Abstract
Peroxisomes are crucial for fatty acid β-oxidation in steatosis, but the role of pexophagy-the selective autophagy of peroxisomes-remains unclear. This study investigated the effects of the peroxisome proliferator-activated receptor-α (PPARα) agonist clofibrate on pexophagy in a coconut oil-based high-fat diet (HFD)-induced hepatocarcinogenesis model. Rats were divided into four groups: control, clofibrate, HFD, and HFD with clofibrate. The HFD induced steatosis, along with a 2.4-fold increase in pexophagy receptor NBR1-positive granules in hepatocytes. Clofibrate significantly inhibited HFD-induced steatosis, increasing p62-, LAMP2-, and Pex5-positive granules by 7.5-, 7.2-, and 71.4-fold, respectively, while decreasing NBR1 expression. The effects were associated with peroxisome proliferation and pexophagy in ultrastructural observations and increased levels of Lc3, p62, Pex2, Pex14, Acox1, and Scd1 in gene expression analysis. The results suggested that clofibrate effectively reduced steatosis through combined peroxisome proliferation and pexophagy, though it had a marginal impact on hepatocarcinogenesis in coconut oil-based HFD-fed rats. These findings highlight the utility of PPARα agonists in studying mammalian pexophagy.