Ubiquitin pathways regulate the pathogenesis of chronic liver disease

Abstract

Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. In this review, we present the function of ubiquitination and latest findings on diverse mechanism of PTMs, UPS and autophagy which significantly contribute to the pathogenesis of alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cirrhosis, and HCC. Despite its high prevalence, morbidity, and mortality, there are only few FDA approved drugs that could be administered to CLD patients. The goal of this review is to present a variety of pathways and therapeutic targets involving ubiquitination in the pathogenesis of CLD. Further, this review summarizes collective views of pharmaceutical inhibition or activation of recent drugs targeting UPS and autophagy system to highlight potential targets and new approaches to treat CLD.

Keywords: Autophagy; Chronic liver disease (CLD); Mitophagy; Post-translational modification (PTM); Ubiquitin; Ubiquitin-proteasome system (UPS).