A novel role of Acyl-CoA Thioesterase 12 in the pathogenesis of renal fibrosis

Lipid mal-metabolism, particularly fatty acid oxidation (FAO) dysfunction, is a major driver of renal fibrosis. However, detailed regulatory mechanisms underlying this process remain unclear. In this study, we demonstrated that acyl-CoA thioesterase 12 (Acot12) is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in a kidney sample of human patients with chronic kidney disease as well as in mouse kidney injury. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12-/- mice with UUO. Moreover, restoration of peroxisome proliferator-activated receptor (PPAR in Acot12-/- Ppar-/- kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas restoration of Acot12 in Acot12-/- Ppar-/- kidneys with UUO significantly reduced lipid accumulation and renal fibrosis suggesting, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPAR. In Acot12-/- kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis. C57BL/6N mice (6-7 weeks old, male) underwent unilateral ureteral obstruction (UUO) surgery and the kidneys were collected on the seventh day. Wildtype and Acot12-/- mice were used.