Evidence map›Paper›PMID 42379304›Full record

Observational studyJHEP reports : innovation in hepatology2026

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

Yiwei Zhu, Neha Gupta, Bruno Cogliati, Yulu He, Asher Leviton, Jihane N Benhammou, Steven-Huy B Han, Zhenqi Zhou, Alexander Nguyen, Xiaotao Zhang and 4 more

Abstract readComparative StudyObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in JHEP reports : innovation in hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Yiwei ZhuVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Neha GuptaVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bruno CogliatiDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Yulu HeDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Asher LevitonDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jihane N BenhammouVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA.
Steven-Huy B HanVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA.
Zhenqi ZhouDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Alexander NguyenVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA.
Xiaotao ZhangDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rajat SinghVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA.
Scott L FriedmanDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Meena B BansalDivision of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Bishuang CaiVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Comprehensive Liver Research Center at UCLA, University of California, Los Angeles, CA, USA; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: BishuangCai@mednet.ucla.edu.

Funding

EHD1-mediated Inflammation and Resolution in AtherosclerosisR01HL167107 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Bishuang Cai · 2023 to 2026
$2.8M
Efferocytosis meets endocytosisR35GM147269 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Bishuang Cai · 2022 to 2026
$2.3M
Disturbed Crosstalk between Cholesterol Homeostasis and Inflammation Resolution in NASHR01DK134610 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Bishuang Cai · 2023 to 2026
$2.2M
NHLBI NIH HHS R01 HL167107NIDDK NIH HHS R01 DK134610NIGMS NIH HHS R35 GM147269
6 · The paper itself

Abstract

BACKGROUND &

aimsThe 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.

methodsCirculating 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.

resultsIn 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).

conclusionsCirculating 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.

Indexed as

Calcium-Binding ProteinsGrowth Arrest-Specific Protein 6Liver CirrhosisNon-alcoholic Fatty Liver DiseaseReceptor Protein-Tyrosine KinasesSex CharacteristicsAdultAgedAnimalsAxl Receptor Tyrosine Kinasec-Mer Tyrosine KinaseDiet, High-FatDisease Models, AnimalFemaleHumansLigandsAXL protein, humanAxl Receptor Tyrosine KinaseAXL receptor tyrosine kinase, mouseCalcium-Binding Proteinsc-Mer Tyrosine KinaseGas6 protein, mouseGrowth Arrest-Specific Protein 6LigandsMERTK protein, humanMertk protein, mousePros1 protein, mouseReceptor Protein-Tyrosine KinasesEstrogenMASHMenopauseMerTKSex differences

Identifiers

PMID42379304
PMCPMC13521018

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.