Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in non-alcoholic steatohepatitis and reversed by alternate day fasting

Abstract

Although general translation declines during fasting, maintaining the translation of a subset or proteins is necessary for metabolic homeostasis and cell viability. Using unbiased proteome analysis of hepatic cells during starvation, we identified a novel pathway in which Esrra-mediated transcription of Rplp1-dependent translation of lysosomal proteins declined during early starvation and recovered after prolonged starvation to restore autophagy-lysosome function. Interestingly, hepatic Esrra-Rplp1-dependent translation rate of lysosomal proteins also was impaired in patients and mice with non-alcoholic steatohepatitis (NASH), and translational response to starvation was dysregulated in mice with NASH. Remarkably, activation of Esrra pharmacologically, genetically, or by alternate day fasting restored protein translation, increased expression of lysosomal proteins, induced autophagy, and reduced lipotoxicity, inflammation, and fibrosis in cell culture and in vivo models of NASH. Thus, hepatic Esrra is essential for ribosome-dependent translation of lysosomal proteins during starvation, and prevention of lipotoxicity and progression in NASH.Lay summaryFasting for weight loss improves non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, the mechanism is not well understood. Our study shows that a nuclear protein, estrogen related receptor alpha (Esrra), increases ribosome-mediated translation of autophagy and lysosome proteins during chronic starvation to maintain essential metabolic pathways for cell survival. Surprisingly, this translational pathway is impaired during NASH with reduced lysosome-autophagy activity accompanied by increased inflammation and fibrosis gene expression in the liver. Pharmacologic, genetic and dietary activation of Esrra decreases lipid-mediated toxicity in liver cells as well as inflammation and fibrosis in livers from mice with NASH. These findings suggest that the Esrra-ribosome-lysosome pathway is important for liver response to fasting and NASH and thus may be a good therapeutic target for the treatment of NASH.

The mechanism of simultaneous intake of Jujuboside A and B in the regulation of sleep at the hypothalamic level

“…The identification and quantitation of protein Mus_musculus_uniprot_2021_7_15 (86544 sequences) database was used to search the resulting spectra by the search engines: Proteome Discoverer 2.4 (PD 2.4, Thermo Fisher, USA). The searched parameters are carried out according to the previous study [14]. The quantitation results were analyzed by T-test, p < 0.05, and |log2 Fold Change (FC)| > 0.25 were considered as a significant difference, and the proteins were defined as differentially expressed proteins (DE proteins, DEPs).…”