Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well.
Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets / C. Bianco, E. Casirati, F. Malvestiti, L. Valenti. - In: JHEP REPORTS. - ISSN 2589-5559. - 3:3(2021), pp. 100284.1-100284.13. [10.1016/j.jhepr.2021.100284]
|Titolo:||Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets|
|Parole Chiave:||alcoholic liver disease; cirrhosis; fatty liver disease; genetics; IL32; interleukin-32; MBOAT7; non-alcoholic fatty liver disease; PNPLA3; precision medicine; steatohepatitis; therapy|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||2021|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.jhepr.2021.100284|
|Appare nelle tipologie:||01 - Articolo su periodico|