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.

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD)

“…Of special note, bisulfite converted DNA assay does not allow discrimination between DNA methylation and hydroxymethylation changes that have been associated with gene silencing and gene activation responses respectively. Indeed, PPARα regulatory functions have recently been described for both DNA methylation as well as hydroxymethylation and may need a more detailed in-depth molecular investigation ( Theys et al, 2022 ).…”

“…Surprisingly, PPARα ligands have only shown limited therapeutic benefits against MASLD in (pre)clinical trial studies ( Lange et al, 2022 ). Of special note, recent evidence suggests a possible involvement of epigenetic silencing mechanisms in PPARα functions in MASLD progression which may counteract therapeutic actions of PPAR ligands ( Theys et al, 2022 ). In this respect, to further characterise reciprocal crosstalk of epigenetic regulatory mechanisms with PPARα functions in lipid metabolism and MASLD progression, we have cross compared DNA methylation and gene expression patterns of chow or CDAHFD hepatocyte-specific PPARα KO mice versus liver biopsies of MASLD/MASH patient samples.…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“…Third, epigenetic modifications and PTMs of targets that induce or inhibit ferroptosis have been identified, and dysregulated epigenetic modifications and PTMs can be feasibly targeted by small molecule compounds. Epigenetic drugs have exhibited viable therapeutic potential for NSDs, 607 – 610 CVDs, 611 – 615 liver diseases, 616 , 617 lung diseases, 618 – 620 and kidney diseases 621 – 623 in preclinical and clinical trials. Epigenetic drugs targeting epigenetic regulators through modulation of epigenetic mechanisms have been applied and clinically translated for the treatment of hematological malignancies, greatly contributing to the development of antitumor drugs.…”

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease

“…Although the exact mechanisms are not fully understood, several key factors have been closely implicated in the development and progression of NAFLD. Growing evidence highlights the critical role of epigenetic regulation in the development and progression of NAFLD [ 25 , 30 , 31 , 32 , 33 ].…”