PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date

ABSTRACT

Introduction

An interaction between metabolic triggers and inherited predisposition underpins the development and progression of non alcoholic fatty liver disease (NAFLD) and fatty liver disease in general. Among the specific NAFLD risk variants, PNPLA3 rs738409 C>G, encoding for the p.I148M protein variant, accounts for the largest fraction of liver disease heritability and is being intensively scrutinized. It promotes intrahepatic lipid accumulation and is associated with lipotoxicity and the more severe phenotypes, including fibrosis and carcinogenesis. Therefore, PNPLA3 appears as an appealing therapeutic target to counter NAFLD progression.

Areas covered

The scope of this review is to briefly describe the PNPLA3 gene and protein function before discussing therapeutic approaches for fatty liver aiming at this target. Literature review was carried out searching through PubMed and clinicaltrials.gov website and focusing on the most recent works and reviews.

Expert opinion

The main therapeutic strategies under development for NAFLD have shown variable efficacy and side-effects likely due to disease heterogeneity and lack of engagement of the main pathogenic drivers of liver disease. To overcome these limitations, new strategies are becoming available for targeting PNPLA3 p.I148M, responsible for a large fraction of disease susceptibility.

KEYWORDS:

• PNPLA3
• hsd17b13
• precision medicine
• nonalcoholic fatty liver disease
• liver organoids

Declaration of interests

L Valenti has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics and Ionis Pharmaceuticals, and received research grants from Gilead. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

L Valenti is supported by grants from the Italian Ministry of Health (Ministero della Salute) MyFirst Grant AIRC n.16888, Ricerca Finalizzata RF-2016-02364358 (‘Impact of whole exome sequencing on the clinical management of patients with advanced nonalcoholic fatty liver and cryptogenic liver disease’); Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Ricerca corrente; Fondazione IRCCS Ca’ Granda core COVID-19 Biobank (RC100017A), ‘Liver BIBLE’ (PR-0391); Innovative Medicines Initiative 2 joint undertaking of European Union’s Horizon 2020 research and innovation programme and EFPIA European Union (EU) ProgrammeHorizon 2020 (under grant agreement No. 777377) for the project LITMUS; The European Union, programme ‘Photonics’ under grant agreement ‘101016726’; Gilead_IN-IT-989-5790.