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Article Open Access

Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model

  • Authors:
    • Aaron Afonso‑Alí
    • Jano Dicroce‑Giacobini
    • Silvia Teixido‑Trujillo
    • Esteban Porrini
    • José Antonio Pérez‑Pérez
    • Sonia García‑Hernández
    • Sergio Luis‑Lima
    • Beatriz Abrante‑Pérez
    • Alberto Hernández‑Bustabad
    • Nieves Guadalupe Acosta‑González
    • Miriam Iglesias‑Hernández
    • Laura Díaz‑Martín
    • Covadonga Rodríguez‑González
    • Manuel Hernández‑Guerra
    • Ana Elena Rodríguez‑Rodríguez
  • View Affiliations / Copyright

    Affiliations: Laboratory of Renal Function, Institute of Biomedical Technologies, University of La Laguna, Tenerife 38200, Spain, Research Unit, University Hospital of The Canary Islands, Tenerife 38200, Spain, Department of Histology and Pathology, University Hospital of The Canary Islands, Tenerife 38200, Spain, Liver Unit, University Hospital of The Canary Islands, Tenerife 38200, Spain, Department of Animal Biology, Edaphology and Geology, Faculty of Biology, University of La Laguna, Tenerife 38205, Spain
    Copyright: © Afonso‑Alí et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 264
    |
    Published online on: July 22, 2025
       https://doi.org/10.3892/mmr.2025.13629
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Abstract

The prevalence of non‑alcoholic fatty liver disease (NAFLD) increases in post‑menopausal women, driven by obesity and metabolic syndrome (MS). However, the pathogenesis of this interaction remains poorly understood. The present study investigated the interplay between obesity, menopause and NAFLD in a C57BL6/J mouse model of diet‑induced obesity. The study included male and female animals, in which a subgroup of females underwent ovariectomy to simulate menopause. Mice were fed a high‑fat diet for 6 months which resulted in them becoming overweight, and developing hyperglycemia and insulin resistance. The present study analyzed liver histology, inflammatory markers and hepatic lipid profiles. All obese animals showed liver steatosis, hepatocyte ballooning and fibrosis. Sex‑related differences were observed, including: i) Obese male mice developed increased expression of inflammatory markers and altered lipid profile; ii) obese female mice exhibited less severe steatosis, hepatic inflammation and lipotoxicity, and iii) ovariectomized obese female mice exhibited exacerbated hepatic lipotoxicity and tissue damage. Ovariectomized obese female mice also had reduced triacylglycerol and cholesteryl ester levels, but increased levels of toxic intermediaries, such as free fatty acids, diacylglycerols and free cholesterol, elevated expression of NF‑κB in the liver and increased levels of serum transaminases, indicating liver damage. These findings suggested that estrogen may protect against NAFLD progression by regulating lipid droplet formation, especially in the context of insulin resistance. More studies in the field are clearly needed to achieve a complete understanding of these pathways, which may serve to improve current therapies.
View Figures

Figure 1

Representative images of liver
sections of female and male mice. Females on (A) SD, (B) SD-OVX,
(C) HFD and (D) HFD-OVX. Males on (E) SD and (F) HFD. SD, standard
diet; HFD, high-fat diet; OVX, ovariectomized.

Figure 2

Western blot analysis of inflammatory
markers in liver. The figure shows the relative expression of
NF-κβ, TNF-α and IL-1β for (A) females and (B) males in liver
homogenates as indicated. Tukey plots indicate the median as the
horizontal line, the top and bottom of the box show the upper and
lower quartiles, maximum and minimum values are displayed as
whiskers. *P<0.05; **P<0.01; ***P<0.001. SD, standard
diet; HFD, high-fat diet; OVX, ovariectomized.

Figure 3

Serum biochemical analysis. (A) Serum
transaminases in females. (B) Serum Chol and TAG levels in females.
(C) Serum transaminases in males. (D) Serum Chol and TAG levels in
males. Boxplots indicate the median as the horizontal line, the top
and bottom of the box show the upper and lower quartiles, maximum
and minimum values are displayed as whiskers. Female significance:
αHFD-OVX vs. HFD, SD and SD-OVX, P<0.05.
βHFD vs. SD, P<0.05, ωHFD-OVX vs. SD-OVX
and SD, P<0.05. Male significance: *HFD vs. SD, P<0.05. Chol,
free cholesterol; TAG, triglyceride AST, aspartate
aminotransferase; ALT, alanine aminotransferase; SD, standard diet;
HFD, high-fat diet; OVX, ovariectomized.

Figure 4

Lipidomic profile of liver tissue in
female mice. (A) Total lipid content. (B) Lipid classes profile.
(C) TAG levels. (D) Fatty acid profile of females as indicated in
the figure. Boxplots show the median as the horizontal line, the
top and bottom of the box show the upper and lower quartiles,
maximum and minimum values are displayed as whiskers. Statistical
significance: αHFD vs. SD, P<0.05,
βHFD-OVX vs. SD-OVX and SD, P<0.05.
ωHFD-OVX vs. SD, SD-OVX and HFD, P<0.05.
θSD-OVX vs. SD, P<0.05. TAG, triglycerides; FFA, free
fatty acid; DAG, diglycerides; Chol, free cholesterol; CE,
cholesterol esters; SD, standard diet; HFD, high-fat diet; OVX,
ovariectomized.

Figure 5

Lipidomic profile of liver tissue in
male mice. (A) Total lipid content. (B) Lipid classes profile. (C)
TAG levels. (D) Fatty acid profile as indicated in the figure.
Boxplots show the median as the horizontal line, the top and bottom
of the box show the upper and lower quartiles, maximum and minimum
values are displayed as whiskers. *P<0.05; ***P<0.001. TAG,
triglycerides; FFA, free fatty acid; DAG, diglycerides; Chol, free
cholesterol; CE, cholesterol esters; SD, standard diet; HFD,
high-fat diet; OVX, ovariectomized; SFAs, saturated fatty acids;
MUFAs, monounsaturated fatty acids; LC-PUFAs, long-chain
polyunsaturated fatty acids.
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Copy and paste a formatted citation
Spandidos Publications style
Afonso‑Alí A, Dicroce‑Giacobini J, Teixido‑Trujillo S, Porrini E, Pérez‑Pérez J, García‑Hernández S, Luis‑Lima S, Abrante‑Pérez B, Hernández‑Bustabad A, Acosta‑González N, Acosta‑González N, et al: Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model. Mol Med Rep 32: 264, 2025.
APA
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S. ... Rodríguez‑Rodríguez, A. (2025). Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model. Molecular Medicine Reports, 32, 264. https://doi.org/10.3892/mmr.2025.13629
MLA
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S., Luis‑Lima, S., Abrante‑Pérez, B., Hernández‑Bustabad, A., Acosta‑González, N., Iglesias‑Hernández, M., Díaz‑Martín, L., Rodríguez‑González, C., Hernández‑Guerra, M., Rodríguez‑Rodríguez, A."Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model". Molecular Medicine Reports 32.4 (2025): 264.
Chicago
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S., Luis‑Lima, S., Abrante‑Pérez, B., Hernández‑Bustabad, A., Acosta‑González, N., Iglesias‑Hernández, M., Díaz‑Martín, L., Rodríguez‑González, C., Hernández‑Guerra, M., Rodríguez‑Rodríguez, A."Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model". Molecular Medicine Reports 32, no. 4 (2025): 264. https://doi.org/10.3892/mmr.2025.13629
Copy and paste a formatted citation
x
Spandidos Publications style
Afonso‑Alí A, Dicroce‑Giacobini J, Teixido‑Trujillo S, Porrini E, Pérez‑Pérez J, García‑Hernández S, Luis‑Lima S, Abrante‑Pérez B, Hernández‑Bustabad A, Acosta‑González N, Acosta‑González N, et al: Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model. Mol Med Rep 32: 264, 2025.
APA
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S. ... Rodríguez‑Rodríguez, A. (2025). Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model. Molecular Medicine Reports, 32, 264. https://doi.org/10.3892/mmr.2025.13629
MLA
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S., Luis‑Lima, S., Abrante‑Pérez, B., Hernández‑Bustabad, A., Acosta‑González, N., Iglesias‑Hernández, M., Díaz‑Martín, L., Rodríguez‑González, C., Hernández‑Guerra, M., Rodríguez‑Rodríguez, A."Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model". Molecular Medicine Reports 32.4 (2025): 264.
Chicago
Afonso‑Alí, A., Dicroce‑Giacobini, J., Teixido‑Trujillo, S., Porrini, E., Pérez‑Pérez, J., García‑Hernández, S., Luis‑Lima, S., Abrante‑Pérez, B., Hernández‑Bustabad, A., Acosta‑González, N., Iglesias‑Hernández, M., Díaz‑Martín, L., Rodríguez‑González, C., Hernández‑Guerra, M., Rodríguez‑Rodríguez, A."Role of obesity and estrogen deficiency in non‑alcoholic fatty liver disease: Insights from a mouse model". Molecular Medicine Reports 32, no. 4 (2025): 264. https://doi.org/10.3892/mmr.2025.13629
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