Elucidating the role of NUDT19 in renal lipid metabolism

Abstract

Coenzyme A (CoA) is an essential cofactor that plays a key role in fuel metabolism, as it is required for glucose oxidation and the synthesis and oxidation of fatty acids, amino acids, and ketone bodies. Three Nudix hydrolases, NUDT7, NUDT8, and NUDT19, hydrolyze CoA species at the phosphodiester bond, potentially contributing to the regulation of specific metabolic processes in the subcellular compartments where they reside. NUDT19 is found in the peroxisomes and is highly expressed in kidney proximal tubule cells (PTC). In vitro, NUDT19 readily hydrolyzes short and medium chain acyl‐CoAs, malonyl‐ and succinyl‐CoA, as well as free CoA. This substrate preference, combined with the peroxisomal localization of NUDT19, suggests a potential role in the regulation of peroxisomal lipid metabolism. To investigate the physiological function of NUDT19, we obtained global Nudt19‐/‐ mice and fed them a high fat diet (HFD) or a low fat control diet (CD) for 15 weeks. On either diet, Nudt19‐/‐ mice exhibit higher total CoA levels compared to wild type mice, indicating that NUDT19 contributes to the regulation of this cofactor. HFD feeding led to a higher albumin‐to‐creatinine ratio in the Nudt19‐/‐ mice compared to wild type mice, indicating a decrease in kidney function. Nudt19‐/‐ mice also exhibited elevated serum triglycerides and a higher body weight, not associated with changes in bone density or adiposity. In mice fed the HFD, deletion of Nudt19 caused only a few changes to the kidney cortex proteome, with only 8 proteins significantly altered, including 3 involved in peroxisomal and mitochondria fatty acid oxidation, which were increased in the kidneys of the Nudt19‐/‐ mice. Measurement of mitochondrial and peroxisomal fatty acid oxidation using 14C‐palmitate in kidney cortex slides did not reveal any differences between genotypes. Conversely, untargeted metabolomics analysis on whole kidneys revealed a general decrease in multiple lipid classes including lysophospholipids, monoacylglycerols, and long chain free fatty acids, without changes in triglycerides levels. Combined, the data support the conclusion that deletion of Nudt19 alters lipid metabolism.