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.
Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for NASH. (Hepatology 2018).
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.
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 β (Aβ) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated β-amyloid precursor protein (βAPP) or treated with Aβ oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aβ through specific increases of β-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and βAPP-derived fragments that could contribute to AD setting and/or progression.
With the prevalence of obesity increasing worldwide, nonalcoholic fatty liver disease (NAFLD) has become the most common form of chronic liver disease. Despite this, knowledge about the molecular mechanisms involved in NAFLD progression is still limited. Recent findings have shown that endoplasmic reticulum (ER) stress links inflammation and hepatocyte death, inherent to the transition from simple steatosis to nonalcoholic steatohepatitis (NASH). Here, we emphasize the central role of the ER stress response and its crosstalk with the inflammasome. We hope to provide new insight on the identification of ER stress-dependent pathways that contribute substantially to chronic liver disease progression as important triggers of cell death and inflammation, and therefore may represent potential therapeutic strategies.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.