PPARα in the Epigenetic Driver Seat of NAFLD: New Therapeutic Opportunities for Epigenetic Drugs?

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic and the most common cause of chronic liver disease worldwide. It consists of a spectrum of liver disorders ranging from simple steatosis to NASH which predisposes patients to further fibrosis, cirrhosis and even hepatocarcinoma. Despite much research, an approved treatment is still lacking. Finding new therapeutic targets has therefore been a main priority. Known as a main regulator of the lipid metabolism and highly expressed in the liver, the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) has been identified as an attractive therapeutic target. Since its expression is silenced by DNA hypermethylation in NAFLD patients, many research strategies have aimed to restore the expression of PPARα and its target genes involved in lipid metabolism. Although previously tested PPARα agonists did not ameliorate the disease, current research has shown that PPARα also interacts and regulates epigenetic DNMT1, JMJD3, TET and SIRT1 enzymes. Moreover, there is a growing body of evidence suggesting the orchestrating role of epigenetics in the development and progression of NAFLD. Therefore, current therapeutic strategies are shifting more towards epigenetic drugs. This review provides a concise overview of the epigenetic regulation of NAFLD with a focus on PPARα regulation and highlights recently identified epigenetic interaction partners of PPARα.