Potential Effect of a Selective Peroxisome Proliferator-activated Receptor Alpha Modulator on Metabolic Dysfunction-associated Fatty Liver Disease

Abstract

The manuscript submitted by Hatanaka et al. reported on the efficacy of pemafibrate for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), particularly in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) (1).NAFLD, characterized by an excessive accumulation of triglycerides (TGs) in the hepatocytes, can be caused by the increased inflow of free fatty acids and de novo hepatic lipogenesis. NAFLD is the most common chronic liver disease in developed countries. Nonalcoholic steatohepatitis (NASH) is a more advanced form of NAFLD, occurring in 59% of NAFLD cases (2).An international panel of experts recently reported on the rationale for the update of the nomenclature. They have proposed MAFLD as a more appropriate term than NAFLD for describing liver disease associated with known metabolic dysfunction. This emphasizes the fact that NAFLD is the hepatic manifestation of a multisystem disorder that is heterogeneous in its underlying causes, presentation, course, and outcomes (3).Agonists of the peroxisome proliferator-activated receptor alpha (PPARα), which is expressed in liver, cardiac muscle, skeletal muscle, and small intestinal mucosa, are crucial for reducing the plasma concentrations of triglyceride (TG)-rich lipoproteins, increasing the levels of high-density lipoprotein (HDL) and reducing vascular inflammation in atherogenic dyslipidemia patients (4). The activation of PPARα causes the hydrolysis of TGs. Pemafibrate selectively binds to PPARα, causing a ligand-specific conformational change and thus has been termed a selective peroxisome proliferator-activated receptor-α modulator (SPPARMα). Use of such an agent may lead to the preferential regulation of genes causing beneficial consequences. Indeed, pemafi-