Fat Burning Problem in Cystic Kidneys: an Emerging Common Mechanism of Chronic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders, occurring in approximately 1 in every 1000 live births (Wilson, 2004). About 50% of people who inherit the mutation will develop chronic kidney disease (CKD), characterized by the development of multiple large cysts in both kidneys followed by functional decline and end-stage renal disease. While the genetic mutations in polycystin 1 and polycystin 2 (PKD1 and PKD2, respectively) (Rangan et al., 2015) were identified more than 30 years ago, the mechanism of disease development remains largely unknown (Reeders et al., 1985). Menezes et al. took an unbiased systemsbiology approach to study Pkd1 gene function and report their results in the current issue of EBioMedicine (Menezes et al., 2016). The authors performed genome wide transcript profiling on mice with conditional deletion of Pkd1, a model of ADPKD. They noted that disease severity was much milder in female mice when compared to their male counterparts. Metabolic genes represented the largest differentially expressed gene cluster, which correlated with disease development. Specifically, they identified differences in expression levels of several important regulators of lipid metabolism, which they probed further with unbiasedmetabolomics and lipidomics studies. Lipidomics studies highlighted several significant differences between control and Pkd1 knockout animals, including significantly lower diacylglycerol levels in mutant kidneys. Diacylglycerol is a byproduct of triglyceride metabolism. This prompted the authors to take a closer look at fatty acid oxidation. Cell culture studies showed that renal epithelial cells lacking Pkd1 have a cell autonomous defect in fatty acid oxidation, as these cells not oxidize palmitate as efficiently as control cells. Even though previous studies indicated changes in glucose metabolism in ADPKD, specifically an increased reliance on glucose as an energy source