Proximal Tubule-Specific Genetic Deficiency of PPARα Worsens Systemic Lipid and Glucose Metabolism During Fasting

The proximal tubule (PT) of the kidney is a highly metabolic organ that regulates systemic homeostasis through ketogenesis and gluconeogenesis. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor controlling fatty acid oxidation (FAO) and homeostasis, is expressed in the PT and is activated by fasting. Although the activation of systemic PPARα is essential for renal and systemic energy metabolism, the role of PPARα in PT has not been established. In this study, kidney PT-specific PPARα knockout mice (Ppara^∆KPT) were generated, and the metabolic changes caused by 48 h of fasting were compared between Ppara^∆KPT mice and controls. In Ppara^∆KPT mice, renal FAO and ketogenesis were severely impaired, leading to lipid accumulation in the kidney after 48 h of fasting. The increase in the renal expression of gluconeogenesis-associated genes due to fasting was insufficient in Ppara^∆KPT mice, causing a decrease in serum glucose levels and liver glycogen content. Fasting caused hepatic micro-steatosis and significantly increased the expression of genes linked to FAO and ketogenesis in the liver of Ppara^∆KPT mice, as well as those associated with lipolysis in the white adipose tissue. These activities likely compensate for the impaired kidney FAO and ketogenesis in Ppara^∆KPT mice and show that PPARα in PT regulates renal and systemic lipid and glucose metabolism during fasting. PPARα in PT may be a critical component in systemic lipid and glucose homeostasis during fasting.