STAT6 contributes to renal fibrosis by modulating PPARα-mediated tubular fatty acid oxidation

• Published in: Cell death & disease Vol. 13; no. 1; p. 66
• Main Authors: Li, Jianzhong, Yang, Youjing, Li, Qianmin, Wei, Shuhui, Zhou, Yujia, Yu, Wangjianfei, Xue, Lian, Zhou, Ling, Shen, Lei, Lu, Guoyuan, Chen, Ling, Tao, Shasha
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/51; 13/95; 631/80/86/2365; 64/60; 692/308; 82/1; 82/80; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Fatty acids; Fatty Acids - metabolism; Fibrosis; High fat diet; Immunology; Kidney - pathology; Kidney Diseases - pathology; Kidneys; Life Sciences; Lipid Metabolism; Lipids; Metabolism; Mice; Mice, Inbred C57BL; Oxidation; PPAR alpha - metabolism; Stat6 protein; STAT6 Transcription Factor - metabolism; Transcription; Ureteral Obstruction - pathology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04515-3

Lipid metabolism, especially fatty acid oxidation (FAO) dysfunction, is a major driver of renal fibrosis; however, the detailed regulatory mechanisms involved remain unclear. In this study, we showed that there existed an association between the signal transducer and activator of transcription 6 (STAT6) and tubular lipid metabolism in fibrotic kidneys. Specifically, STAT6 was activated along with the accumulation of lipids via the downregulation of FAO-related genes when mice were subjected to unilateral ureteral obstruction (UUO) or high-fat diet challenge. Tubular-specific depletion, or pharmacologic inhibitor of Stat6 in mice, and Stat6 knockdown in cultured tubular cells attenuated lipid accumulation and renal fibrosis by enhancing FAO. Mechanistically, STAT6 transcriptionally inhibited the expression of PPARα and its FAO-related target genes through a sis-inducible element located in the promoter region of the protein. In conclusion, our study demonstrates the mechanistic details of STAT6-mediated FAO dysregulation in the progression of renal fibrosis and provides a preclinical rationale for efforts to improve the management of renal fibrosis brought about by FAO dysregulation.