Nascent proteome reveals key regulators in the development of alcoholic liver disease

ABSTRACT: Alcoholic liver disease (ALD) poses a significant global health challenge, and the global proteome will change dynamically and dramatically for the response to alcohol stress. However, due to the lack of method for labeling and identification of tissue-specific nascent proteome in living mouse, the underlying molecular mechanism of the pathogenesis remains poorly understood. Here, we developed the stochastic orthogonal recoding of translation induced by AAV-delivered Cre (SORT-AC) strategy to precisely identify the nascent proteome in the hepatocyte of living mice. We applied this strategy to investigate the nascent proteome and underlying molecular mechanism in ALD mouse model. We identified 187 newly synthesized proteins involved in protein and metabolite processing in liver of ALD model mice. We found that upregulated Phb1/2 is responsible for the transcription of ethanol metabolism related genes and the downstream substrate, Hsp family proteins were responsible to protect from misfolded protein aggregation. Another downstream substrate of Phb1/2, Acsl1/5 participated in the lipid accumulation. Furthermore, the inhibition of Acsl1/5 protected cultured cells and mice from lipid accumulation by alcohol exposure, which might be a brand-new therapeutic target to antagonist the hepatocyte damage of ALD. More broadly, these results pave the new way for the nascent proteome investigation in living animal models in a tissue-specific manner.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Shixian Lin  

PROVIDER: PXD051725 | iProX | Tue May 20 00:00:00 GMT+01:00 2025

REPOSITORIES: iProX