HFD feeding for seven months abolishes STING disruption-driven but not female sex-based protection against hepatic steatosis and inflammation in mice.

Stimulator of interferon genes (STING) is positively correlated with the degrees of liver inflammation in human metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, STING disruption alleviates MASLD in mice fed a high-fat diet (HFD) for 3 months (3-m-HFD). Here we investigated the role of the duration of dietary feeding in regulating MASLD in mice and explored the involvement of STING in sex differences in MASLD. Both male and female STING-disrupted (STING) and wild-type C57BL/6J mice were fed an HFD for 3 or 7 months (7-m-HFD). Additionally, female STING mice upon ovariectomy (OVX) and 3-m-HFD were analyzed for MASLD. Upon 3-m-HFD, STING mice exhibited decreased severity of MASLD compared to control. However, upon 7-m-HFD, STING mice were comparable with wild-type mice in body weight, fat mass, and MASLD. Regarding regulating the liver RNA transcriptome, 7-m-HFD increased the expression of genes indicating proinflammatory activation of various liver cells. Interestingly, the severity of MASLD in female mice was much lighter than in male mice, regardless of STING disruption. Upon OVX, female STING mice showed significantly increased severity of MASLD relative to sham control but were comparable with male STING mice. Upon treatment with 17-beta estradiol (E2), hepatocytes revealed decreased fat deposition while macrophages displayed decreases in lipopolysaccharide-induced phosphorylation of Nfkb p65 and Jnk p46 independent of STING. These results suggest that 7-m-HFD, without altering female sex-based protection, abolishes STING disruption-driven protection of MASLD, likely through causing proinflammatory activation of multiple types of liver cells to offset the effect of STING disruption.