Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice.

Endoplasmic reticulum (ER) stress is activated in nonalcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation, and cell death underlie the transition from steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH). B-cell lymphoma 2 (BCL2)-associated X protein (Bax) inhibitor-1 (BI-1), a negative regulator of the ER stress sensor, inositol-requiring enzyme 1 alpha (IRE1α), has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH because of unrestrained IRE1α signaling. ER stress was induced in wild-type and BI-1-/- mice acutely by tunicamycin (TM) injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine NAFLD phenotype. Livers of TM-treated BI-1-/- mice showed IRE1α-dependent NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, hepatocyte death, fibrosis, and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI-1 down-regulation parallel to the up-regulation of IRE1α endoribonuclease (RNase) signaling. In HFD-fed BI-1-/- mice that presented NASH and type 2 diabetes, exaggerated hepatic IRE1α, X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP) expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and alanine transaminase (ALT)/aspartate transaminase (AST) levels revealed significant inflammation and injury, respectively. Pharmacological inhibition of IRE1α RNase activity with the small molecules, STF-083010 or 4µ8c, was evaluated in HFD-induced NAFLD. In BI-1-/- mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF-083010 or 4µ8c. CONCLUSION: Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for NASH. (Hepatology 2018).

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

The global epidemic of obesity has been accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD), with manifestations ranging from simple steatosis to non-alcoholic steatohepatitis, potentially developing into hepatocellular carcinoma. Although much attention has focused on NAFLD, its pathogenesis remains largely obscure. The hallmark of NAFLD is the hepatic accumulation of lipids, which subsequently leads to cellular stress and hepatic injury, eventually resulting in chronic liver disease. Abnormal lipid accumulation often coincides with insulin resistance in steatotic livers and is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. In response to chronic ER stress, an adaptive signalling pathway known as the unfolded protein response is triggered to restore ER proteostasis. However, the unfolded protein response can cause inflammation, inflammasome activation and, in the case of non-resolvable ER stress, the death of hepatocytes. Experimental data suggest that the unfolded protein response influences hepatic tumour development, aggressiveness and response to treatment, offering novel therapeutic avenues. Herein, we provide an overview of the evidence linking ER stress to NAFLD and discuss possible points of intervention.

[Endoplasmic reticulum stress response and pathogenesis of non-alcoholic steatohepatitis]. / La réponse au stress du réticulum endoplasmique dans la physiopathologie des maladies chroniques du foie.

The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. Non-alcoholic fatty liver disease (NAFLD) is currently affecting 20-30% of the general population and 75-100% of obese individuals. NAFLD ranges from simple steatosis to damaging non-alcoholic steatohepatitis (NASH), potentially developing into hepatocellular carcinoma. No efficient pharmacological treatment is yet available. During obesity, the hepatic ER stress response can arise from extracellular stress (lipids, glucose, cytokines) and from intracellular stress including lipid buildup in the hepatocyte (steatosis), a hallmark of NAFLD. The chronic activation of the hepatic ER stress response may be a crucial event in the steatosis-NASH transition, triggering cell death, inflammation and accelerating metabolic disorders. We discuss these aspects and we propose that targeting the ER stress response could be effective in treating NAFLD.

TITLE: La réponse au stress du réticulum endoplasmique dans la physiopathologie des maladies chroniques du foie. ABSTRACT: La prévalence des maladies chroniques du foie ne cesse d'augmenter, du fait de la pandémie de l'obésité. Ces maladies s'étendent de la bégnine stéatose à la stéatopathie non alcoolique (NASH) qui peut évoluer vers le carcinome hépatocellulaire. Il n'existe pas de traitement pour ces maladies. La transition stéatose-NASH apparaît déterminante dans leur progression. Au cours de l'obésité, l'activation chronique de la réponse au stress du réticulum endoplasmique (RE) jouerait un rôle crucial dans cette transition, conduisant à la mort cellulaire, à l'inflammation et à l'aggravation des désordres métaboliques. Dans cette revue, nous discutons ces aspects et proposons que le ciblage de cette réponse au stress du RE puisse être pertinent dans la prise en charge thérapeutique de la NASH.

BAX inhibitor-1: between stress and survival.

Cellular gatekeepers are essential to maintain order within a cell and anticipate signals of stress to promote survival. BCL2 associated X, apoptosis regulator (BAX) inhibitor-1 (BI-1), also named transmembrane BAX inhibitor motif containing-6, is a highly conserved endoplasmic reticulum (ER) transmembrane protein. Originally identified as an inhibitor of BAX-induced apoptosis, its pro-survival properties have been expanded to include functions targeted against ER stress, calcium imbalance, reactive oxygen species accumulation, and metabolic dysregulation. Nevertheless, the structural biology and biochemical mechanism of action of BI-1 are still under debate. BI-1 has been implicated in several diseases, including chronic liver disease, diabetes, ischemia/reperfusion injury, neurodegeneration, and cancer. While most studies have demonstrated a beneficial role for BI-1 in the ubiquitous maintenance of cellular homeostasis, its expression in cancer cells seems most often to contribute to tumorigenesis and metastasis. Here, we summarize what is known about BI-1 and encourage future studies on BI-1's contribution to cellular life and death decisions to advocate its potential as a target for drug development and other therapeutic strategies.

Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer's Disease.

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid ß (Aß) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated ß-amyloid precursor protein (ßAPP) or treated with Aß oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aß through specific increases of ß-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and ßAPP-derived fragments that could contribute to AD setting and/or progression.