Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and Humans

Abstract

Chronic plus binge alcohol impaired transcription factor EBmediated lysosomal biogenesis in the mouse pancreas, resulting in insufficient autophagy and pancreatitis. Genetic deletion or overexpression of transcription factor EB in the mouse pancreas exacerbated or protected against alcoholinduced pancreatic damage. BACKGROUND & AIMS: Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis. METHODS: Using a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice. RESULTS: We found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues. CONCLUSIONS: our results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcoholinduced pancreatitis.

S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis

“…The protein levels of autophagy related 7 (ATG7) and LC3-phosphatidylethanolamine conjugate (LC3-II), 2 widely used autophagy markers, were consistently and notably up-regulated under S100A11 overexpression both in vivo ( Figure 8 C and D ) and in vitro ( Figure 8 F and G ). Another autophagic protein, the widely used P62, 48 was decreased significantly in the S100A11 overexpression Hepa 1–6 cells ( Figure 8 I and J ) and Hep 3B cells ( Figure 9 A and B ), indicating an activated autophagic status. Similarly, the mRNA levels of some of the autophagic genes, such as Atg5 and Atg7 , were slightly but significantly increased in the CON + S100A11 group compared with the CON + GFP group ( Figure 9 C–E ).…”

The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source

“…53 There are recent reports of TFEB in lysosomal biogenesis during pancreatitis. 54,55 Further work is required to investigate the role of calcineurin substrates in transducing calcium-calcineurin signals during pancreatic acinar cell injury.…”

FLCN Gene Ablation Reduces Fibrosis and Inflammation in a Diet-Induced NASH Model

“…Interestingly, previous groups demonstrated a role for both TFEB and TFE3 in the regulation of lipid metabolism and energy homeostasis in the liver, where TFEB and TFE3 overexpression was sufficient to reverse weight gain and metabolic syndrome in diet-induced and genetic models of obesity, while TFEB/TFE3 deficiency aggravated the phenotype [39,65]. TFEB overexpression also protected from liver damage in alcohol-induced pancreatitis and alcoholic steatohepatitis mouse models [66,67]. We have previously shown that loss of FLCN in C. elegans and mammalian cells increased innate immune response in a process dependent on TFEB and TFE3 [43].…”