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Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling

Nature Metabolism volume 8, pages 116–138 (2026)Cite this article

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Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha (Esr1). Mechanistically, GPR110 couples to Gαs and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed Esr1 transcription in hepatocytes. Taken together, these results demonstrate a sex-specific role of GPR110 in MASH by regulating hepatic oestrogen sensitivity, suggesting inhibition of GPR110 as a potential sex-specific therapy for MASH.

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Fig. 1: GPR110 is a liver-enriched GPCR and its hepatic expression is decreased in mouse models of MASH.
Fig. 2: Loss of Gpr110 in hepatocytes ameliorates the MASH-prone phenotype in female mice, but not male mice.
Fig. 3: Amelioration of MASH in female Gpr110 LKO mice is associated with increased hepatic expression of Esr1.
Fig. 4: Mice with hepatocyte-specific deletion of Gpr110 are more sensitive to oestradiol-induced benefits on MASH.
Fig. 5: Knockdown of Esr1 in the liver is sufficient to drive the MASH-prone phenotype in female Gpr110 LKO mice.
Fig. 6: GPR110 inhibits Esr1 transcription via the PKA–NFAT2 signalling pathway in hepatocytes.
Fig. 7: Association of GPR110 variant rs937057 T > C with MASLD in human indicating a pronounced sex difference.
Fig. 8: Hepatocyte-targeted GalNAc-conjugated siRNA against Gpr110 alleviates MASH in female mice.

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Data availability

The data supporting the findings from this study are available within the manuscript and its Supplementary Information. RNA-seq data are available in the Genome Sequence Archive under accession number PRJCA049229. Source imaging data are available in figshare (https://doi.org/10.6084/m9.figshare.28532336)91. Further information and requests for resources and reagents should be directed to and will be fulfilled by the corresponding author. Source data are provided with this paper.

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This paper does not report original code.

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Acknowledgements

We thank the Core Facility and Technical Service Center for School of Life Sciences and Biotechnology and the Laboratory Animal Center at Shanghai Jiao Tong University. This work was supported by the National Key Research and Development Program of China (2022YFA1004800), National Natural Science Foundation of China (82370865, 82100906), the Natural Science Foundation of Shanghai by Shanghai Municipal Science and Technology Commission (22ZR1430400) to Z.H. and Program of Science and Technology Cooperation with Hong Kong, Macao and Taiwan (22410760500) to S.Z. The schematics in Figs. 2a, 4a, 5a, 7b and 8a–c and Extended Data Figs. 3a,n, 5a, 7d and 9a were created with BioRender.com.

Author information

Author notes

  1. These authors contributed equally: Fang Yang, Wei Wang.

  2. These authors jointly supervised this work: Ping Gu, Shufei Zang, Weimin Jiang, Zhe Huang.

Authors and Affiliations

  1. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Fang Yang, Feng Qiu, Rui Qing, Qingying Gao, Xingqun Yan, Chunhao Long, Yixuan Zhang, Siwei Ji & Zhe Huang

  2. Department of Endocrinology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Wei Wang, Daiqiang Xu & Ping Gu

  3. Guangzhou Institute of Biomedical Health, Chinese Academy of Sciences, Guangzhou, China

    Donghai Wu

  4. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Hannah Xiaoyan Hui

  5. School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China

    Rui Dang & Guozhi Jiang

  6. Department of Clinical Epidemiology, Ningbo, China

    Liyuan Han

  7. Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Guoke Ningbo Life Science and Health Industry Research Institute, University of Chinese Academy of Sciences, Ningbo, China

    Liyuan Han

  8. Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

    Shuang Hua & Weimin Jiang

  9. School of Life Sciences, Westlake University, Hangzhou, China

    Lu Xu

  10. Department of Ultrasound, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Chen Zhou

  11. Precision Medicine-Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Alessandro Cherubini & Luca Valenti

  12. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

    Luca Valenti

  13. Department of Endocrinology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China

    Ping Gu

  14. Department of Endocrinology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Shufei Zang

  15. Department of Cardiology, Shanghai Pudong New Area People’s Hospital, Shanghai, China

    Zhe Huang

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Contributions

Z.H. conceptualized the study and supervised the project. F.Y. and W.W. carried out the research, analysed and interpreted the results. R.Q. and Q.G. performed the molecular dynamics stimulation study. R.D., G.J. and L.H. carried out the formal analysis of the UK Biobank SNP data and curated the dataset. F.Q., X.Y., S.H., Y.Z., S.J. and L.X. provided additional support for the animal experiments. C.Z. and D.X. provided support for the clinical experiment. D.W. and H.X.H. reviewed and edited the manuscript. C.L. analysed the human transcriptomic data. A.C. and L.V. discussed the human data and provided support for the human data interpretation. P.G., S.Z. and W.J. provided support for the human study and discussed the results. F.Y. and Z.H. wrote and edited the manuscript with input from all other authors.

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Correspondence to Ping Gu, Shufei Zang, Weimin Jiang or Zhe Huang.

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Nature Metabolism thanks Robert Schwabe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Revati Dewal, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Expression of GPR110 is reduced in human MASH liver and transcriptionally repressed by rosiglitazone.

a, Hepatic expression of GPR110 in patients with MASH and control individuals by analyzing the following GEO datasets: GSE159676 and GSE66676 (n = 54). b, Schematic diagram showing the locations of four predicted PPARγ response elements (PPREs, sequence indicated in red) within the promoter region of mouse Gpr110 gene as identified by in silico analysis with JASPAR (2024) and PROMO. c, Luciferase reporter assay on Gpr110 promoter in response to rosiglitazone treatment by truncation analysis. Hepa1-6 cells were transfected with luciferase-expressing vector driven by the Gpr110 promoter with different lengths as indicated. The cells were treated with rosiglitazone (20 μM) or DMSO control 4 hours post-transfection for 24 hours. The firefly luciferase activity was measured and normalized to renilla luciferase activity (n = 4/group). Data are presented as mean ± SD; Statistical significance was calculated using two-tailed Welch’s t-test (a) or two-tailed Student’s t-test (c).

Source data

Extended Data Fig. 2 AAV-mediated hepatic overexpression of GPR110 does not affect serum lipid levels in mice.

9-week-old male and female C57BL/6 J mice placed on STC were administered with AAV encoding Gpr110 (AAV-GPR110) or Gfp (AAV-GFP) driven by thyroxine-binding globulin (Tbg) promoter via tail-vein injection (2×1011 copies of AAV/mouse). After 1 week, the mice were switched to CDAHF60 diet for 12 weeks (n = 6/group). a,c, AAV-mediated selective overexpression of Gpr110 in the liver, but not in subcutaneous white adipose tissue (sWAT), epididymal white adipose tissue (eWAT), gastrocnemius muscle (Gastroc) or hypothalamus (Hypo) in male (a) and female (c) mice was confirmed by quantitative real-time PCR analysis. b,d, Hepatic protein expression of GPR110 induced by AAV-GPR110 in male (b) and female (d) mice was validated by western blot. The bottom panels are the densitometric analyses for the relative abundance of GPR110 normalized with GAPDH. e-h, Serum levels of triglyceride (TG) and total cholesterol (TC) in male (e,f) and female (g,h) mice. Data are presented as mean ± SD; Statistical significance was calculated using two-tailed Student’s t-test (a-h).

Source data

Extended Data Fig. 3 AAV-mediated hepatic overexpression of GPR110 exacerbates MASH development and progression in female mice, but not male mice.

9-week-old male and female C57BL/6 J mice placed on STC were administered with AAV encoding Gpr110 (AAV-GPR110) or Gfp (AAV-GFP) driven by thyroxine-binding globulin (Tbg) promoter via tail-vein injection (2×1011 copies of AAV/mouse). One week later, mice were switched to CDAHF60 diet for 12 weeks (n = 6/group). a,n, Experimental design for male mice (a) and female mice (n). b,o, Body weight of male (b) and female (o) mice. c,p, Liver/body weight ratio of male (c) and female (p) mice. d,e,q,r, Serum ALT and AST levels in male (d,e) and female (q,r) mice. f,s, Representative images of H&E staining (top), immunohistochemistry for F4/80 (middle) and Sirius Red staining (bottom) of liver sections from male (f) and female (s) mice; Scale bars, 100 μm. g-k, NAFLD activity score (g), hepatic steatosis score (h), inflammatory foci per field (i), percentage of F4/80-positive area (j) and percentage of fibrosis area (k) in the liver of male mice. t-x, NAFLD activity score (t), hepatic steatosis score (u), inflammatory foci per field (v), percentage of F4/80-positive area (w) and percentage of fibrosis area (x) in the liver of female mice. l,y, Hepatic triglyceride (TG) content in male (l) and female (y) mice. m,z, Hepatic hydroxyproline content in male (m) and female (z) mice. Data are presented as mean ± SD; Statistical significance was calculated using two-tailed Student’s t-test (b-e,g-m,o-r,t-z). Schematic in a and n created with BioRender.com.

Source data

Extended Data Fig. 4 Generation and characterization of Gpr110 LKO mice.

a, Schematic diagram for the generation of hepatocyte-specific Gpr110 knockout (LKO) mice. loxP sites were inserted upstream and downstream of exon 4 of Gpr110. Locations of the primers for PCR analysis of the wild-type (WT) and Gpr110-floxed alleles are indicated. The primers F1 and R1 detect the presence of the loxP region and amplify a band of 320 bp in Gpr110-floxed mice and 286 bp in WT mice. A set of Cre-recombinase (Cre) coding sequence-specific primers amplifies a band of 390 bp in Cre+ mice. b, Genotyping of LKO mice by genomic PCR analysis. c, Selective deletion of Gpr110 in the liver, but not in eWAT, colon or Hypo in LKO mice was confirmed by RT-qPCR analysis (n = 4 mice/group). d, Gpr110 mRNA expression in hepatocytes and non-parenchymal cells (NPCs) from LKO and WT mice (n = 4/group). e, Reduction of GPR110 in the liver of LKO mice as compared to the WT mice was validated at the protein level (n = 3/group). f-k, 10-week-old male and female LKO mice and their Gpr110fl/fl (WT) littermates were fed STC or CDAHF60 for 12 weeks (n = 5/group for male and female WT and LKO mice on STC, n = 9/group for male WT mice on CDAHF60, n = 7/group for male LKO mice on CDAHF60, n = 11/group for female WT mice on CDAHF60, n = 13/group for female LKO mice on CDAHF60). f,i, Body weight of male (f) and female (i) mice. g,h,j,k, Serum levels of TG and TC in male (g,h) and female (j,k) mice. l,m, Livers from male WT or LKO mice fed STC or CDAHF60 were harvested for transcriptomic analysis. Differentially expressed genes (DEGs) were identified (Adjusted p value < 0.05 and fold change > 1.5) (n = 3/group). GO enrichment analysis of DEGs induced by GPR110 ablation in male (upper) and female (lower) mice (l). Venn diagram identifies the genes induced by MASH and reversed in LKO or suppressed by MASH and reversed in LKO mice (m). Data are presented as mean ± SD; Statistical significance was calculated using two-tailed Student’s t-test (c-e) or one-way ANOVA followed by Tukey’s multiple comparisons test (f-k), one-sided p values by hypergeometric test and performed adjustments for multiple testing (l).

Source data

Extended Data Fig. 5 Loss of hepatic Gpr110 ameliorates MASH and its related hepatic fibrosis induced by an CDHF45 diet in female mice, but not in male mice.

10-week-old male and female LKO mice and their WT littermates were fed with STC or choline-deficient high-fat (CDHF45) diet for 32 weeks (n = 5/group for male and female WT and LKO mice on STC, n = 6/group for male and female WT and LKO mice on CDHF45 for b-y). a, Experimental design. b,d, Body weight in male (b) and female (d) mice. c,e, Liver/body weight ratio of male (c) and female (e) mice. f-i, Serum ALT and AST levels in male (f,g) and female (h,i) mice. j,r, Representative images of H&E staining (top), immunohistochemistry for F4/80 (middle) and Sirius Red staining (bottom) of liver sections from male (j) and female (r) mice; Scale bars, 100 μm. k-o, NAFLD activity score (k), hepatic steatosis score (l), inflammatory foci per field (m), percentage of F4/80-positive area (n) and percentage of fibrosis area (o) in the liver of male mice. s-w, NAFLD activity score (s), hepatic steatosis score (t), inflammatory foci per field (u), percentage of F4/80-positive area (v) and percentage of fibrosis area (w) in the liver of female mice. p,x, Hepatic TG content in male (p) and female (x) mice. q,y, Hepatic hydroxyproline content in male (q) and female (y) mice. z,aa, Western blot analysis for α-SMA protein expression in the liver of male (a) and female (aa) mice. The right panels are the densitometric analyses for the relative abundance of α-SMA normalized with GAPDH (n = 3/group). Data are presented as mean ± SD; Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple comparisons test (b-i,k-q,s-aa). Schematic in a created with BioRender.com.

Source data

Extended Data Fig. 6 Loss of hepatic Gpr110 has no obvious effects on serum lipid and glucose levels or glucose metabolism in male or female mice.

10-week-old male and female LKO mice and their WT littermates were fed with STC or choline-deficient high-fat (CDHF45) diet for 32 weeks. a,b,d,e, Serum levels of TG and FFA in male (a,b) and female (d,e) mice. c,f, Blood glucose levels at fed and fasting states in male (c) and female (f) mice. g-l, Serum levels of TC, HDL and LDL in male (g,h,i) and female (j,k,l) mice. m,n, Glucose tolerance test (GTT) performed at the 30th week of study and the area under curve (AUC) during GTT in male (m) and female (n) mice. o,p, Insulin tolerance test (ITT) performed at the last week of study and AUC during ITT in male (o) and female (p) mice. n = 5/group for male and female WT and LKO mice on STC, n = 6/group for male and female WT and LKO mice on CDHF45. Data are presented as mean ± SD; Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple comparisons test (a-l,m-p right panels) or two-way ANOVA followed by Tukey’s multiple comparisons test (m-p left panels).

Source data

Extended Data Fig. 7 Global deletion of Gpr110 ameliorates CDAHF60-induced MASH in female mice.

a, Schematic diagram for the generation of global Gpr110 knockout (GKO) mice. A pair of sgRNAs targeting exon 4 of Gpr110 gene was designed. The CRISPR/Cas9 system was utilized to produce GKO mice. Locations of the primers for PCR analysis of the wild-type (WT) and GKO alleles are indicated. The primers F1 and R1 detect the presence of exon 4 and amplify a band of 447 bp in WT mice. The primers F2 and R2 spanning the exon 4 amplify a band of 280 bp in GKO mice. b, Genotyping of GKO mice by genomic PCR analysis. c, Deletion of GPR110 in the liver of GKO mice at the protein level was validated (n = 3/group). d-ab, 10-week-old male and female GKO mice and their WT littermates were fed STC or CDAHF60 for 12 weeks (n = 5/group for male and female WT and GKO mice on STC, n = 7/group for male WT mice on CDAHF60, n = 5/group for male GKO mice on CDAHF60, n = 7/group for female WT mice on CDAHF60, n = 6/group for female GKO mice on CDAHF60 for e-x). d, Experimental design. e,h, Liver/body weight ratio of male (e) and female (h) mice. f,g,i,j, Serum ALT and AST levels in male (f,g) and female (i,j) mice. k,s, Representative images of H&E staining (top), immunohistochemistry for F4/80 (middle) and Sirius Red staining (bottom) of liver sections from male (k) and female (s) mice; Scale bars, 100 μm. l-p, NAFLD activity score (l), hepatic steatosis score (m), inflammatory foci per field (n), percentage of F4/80-positive area (o) and percentage of fibrosis area (p) in the liver of male mice. t-x, NAFLD activity score (t), hepatic steatosis score (u), inflammatory foci per field (v), percentage of F4/80-positive area (w) and percentage of fibrosis area (x) in the liver of female mice. q,y, Hepatic TG content in male (q) and female (y) mice. r,z, Hepatic hydroxyproline content in male (r) and female (z) mice. aa,ab, Western blot analysis for α-SMA protein expression in the liver of male (aa) and female (ab) mice. The right panels are the densitometric analyses for the relative abundance of α-SMA normalized with GAPDH (n = 3/group). Data are presented as mean ± SD; Statistical significance was calculated using two-tailed Student’s t-test (c) or one-way ANOVA followed by Tukey’s multiple comparisons test (e-j,l-r,t-ab). Schematic in d and n created with BioRender.com.

Source data

Extended Data Fig. 8 GPR110 expression in male and female mice.

a,b, The expression of GPR110 at mRNA (a) and protein (b) levels in the liver of WT male and female mice fed with STC or CDAHF60 diet for 12 weeks; The expression levels in all other groups were compared to the expression level in male-STC group (n = 3/group). c,d, The mRNA expression levels of Esr2 (c) and Gpr30 (d) in the liver of WT or LKO male (left panel) and female (right panel) mice fed with either STC or CDAHF60 diet; The expression levels in all other groups were compared to the expression level in WT-STC male group (n = 5/group for male and female WT and LKO mice on STC, n = 9/group for male WT mice on CDAHF60, n = 7/group for male LKO mice on CDAHF60, n = 11/group for female WT mice on CDAHF60, n = 13/group for female LKO mice on CDAHF60). Data are presented as mean ± SD; Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple comparisons test (a-d).

Source data

Extended Data Fig. 9 Gender differences in the influence of Gpr110 deletion on liver phenotypes are imposed by the oestrogen signaling.

8-week-old female LKO and WT mice underwent ovariectomy (OVX) or sham operation. After 2-week recovery, all mice were placed on CDAHF60 diet (n = 6/group). a, Experimental design. b, Liver/body weight ratio of these mice. c,d, Serum levels of ALT (c) and AST (d). e, Representative images of H&E staining (top), immunohistochemistry for F4/80 (middle) and Sirius Red staining (bottom) of liver sections; Scale bars, 100 μm. f-j, NAFLD activity score (f), hepatic steatosis score (g), inflammatory foci per field (h), percentage of F4/80-positive area (i) and percentage of fibrosis area (j) in the liver. k,l, Hepatic contents of TG (k) and hydroxyproline (l). Data are presented as mean ± SD; Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple comparisons test (b-d,f-l). Schematic in a created with BioRender.com.

Source data

Extended Data Fig. 10 Association of GPR110 rs937057 T > C variant with MASLD and its functional impact.

a, Representative allelic discrimination plot showing genotypes of samples for the GPR110 variant rs937057 T > C (p.I571M); Homozygous: T/T, C/C; Heterozygous: T/C. b, Allele frequencies of rs937057 T > C in MASLD and control groups in the case control cohort (n = 396). c,d, Molecular dynamic simulation on I571M mutation on the autoactivation of GPR110567-910. c, Root mean square deviation (RMSD) values of Cα atoms for wild-type I571stalk GPR110567-910 (green) and stalk mutation I571stalkM GPR110567-910 (cyan). d, The molecular dynamics (MD) stimulated structures of wild-type I571stalk GPR110567-910 and stalk mutation I571stalkM GPR110567-910 were superimposed, showing a deviation of 2.213 Å. Two different side views were shown in the left and middle panels, and the top view was shown in the right panel. e, Human female hepatoma Mahlavu cells were transfected with plasmids overexpressing WT GPR110 (I571), mutant GPR110 (M571) or GFP as the control for 24 hours for the detection of GPR110 mRNA expression (n = 6/group). Data are presented as mean ± SD; Statistical analyses were performed using two-sided χ2 test (b); Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple comparisons test (e).

Source data

Supplementary information

Supplementary Information (download PDF )

Supplementary Tables 1–6, Extended Data Fig. 1–10 legends and Supplementary Figs. 1–10.

Reporting Summary (download PDF )

Supplementary Data 2 (download XLSX )

Supplementary Fig. 2: Hepatic expression of Scd1 in different interventions. a,b, Hepatic expression of Scd1 in the livers of male (a) and female (b) LKO and WT mice fed with 12-week CDAHF60 (n = 9 per group for male WT mice, n = 7 per group for male LKO mice, n = 11 per group for female WT mice, n = 13 per group for female LKO mice). c,d, Hepatic expression of Scd1 in the livers of male (c) and female (d) mice with AAV-mediated overexpression of GPR110 or GFP control fed with 12-week CDAHF60 (n = 6 per group for male mice receiving AAV, n = 8 per group for female mice receiving AAV). Data are presented as the mean ± s.d. Statistical significance was calculated using a two-tailed Student’s t-test (a–d).

Supplementary Data 3 (download XLSX )

Supplementary Fig. 3: Loss of Gpr110 in hepatocytes ameliorates hepatic steatosis in female, but not male mice. Ten-week-old male and female LKO mice and their WT littermates were fed with CDAHF60 diet for 2 weeks (n = 6 per group for male WT and LKO mice, n = 7 per group for female WT mice, n = 6 per group for female LKO mice). a,e, Liver/body weight ratio of male (a) and female (e) mice. b,c,f,g, Serum ALT and AST levels in male (b and c) and female (f and g) mice. d,h, Serum TG level of male (d) and female (h) mice. i,l, Representative images of H&E staining (top) and Oil-Red O staining (bottom) of liver sections from male (i) and female (l) mice; Scale bars, 100 μm. j,m, hepatic steatosis score in the liver of male (j) and female (m) mice. k,n, Hepatic TG content in male (k) and female (n) mice. o,p, Real-time PCR analysis of liver tissues for genes involved in the regulation of lipid metabolism in male (o) and female (p) mice. Data are presented as the mean ± s.d. Statistical significance was calculated using a two-tailed Student’s t-test (a–h, j, k and m–p).

Supplementary Data 4 (download XLSX )

Supplementary Fig. 4: AAV-mediated delivery of shRNA specifically knocks down Esr1 expression in the liver. a,b, Hepa1-6 cells were transfected with plasmids encoding shRNA against various sequences in Esr1 (shEsr1-1, shEsr1-2 and shEsr1-3) or scramble sequence (Scramble). The expression of ERα at mRNA (a) and protein (b) levels in the cells were determined by real-time qPCR and western blot analyses (n = 3 per group). shEsr1-1 was selected for subsequent AAV packaging as it demonstrated highest Esr1 knockdown efficiency. c,d, 9-week-old female WT mice were infected with AAV encoding shRNA against Esr1 (AAV-shEsr1) or with scramble sequence (AAV-Scramble) via tail-vein injection (2 × 1011 genome copies of AAV per mouse; n = 4 per group). Three weeks after infection, the mRNA expression of Esr1 in the liver, gastrocnemius and ovaries (c) and the protein expression of ERα in the liver (d) was measured by real-time qPCR and western blot, respectively. e–g, 9-week-old female LKO and WT mice fed with STC were administered with AAV-shEsr1 or AAV-Scramble via tail-vein injection. One week after injection, the mice were switched to a CDAHF60 diet for 12 weeks (n = 8 per group for WT mice receiving Scramble, n = 7 per group for LKO mice receiving Scramble and WT/LKO mice receiving shEsr1). e, Body weight of the mice. f,g, Serum levels of TG (f) and TC (g) in the mice. Data are presented as the mean ± s.d. Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple-comparisons test (a, b and e–g) or two-tailed Student’s t-test (c and d).

Supplementary Data 5 (download XLSX )

Supplementary Fig. 5: The NFAT2–ERα signalling is specifically coupled to GPR110, but not general PKA activation in hepatocytes. Hepa1-6 cells transfected with GFP or GPR110 were treated with P12 (100 μM) or forskolin (FSK, 5 μM) as indicated for 2 h. a–c, The cells were subjected to the detection of PKA activity (n = 4 per group; a), NFAT2 phosphorylation (n = 3 per group; b) and Esr1 mRNA expression (n = 6 per group; c). Data are presented as the mean ± s.d. Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple-comparisons test (a–c).

Supplementary Data 6 (download XLSX )

Supplementary Fig. 6: Effects of P12 on hepatic PKA–NFAT2–ERα signalling in vivo. Ten-week-old female C57BL/6J mice were injected with P12 (low dose: 2 mg per kg, high dose: 5 mg per kg) or PBS control via tail vein. a–c, Liver tissues were collected 4 h after injection for the detection of PKA activity (n = 4 per group; a), NFAT2 phosphorylation (n = 3 per group; b) and Esr1 mRNA expression (n = 4 per group; c). Data are presented as the mean ± s.d. Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple-comparisons test (a–c).

Supplementary Data 8 (download XLSX )

Supplementary Fig. 8: Knockdown efficiency of siRNAs against Gpr110 in vitro. a,b, Hepa1-6 (a) and AML12 (b) cells were transfected with siRNA against various sequences in mouse Gpr110 (siRNA-1, siRNA-2 and siRNA-3) or scramble sequence (Scramble). The mRNA expression of Gpr110 in the cells were determined by real-time qPCR (n = 3 per group). siRNA-3 was selected for subsequent chemical modifications and GalNAc conjugation as it demonstrated highest Gpr110 knockdown efficiency. Data are presented as the mean ± s.d.; Statistical significance was calculated using one-way ANOVA followed by Tukey’s multiple-comparisons test (a and b).

Supplementary Data 9 (download XLSX )

Supplementary Fig. 9: GalNAc-conjugated siRNA against Gpr110 suppresses hepatic expression of genes related to inflammation and fibrosis in female mice. Male and female mice fed with CDAHF60 for 2 weeks were subjected to siGpr110 or Scramble via subcutaneous injection (5 mg per kg body weight biweekly, four doses). These mice were maintained on CDAHF60 for another 8 weeks (n = 6 per group for male mice receiving Scramble or siGpr110, n = 8 per group for female mice receiving Scramble or siGpr110 for a–d). Hepatic mRNA expression of genes related to inflammation (a and c) and fibrosis (b and d) in male (a and b) and female (c and d) mice. Data are presented as the mean ± s.d. Statistical significance was calculated using two-tailed Student’s t-test (a–d).

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Yang, F., Wang, W., Qiu, F. et al. Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling. Nat Metab 8, 116–138 (2026). https://doi.org/10.1038/s42255-025-01436-1

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