatic pathological damage, nutritional factors or genetic factors. Impaired mitochondrial OXPHOS complexes further decreased the mitochondrial fatty acid b-oxidation and enhanced TG accumulation.…”

Aldehyde dehydrogenase 2 activation ameliorates CCl4‐induced chronic liver fibrosis in mice by up‐regulating Nrf2/HO‐1 antioxidant pathway

“…Nearly, half of the East‐Asian population possessed the genetic mutation which results in the deficiency of ALDH2 activity . Findings from our laboratory and others revealed a beneficial role of ALDH2 in rescuing against certain diseases, such as ischemia heart disease, alcoholic liver disease and stroke, which might be mediated through regulating oxidation stress, apoptosis and autophagy . Nevertheless, the role of ALDH2 in CCl 4 ‐induced chronic liver fibrosis and the underlying mechanisms remains to be further elucidated.…”