ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5

Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. 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, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12−/−Pparα−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12−/− Pparα−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. 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. Chronic kidney disease (CKD) is a serious condition that affects kidney function over time. It can lead to other health problems, but current treatments are limited. Here the authors wanted to explore new ways to treat CKD by focusing on kidney fibrosis, a major factor in CKD progression. This study demonstrates that decreased level of ACOT12, a critical enzyme in lipid metabolism, correlates with increased fibrosis and lipid accumulation in the kidney tissues. Mice lacking ACOT12 had more kidney fibrosis and lipid accumulation, suggesting that ACOT12 plays a protective role, while restoring ACOT12 in these mice reduced fibrosis and lipid buildup. These findings suggest that targeting ACOT12 could be a novel therapeutic approach for preventing kidney fibrosis by regulating lipid metabolism in CKD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.