Transcriptional changes impact hepatic proteome in autophagy-impaired liver

Hepatic proteomes are finely regulated by their biosynthesis, extracellular secretion, and intrahepatic degradation. Autophagy regulates the lysosome mediated intrahepatic degradation and regulates the hepatic proteome. Impaired autophagy results in intrahepatic protein accumulation resulting in proteinopathy. Through this study, we aim to determine whether autophagy can also modulate hepatic proteome in a non-degradative manner. With conditional, inducible, and hepatotoxin models of hepatic autophagy impairment, we analyzed the expression status of the overall hepatic proteome by Coomassie brilliant blue (CBB) and Liquid chromatography tandem mass spectrometry (LC/MS). We identified and validated four specific hepatic proteins- Cps1, Ahcy, Ca3, and Gstm1 that were selectively altered in the autophagy-impaired liver. Cps1, Ahcy, and Ca3 protein expressions were dramatically downregulated while Gstm1 protein expression was upregulated in autophagy-impaired livers. Notably, the altered level of these hepatic proteins was not related to impaired autophagic degradation rather it was related to the change in the mRNA transcript level. In addition, persistent activation of nuclear factor erytheroid-derived-2-like 2 (Nrf2) transcription factor due to autophagic impairment transcriptionally regulates the mRNA expression of these hepatic proteins. Out results suggest that autophagy can regulate hepatic protein through non-degradative transcriptional mechanisms by regulating Nrf2.