Fam172a deletion exacerbates hepatic steatosis and alters SRSF3-associated PPARγ isoform regulation

This is the authors' abstract. We don't add key points for this paper.

Family with sequence similarity 172 member A (FAM172A) has recently been implicated in metabolic diseases such as obesity and atherosclerosis; however, its hepatocyte-specific functions and downstream mechanisms in hepatic steatosis remain incompletely defined. In this study, we observed significant upregulation of FAM172A in the livers of mice with diet-induced hepatic steatosis. Liver-specific deletion of Fam172a exacerbated high-fat diet (HFD)-induced hepatic steatosis and metabolic dysfunction, accompanied by increased expression of peroxisome proliferator-activated receptor γ (PPARγ) and genes involved in fatty acid uptake and lipogenesis. In vitro, Fam172a overexpression attenuated triglyceride accumulation and reduced PPARγ expression, while the PPARγ antagonist GW9662 attenuated lipid accumulation in Fam172a-deficient primary hepatocytes. Proteomic analysis and co-immunoprecipitation identified serine/arginine-rich splicing factor 3 (SRSF3) as an interacting protein of FAM172A. Fam172a deletion reduced hepatic SRSF3 expression and was associated with altered Pparg splicing in liver tissue. In primary hepatocytes, Fam172a deletion increased the PPARγ2/PPARγ1 ratio at both the mRNA and protein levels. SRSF3 restoration partially rescued lipid accumulation in Fam172a-deficient hepatocytes, while SRSF3 knockdown partially attenuated the protective effect of FAM172A overexpression. CLIP-seq provided evidence of an interaction between SRSF3 and Pparg RNA. Collectively, these findings support a protective role for hepatic FAM172A and implicate SRSF3-associated regulation of PPARγ isoform expression in its effects on lipid accumulation, highlighting FAM172A as a potential therapeutic target.