Fatty Liver Disease and the UPR

Role of Unfolded Protein Response in fatty liver disease

 

Non-alcoholic fatty liver disease is composed of a spectrum of disorders ranging from simple steatosis, which is relatively benign, to non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. Free fatty acid (FFA) induced cell death is thought to be a critical feature in the progression of NASH, but the underlying mechanisms are not fully understood. We and others demonstrated that induction of endoplasmic reticulum (ER) stress and the ensuing activation of the unfolded protein response (UPR) and its downstream effectors are associated with NASH.  However, their mechanistic roles in FFA-induced hepatotoxicity and the biological networks affected have not yet been resolved. We are employing in vitro and in vivo models to evaluate the role of the UPR in NASH. Our results suggest that saturated FFAs, but not unsaturated FFAs, induce hepatotoxicity coincident with activation of the UPR. Supporting these ideas, we assayed patient liver biopsy samples and found up-regulation of key UPR and downstream cellular markers coincident in NASH patients. These studies involve collaborative efforts between faculty in the basic and clinical sciences and will provide for a better understanding of the role of the UPR in liver diseases, such as NASH.

Electron microscopy showing ultrastructural changes of cultured human hepatocytes following treatment with the saturated free fatty acid, palmitate.  

References:

Fusakio, M.E., Willy, J.A., Wang, Y., Mirek, E.T., Al Baghdadi, R.J.T., Adams, C.M., Anthony, T.G., and Wek, R.C. (2016)  Transcription factor ATF4 directs basal and select induced gene expression in the unfolded protein response and cholesterol metabolism in liver.  Molecular Biology of the Cell 27,1536-1551.

 

Willy, J.A., Young, S.K., Stevens, J.L., Masuoka, H.C., and Wek, R.C. (2015) CHOP links endoplasmic reticulum stress to NF-κB activation in the pathogenesis of Nonalcoholic Steatohepatitis. Molecular Biology of the Cell 26, 2190-2204.

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