TRIM24 upregulates ORM2 to alleviate abnormal lipid metabolism, inflammation, and oxidative stress in mice with obstructive sleep apnea syndrome & metabolic dysfunction-associated steatotic liver disease.

Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Tripartite Motif Containing 24 (TRIM24) deficiency was reported to cause hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS & MASLD remain unclear. OSAS & MASLD mouse model was established by intermittent hypoxia (IH) & high-fat diet. IH- & 1% free fatty acid-induced mouse liver cells were served as in vitro model. TRIM24 and HIF-1α were upregulated under IH condition. HIF-1α enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of TC, TG, and LDL-C, and increased serum levels of HDL-C in OSAS & MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation, oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 upregulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting RAR-alpha to ORM2 promoter. The cell rescue model verified that ORM2 mediated the hepatoprotective effects of TRIM24. Our evidence reveals the important role of TRIM24 as an epigenetic co-regulator of transcription in OSAS & MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS & MASLD.