Context and objectives
The high-mobility group box gene 9 (SOX9) linked to the transcription factor sex-determining region Y plays an essential role in organ development. Although SOX9 has been implicated in the regulation of lipid metabolism in vitroits specific role in metabolic dysfunction-associated steatohepatitis (MASH) remains poorly understood. This study aimed to investigate the role of SOX9 in the pathogenesis of MASH and explore the underlying mechanisms.
Methods
MASH models were established using mice fed either a methionine-choline-deficient (MCD) diet or a high-fat, high-fructose diet. To evaluate the effects of SOX9, hepatocyte-specific knockdown or overexpression of SOX9 was performed. Lipidomic analyzes were performed to evaluate the influence of SOX9 on hepatic lipid metabolism. RNA sequencing was used to identify pathways modulated by SOX9 during MASH progression. To further elucidate the mechanism, HepG2 cells were treated with adenosine monophosphate-activated protein kinase (AMPK) inhibitor to test whether SOX9 acts via AMPK activation.
Results
SOX9 expression was significantly elevated in hepatocytes of MASH mice. Hepatocyte-specific deletion of SOX9 exacerbated MCD-induced MASH, while SOX9 overexpression attenuated MASH induced by high fat and high fructose. Lipidomic and RNA sequencing analyzes revealed that SOX9 suppresses the expression of genes associated with lipid metabolism, inflammation, and fibrosis in MCD-fed mice. Furthermore, knockdown of SOX9 inhibited AMPK pathway activation, while overexpression of SOX9 enhanced it. Notably, administration of an AMPK inhibitor reversed the protective effects of SOX9 overexpression, leading to increased lipid accumulation in HepG2 cells.
Conclusions
Our results demonstrate that SOX9 overexpression attenuates hepatic lipid accumulation in MASH by activating the AMPK pathway. These results highlight SOX9 as a promising therapeutic target to treat MASH.
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