Background/Objectives: Kidneys are fatty acid (FA)-consuming organs that use adenosine triphosphate (ATP) for tubular functions, including endocytosis for protein reabsorption to prevent urinary protein loss. Peroxisome proliferator-activated receptor α (PPARα) is a master regulator of FA metabolism and energy production, with high renal expression. Although polyunsaturated fatty acids (PUFAs) are essential nutrients that are natural PPARα ligands, their role in tubular protein reabsorption remains unclear. As clinical PUFA deficiency occurs in humans under various conditions, we used a mouse model that mimics these conditions. Methods: We administered a 2-week intraperitoneal protein-overload (PO) treatment to mice that had been continuously fed a PUFA-deficient diet. We compared the phenotypic changes with those in mice fed a standard diet and those in mice fed a PUFA-deficient diet with PUFA supplementation. Results: In the absence of PO, the PUFA-deficient diet induced increased lysosomal autophagy activation; however, other phenotypic differences were not detected among the diet groups. In the PO experimental condition, the PUFA-deficient diet increased daily urinary protein excretion and tubular lysosomes; suppressed adaptive endocytosis activation, which was probably enhanced by continuous autophagy activation; and worsened FA metabolism and PPARα-mediated responses to PO, which disrupted renal energy homeostasis. However, these changes were attenuated by PUFA supplementation at the physiological intake level. Conclusions: PUFAs are essential nutrients for the tubular adaptive reabsorption response against urinary protein loss. Therefore, active PUFA intake may be important for patients with kidney disease-associated proteinuria, especially those with various PUFA deficiency-inducing conditions.

We previously demonstrated that a clinically relevant dose of pemafibrate (PEM), a selective peroxisome proliferator-activated receptor α (PPARα) modulator (SPPARMα), reduces serum triglyceride (TG) levels in mice via hepatic PPARα activation. However, the specific contribution of hepatocyte PPARα remains unclear. To address this, male Ppara-floxed (Ppara^fl/fl) and hepatocyte-specific Ppara-disrupted (Ppara^ΔHep) mice were fed a diet with or without a clinically relevant dose of PEM (0.00005%) for four weeks. In Ppara^fl/fl mice, PEM significantly reduced circulating TG and non-esterified fatty acid levels by enhancing hepatic fatty acid uptake and β-oxidation. In contrast, these effects were absent in Ppara^ΔHep mice. Notably, PEM did not activate PPARα in extrahepatic tissues, including white/brown adipose tissue, kidney, and skeletal muscle in either genotype. These findings underscore the essential role of hepatocyte PPARα in mediating the pharmacological effects of PEM at clinically relevant doses.