Alternative splicing and liver disease.

Alternative splicing produces complex and dynamic changes in the protein isoforms that are necessary for the proper biological functioning of the metabolic pathways involved in liver development and hepatocyte homeostasis. Changes in the physiological state of alternatively spliced forms are increasingly linked to liver pathologies. This may occur when the expression or function of the set of proteins controlling the alternative splicing processes are altered by external effectors such as oxidative stress and other environmental variations. Studies addressing these modifications reveal a complex interplay between the expression levels of different proteins that regulate the alternative splicing process as well as the changes in alternative splicing. This interplay results in a cascade of different protein isoforms that correlate with the progression of non-alcoholic fatty liver disease, hepatocellular carcinoma, and alcoholic liver disease. However, research on the detailed molecular mechanism underlying the production of these isoforms is needed. It is imperative to identify the physiological processes affected by the differentially spliced isoforms and confirm their role on the onset and maintenance of the pathology. This is required to design potential therapeutic approaches targeting the key splicing changes to revert the pathological condition as well as identify prognostic markers. In this review, we describe the complexity of the splicing process through an example to encourage researchers to go down this path. Subsequently, rather than a catalog of splicing events we have hand-picked and discuss a few selected studies of specific liver pathologies and suggested ways to focus research on these areas.