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Exp. Mol. Med., 13 February 2025 | https://doi.org/10.1038/s12276-025-01406-3
ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5
Ee Hyun Kim 1,2, Mi Kyung Kim 3, MiSun Choe 4, Ji Hyun Ryu 5, Eun Seon Pak 1, Hunjoo Ha 1,* and Eun-Jung Jin 2,5,*
1Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
2Integrated Omics Institute, Wonkwang University, Iksan, South Korea.
3Department of Internal Medicine, School of Medicine, Keimyung University, Daegu, South Korea.
4Department of Pathology, School of Medicine, Keimyung University, Daegu, South Korea.
5Department of Biomedical Materials Science, Graduate School of JABA, Wonkwang University, Iksan, South Korea.
2Integrated Omics Institute, Wonkwang University, Iksan, South Korea.
3Department of Internal Medicine, School of Medicine, Keimyung University, Daegu, South Korea.
4Department of Pathology, School of Medicine, Keimyung University, Daegu, South Korea.
5Department of Biomedical Materials Science, Graduate School of JABA, Wonkwang University, Iksan, South Korea.
*Corresponding authors: correspondence to Hunjoo Ha or Eun-Jung Jin
Abstract
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-13)
- 국내 연구진
- 의약학 > 분자세포의학
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