When it comes to liver disease, it seems most of the attention (and research) goes to the variety that is associated with the consumption of alcohol. While that’s a big concern for those of us enjoy the occasional adult beverage, it’s left non-alcoholic fatty liver disease (NAFLD) under-studied.
But now that’s changing. According to Rui Castro at the University of Lisbon (Portugal) “Our laboratory has been dedicating much effort in elucidating the molecular pathogenesis of NAFLD, in the hope of discovering key targets that may contribute for the development of a suitable therapeutic strategy. In fact, there is currently no proven pharmacological treatment of NAFLD, in part due to the poor understanding of the underlying mechanisms for its pathological progression.”
Castro and his team explored the epigenetic mechanisms of NAFLD and have recently shown that miRNAs have a thing or two teach us about the progression of non-alcoholic liver diseases. The team showed that hepatic expression of miRNAs is modulated with NAFLD severity and recalled an earlier study of theirs showing that patients also display higher levels of deoxycholic acid (DCA), an endogenous apoptotic bile acid, and that the accumulation of bile acids contribute to apoptosis, liver injury and failure.
The Portuguese group wanted to further dissect the mechanism(s) responsible for p53/miR-34a activation in hepatocytes, and chose c-Jun N-Terminal Kinase (JNK) as a possible upstream regulator worth studying. “Therefore, we asked whether JNK could be responsible for either DCA-dependent (a) and/or –independent (b) activation of the miR-34a pro-apoptotic pathway in primary rat hepatocytes.” explained Castro. Here’s what they discovered:
- DCA activates the miR-34a/SIRT1/p53 pro-apoptotic pathway in primary rat hepatocytes, in a dose- and time-dependent manner.
- miR-34a inhibition and Sirtuin-1 (SIRT1) overexpression significantly rescued targeting of the miR-34a pathway and apoptosis by DCA.
- DCA increased p53 expression as well as p53 transcriptional activation of PUMA and miR-34a itself, providing a functional mechanism for miR-34a activation. JNK1 and c-Jun were shown to be major targets of DCA, upstream of p53, in engaging the miR-34a pathway and apoptosis. Further, sole activation of the miR-34a pro-apoptotic pathway is also JNK1-dependent.
- To put the icing on the cake, the team also showed that activation of this JNK1/miR-34a proapoptotic circuit occurs in vivo in the rat liver.
Castro shares that “Importantly, our findings also support a role for the JNK1/c-Jun-mediated activation of the p53/miR-34a/SIRT1 circuit during apoptosis by DCA in vivo, attesting to the physiological relevance of this pathway. Based on these findings, it may be hypothesized that activation of miR-34a-dependent cytotoxicity by DCA may play an important role in liver disease.”
Go check out how much JNK is in your liver over at Molecular and Cellular Biology, February 2014