Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol‐impaired TFEB and liver injury in mice

Abstract

Background Recent evidence demonstrates that alcohol activates the mechanistic target of rapamycin (mTOR) and impairs hepatic transcription factor EB (TFEB) reducing autophagy and contributing to alcohol‐induced liver injury. Trehalose, a disaccharide, activates TFEB and protects against diet‐induced nonalcoholic fatty liver disease in mice. The aim of the present study was to investigate whether trehalose would reverse the impairment of TFEB induced by alcohol and protect against alcohol‐induced liver injury. Methods Male C57BL/6J mice were subjected to chronic‐plus‐binge (Gao‐binge) alcohol feeding with and without trehalose supplementation. Some mice were also administrered Alda‐1, an aldehyde dehydrogenase 2 agonist. Results We found that Alda‐1 did not affect Gao‐binge alcohol‐induced mTOR activation and impaired TFEB in mouse livers. Trehalose increased TFEB nuclear translocation, elevated levels of LC3‐II and lysosomal proteins in mouse livers and cultured AML12 cells, confirming the activation of TFEB by trehalose. However, trehalose did not improve the impairment in TFEB induced by Gao‐binge alcohol. Both Alda‐1 and trehalose failed to protect against Gao‐binge alcohol‐induced steatosis and liver injury, based on the serum levels of alanine aminotransferase (ALT), histological analysis, and levels of hepatic triglyceride. Interestingly, trehalose increased expression of pro‐inflammatory genes in mouse macrophage RAW264.7 cells and slightly increased the infiltration of hepatic neutrophils and inflammatory cytokine gene expression in Gao‐binge alcohol‐fed mice livers. Conclusions Trehalose fails to improve the impaired TFEB induced by Gao‐binge alcohol and does not protect against alcohol‐induced liver injury.

Polydatin attenuates chronic alcohol consumption-induced cardiomyopathy through a SIRT6-dependent mechanism

“…30–32 However, there is considerable inconsistency in the previous literature concerning alcohol-induced alteration in mTOR signaling. For example, alcohol-induced mTOR activation was reported in an alcoholic liver disease model, 42–44 fetal alcohol spectrum disorders, 45 fetal brain tissue, 46,47 gastric mucosa 48,49 and importantly, the chronic alcohol-induced cardiac fibrotic model, 50 while the inhibitory effect of alcohol on tissue mTOR signaling was also documented in multiple studies. 51,52 It has been revealed that the inconsistency might result from whether the alcohol intake was conducted in an acute or chronic manner.…”

“…[30][31][32] However, there is considerable inconsistency in the previous literature concerning alcohol-induced alteration in mTOR signaling. For example, alcohol-induced mTOR activation was reported in an alcoholic liver disease model, [42][43][44] fetal alcohol spectrum disorders, 45 fetal brain tissue, 46,47 gastric mucosa 48,49 and importantly, the chronic…”

Trehalose Activates Hepatic and Myocardial Autophagy and Has Anti-Inflammatory Effects in db/db Diabetic Mice

“…The mechanisms underlying the protective influence of trehalose include activation of hepatic transcription factor EB (TFEB); it was reported that trehalose protects against diet-induced nonalcoholic fatty liver disease in mice [ 79 ]. Namely, trehalose enhanced TFEB nuclear translocation and upregulated LC3-II and lysosomal proteins in the mouse liver (thereby confirming the activation of TFEB by trehalose).…”

High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice

“…When cells were incubated with salinomycin or torin 1, DMEM/F-12 medium supplemented with 10% FBS and 1% l -glutamine and penicillin/streptomycin was used. Stable expressing pEGFP-TFEB AML12 cell line was established and cultured as previously described 24 . Fluorescence images were acquired using a fluorescence microscope (Nikon Eclipse 200) with MetaMorph software.…”