Sexual dimorphism in the association of circulating TAM receptors-ligands with MASLD-related fibrosis.

BACKGROUND & AIMS: The TAM receptors (MerTK and Axl) and their ligands (Gas6 and Protein S) have been implicated in MASLD-related fibrosis. However, whether circulating levels are associated with fibrosis stage and whether these associations differ by sex remain unclear. This study aimed to characterize circulating TAM receptors and ligands across fibrosis stages in men and women with MASLD.

METHODS: Circulating TAM receptors and ligands were measured in men (n = 75) and women (n = 78) with MASLD and analyzed for associations with fibrosis stage. Time-course choline-deficient, amino acid-defined, high-fat diet mouse models were established in male and female mice to assess circulating TAM members. These markers were further compared between premenopausal and postmenopausal women with MASLD. In addition, circulating soluble MerTK (sol-MerTK) was measured in mice treated with 17β-estradiol. In vitro, macrophages were treated with 17β-estradiol, and sol-MerTK and Mertk mRNA levels were measured.

RESULTS: In men with MASLD, circulating sol-MerTK was inversely associated with fibrosis stage (adjusted ordinal regression: odds ratio 0.63; 95% CI 0.51-0.78; p <0.0001) and decreased with fibrosis progression in male mice. In contrast, sol-MerTK showed no significant association with fibrosis stage in women (odds ratio 1.12; 95% CI 1.00-1.25; p = 0.0543) or female mice. Higher circulating sol-Axl and Gas6 levels were associated with more advanced fibrosis in both men and women with MASLD. Circulating sol-MerTK levels were higher in premenopausal than postmenopausal women (p = 0.0306). Treatment with 17β-estradiol increased circulating sol-MerTK levels in mice (p = 0.0119). In macrophages, 17β-estradiol increased sol-MerTK release in a dose-dependent manner (p <0.05), with a non-significant trend toward reduced Mertk mRNA expression (p >0.05).

CONCLUSIONS: Circulating TAM receptors and ligands were associated with fibrosis stage in MASLD, with sex-specific associations observed for sol-MerTK. Furthermore, 17β-estradiol promoted MerTK cleavage, providing a potential mechanism underlying these sex differences.

CLINICAL TRIAL NUMBER: N/A.

IMPACT AND IMPLICATIONS: MASLD-related fibrosis is progressive and sexually dimorphic. Our findings reveal sex-specific associations of circulating sol-MerTK and Protein S with liver fibrosis stages in MASLD, highlighting the need to incorporate sex as a biological variable in MerTK- and Protein S-related studies. In contrast, circulating sol-Axl and Gas6 were positively associated with liver fibrosis stages in both sexes, suggesting their potential as sex-independent indicators of fibrosis progression in MASLD. We further show that circulating sol-MerTK levels are higher in premenopausal than in postmenopausal women, and that estrogen increases circulating sol-MerTK levels in mice and promotes MerTK cleavage in macrophages. Given the reported roles of estrogen and MerTK cleavage in MASLD-related fibrosis, our study provides potential mechanistic insights into sex differences in MASLD-related fibrosis.