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,...

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Bibliographic Details
Published in:Journal of hepatology 2018-10, Vol.69 (4), p.927-947
Main Authors: Lebeaupin, Cynthia, Vallée, Deborah, Hazari, Younis, Hetz, Claudio, Chevet, Eric, Bailly-Maitre, Béatrice
Format: Article
Language:English
Subjects:
Cancer
Cell death
Cellular stress response
Endoplasmic reticulum
Endoplasmic Reticulum Stress
Fatty liver
Hepatocellular carcinoma
Hepatocytes
Human health and pathology
Hépatology and Gastroenterology
Inflammasomes
Inflammation
Insulin
Life Sciences
Lipids
Liver
Liver Cancer
Liver diseases
Obesity
Pathogenesis
Protein folding
Signal transduction
Steatohepatitis
Steatosis
Therapeutic Targets
Tumors
Unfolded Protein Response
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Summary: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.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2018.06.008