Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from patients with diabetes. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.
Fatty acid oxidation has been a critical contributor to podocyte injury and pathological changes in diabetic kidney disease. However, the role of carnitine palmitoyltransferase-1A (CPT1A), which is the initial key rate-limiting enzyme of mitochondrial fatty acid oxidation in diabetic kidney disease, remains largely unknown.
We investigate whether CPT1A modulates the progression of diabetic kidney disease.
CPT1A ameliorated albuminuria and glomerular sclerosis, and mitigated glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice.
Our study reveals a promising avenue for diabetic kidney disease prevention and clarifies a new regulatory mechanism for CPT1A in podocytes.
This article contains supplementary material online at https://doi.org/10.2337/figshare.25420921.
