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Article

Obeticholic Acid Reduces Atherosclerosis Progression in Mice After Bilateral Ovariectomy

by
Jiangdong Sun
1,
Yufeng Yin
1,
Yu Jiang
2 and
Dongmeng Qian
1,*
1
Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, China
2
Biomedical Center Experimental Animal Platform, Qingdao University, Qingdao 266071, China
*
Author to whom correspondence should be addressed.
J. Gerontol. Geriatr. 2026, 74(3), 17; https://doi.org/10.3390/jgg74030017
Submission received: 24 March 2026 / Revised: 22 June 2026 / Accepted: 23 June 2026 / Published: 26 June 2026
Browse Figures
Versions Notes

Abstract

As women age—especially after menopause—the risk of atherosclerosis increases significantly, but its physiological mechanism is still unclear. To explore potential strategies for preventing and treating postmenopausal atherosclerosis in women, in this study, we simulated the physiological state of menopause by constructing a bilateral ovariectomized mouse model to detect the proteome, blood lipids, platelet-activating factor in mouse plasma, LPS, diamine oxidase, platelet activation rate, and lipid deposition at the aortic arch position. The data showed that protein expression in the plasma of postmenopausal mice changed significantly, the platelet activation rate increased significantly, the intestinal barrier was damaged, and the plasma LPS increased. In postmenopausal mice, OCA could improve the intestinal barrier, reduce the plasma LPS and platelet activation rate, and slow the progression of atherosclerosis. This study describes the phenomenon of OCA being able to reduce the progression of atherosclerosis in mice after bilateral oophorectomy; however, this cannot be considered definitive evidence of a fully established mechanism, and further research is still needed.

1. Introduction

Atherosclerosis is a primary cause of ischemic stroke [1,2,3,4] and subsequently results in serious health problems such as disabilities [5], seriously threatening human health [6,7,8]. Its pathogenesis involves inflammation [9,10], metabolic abnormalities [11,12], genetics [13], vascular calcification [14,15,16], and dyslipidemia [17,18]. In clinical treatment, atherosclerosis can be treated by targeting inflammation [19] and blood lipids [20,21,22], which can reduce plaque formation [23] and the incidence of cardiovascular disease [24].
Atherosclerosis risk increases in aging women [25,26,27,28], especially in those with natural premature menopause [29]. Previous studies have shown that estrogen has a protective effect on cardiovascular diseases [30,31,32]; estradiol can inhibit vascular smooth muscle cell apoptosis [33] and atherosclerosis [34]. In postmenopausal women, the systemic estradiol level was found to decrease [35], and the expression of estrogen receptors in tissues was abnormal [36], while the risk of atherosclerosis in those receiving hormone treatment was reduced [37,38], suggesting that changes in estrogen levels may play a key role in postmenopausal atherosclerosis risk.
Menopause is also associated with intestinal barrier impairment [39], which can cause more intestinal microorganisms to enter the bloodstream, stimulating an increase in platelet activation rate [40], and excessive platelet activation has been implicated in the pathogenesis of atherosclerosis [40,41]. Therefore, restoring intestinal barrier integrity after menopause may help to reduce bacterial translocation, lower platelet activation rate, and attenuate atherosclerosis progression.
As a synthetic bile acid and Farnesoid X Receptor (FXR) agonist, obeticholic acid (OCA) has been shown to enhance intestinal barrier function [42,43] and inhibit platelet activation [44]. Therefore, OCA may slow the progression of postmenopausal atherosclerosis by improving intestinal barrier integrity and reducing hypercoagulability. In female mice after bilateral ovariectomy (OVX), it is possible to simulate the physiological state of menopause [45,46], so in this study we focus on female mice as the research subjects and establish an OVX mouse model to evaluate the effects and potential mechanisms of OCA on atherosclerosis risk following menopause, with the aim of identifying potential therapeutic approaches for preventing atherosclerosis in aging women.

2. Materials and Methods

2.1. Experiment Animals

This study was approved by the Ethics Committee of Qingdao University Medical College (2021, No. 20210825C573520220315179). A total of 45 eight-week-old female C57BL/6J mice (weight: 19–20 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China), and were housed under specific pathogen-free conditions (22–25 °C, 50–60% humidity, 12 h light/dark cycle) with free access to AIN93M feed and sterile water. We then conducted grouping and various experimental interventions. To reduce potential confounders, all mice used for intergroup comparison in this study were placed in adjacent positions for feeding and their interventions conducted during the same time period.

2.2. Mouse Grouping and Intervention

OVX procedure: Mice were anesthetized with isoflurane gas (R500, Shenzhen RWD Life Science and Technology Co., Ltd., Shenzhen, China) and placed in a supine position on a heating pad. After shaving and disinfecting the dorsal surface, a 1 cm longitudinal incision was made along the midline of the back. We gently separated the skin and muscles to expose the adipose tissue around the ovaries, ligated the fallopian tubes above and below the uterine horn, removed the ovaries, sutured the incision layer by layer, and disinfect the surgical wound with iodophor. The sham group underwent the same surgical procedure without ovary removal. Referring to previous in vivo mouse model studies [47,48], we assigned 5 mice per group.
To investigate the changes in plasma protein expression in postmenopausal mice, 10 8-week-old mice were randomly divided into the sham and OVX groups (n = 5 in each group) by flipping a coin. On the 300th day after OVX, plasma was collected and subjected to proteomic testing.
To investigate the effect of OCA on postmenopausal atherosclerosis, we randomly divided the mice into three groups by flipping a coin (n = 5 per group): sham operation (sham group), ovariectomized (OVX group), and ovariectomized plus OCA treatment groups (OVX + OCA group). All mice were orally administered a water suspension of OCA (30 mg/kg) [49] or an equal volume of water from day 1 to 300 after surgery. According to the ARRIVE guidelines 2.0, when one mouse in the sham group showed severe hair loss, it was excluded, and the remaining mice were euthanized after the intervention to collect samples.
To investigate the short-term effects of OCA on OVX mice, we randomly divided 10 8-week-old mice into the OVX and OVX + OCA groups by flipping a coin (n = 5 per group). OCA (30 mg/kg) [49] was administered orally from day 8 to 14 post-OVX; afterwards, we collected blood samples to test the platelet activation rate.
To assess the impact of lipopolysaccharides (LPS) on platelet activation rate, we randomly divided 10 8-week-old mice into the LPS and sham surgery groups by flipping a coin (n = 5 per group). The LPS group received an intraperitoneal injection of LPS (Sigma, St. Louis, MO, USA; 2 mg/kg) dissolved in saline [50], while the sham group received PBS alone. Blood was collected 30 min after injection for analysis.
To evaluate the long-term effects of chronic LPS exposure, we randomly divided 10 8-week-old mice into the LPS slow-release (LPS group) and saline slow-release groups (saline group) by flipping a coin (n = 5 per group). A sustained-release pump (RWD, Shenzhen, China) containing LPS (1 mg/kg/day) or saline (saline group) was implanted into the abdominal cavity [51], and tissue samples were collected for testing after 30 days.

2.3. Frozen Section

We placed the heart tissue in 4% paraformaldehyde and fixed it at room temperature for 24 h. Afterwards, we embedded the tissue in an optimum-cutting-temperature compound (Sakura, Torrance, CA, USA), precooled it for 3 min in a −18 °C low-temperature thermostat, and then sliced at the aortic arch position with a thickness of 10 μm. We stored the slices at 4 °C until stained.

2.4. Plasma Collection

After anesthetizing the mice using an isoflurane anesthesia machine (R500, RWD, China), blood was collected from the venous plexus behind the mouse eye socket. The whole blood was collected into a blood collection tube containing sodium citrate anticoagulant placed on ice, and then centrifuged at 3000 rpm for 10 min. Plasma was collected for subsequent testing.

2.5. Oil Red O Staining

After immersing the aortic arch slices in 50% ethanol for 60 s, we stained them with Oil Red O for 15 min, rapidly differentiated with 60% isopropanol for 10 s, removed excess dye, and then counterstained with hematoxylin. After sealing, we observed and photographed them under a microscope (Nikon, Tokyo, Japan). Lipid deposition was quantified using ImageJ 1.51j8 version software (NIH, Bethesda, MD, USA).

2.6. Paraffin Embedding and HE Staining

Intestinal tissues were fixed in 4% paraformaldehyde for 24 h, dehydrated in graded ethanol, and embedded in paraffin. We used a paraffin slicer to create slices with a thickness of 8 μ m and stored them at 4 °C. For hematoxylin–eosin staining (HE staining), sections were dewaxed, stained with hematoxylin for 5 min, rinsed, differentiated, and counterstained with eosin; afterwards, we sealed the slice and observed and photographed it under a microscope (Nikon Japan).

2.7. Blood Lipid Analysis

We thawed the plasma samples stored at −80 °C at 4 °C and analyzed them using a fully automated Hitachi biochemical analyzer (Hitachi, Tokyo, Japan).

2.8. Plasma Proteome Detection and Analysis

We entrusted Beijing Tsingke Biotech Co., Ltd. (Beijing, China) to conduct proteomic testing and analysis of plasma. Plasma samples were subjected to specific removal of high concentrations of interfering proteins such as albumin (Album) and immunoglobulin (IgG) using the Pierce Albumin Depletion Kit (ThermoFisher, Waltham, MA, USA), followed by proteomic testing and analysis.

2.9. Flow Cytometric Analysis of Platelet Activation

Referring to previous research [52,53,54], after anesthetizing mice with isoflurane, fresh blood samples were collected from the orbital venous plexus. After mixing 5 μL of blood with sodium citrate, we mixed this with CD61 (PE channel, BioLegend, San Diego, CA, USA) and CD62p (APC channel, BioLegend, San Diego, CA, USA) antibodies for 15 min at room temperature in the dark. After dilution and filtration through a 70 μm mesh, samples were analyzed by flow cytometry (10,000 events per sample). We used FlowJo v10.8.1 (BD, Franklin Lake, NJ, USA) to analyze the data, a flow cytometer without antibody staining was used as a blank control for cross circle gating, and CD61 and CD62p double-positive particles were used as activated platelet counts for statistical analysis.

2.10. ELISA Detection of Estradiol, Platelet-Activating Factor, and Diamine Oxidase

We use the commercial ELISA kit (Shanghai Jianglai Biotechnology Co., Ltd., Shanghai, China) to measure the levels of estradiol, platelet-activating factor, and diamine oxidase (DAO) in plasma. After completing the experimental steps according to the kit instructions, we measure the absorbance at 450 nm and calculate the concentration based on the standard curve.

2.11. Plasma LPS Measurement

Plasma LPS concentrations were measured using a Gram-negative bacterial endotoxin detection kit (BK-001, Zhanjiang Andus Biotechnology Co., Ltd. Zhanjiang, China) and a dynamic tube detector (LKM-02-64, Andus Biotechnology, Zhanjiang, China). If the LPS concentration in the sample exceeded the detection range, we diluted the sample and retested it.

2.12. Statistical Analysis

Data was analyzed using GraphPad Prism 9.10 (GraphPad Software, San Diego, CA, USA) to plot data into a bar chart and express it as mean ± SEM. The data between two groups were tested using Student’s t-test, where p < 0.05 is considered significant and p ≥ 0.05 insignificant. The significance analysis among the three groups was conducted using multiple factor analysis of variance (ANOVA, p < 0.05 is considered significant and p ≥ 0.05 insignificant), if significant differences were found, post hoc tests were used to test which groups had significant differences (p < 0.05 is considered significant and p ≥ 0.05 insignificant).

3. Results

3.1. At 300 Days After OVX, Protein Expression Is Significantly Altered in Mouse Plasma

To explore the underlying reasons for the increased progression of ovariectomy and atherosclerosis, this study examined the plasma proteome of mice at 300 days after oophorectomy. Compared with the sham group, the expression levels of 161 proteins in the plasma of OVX mice increased, while those of 177 protein groups decreased (Figure 1A,B), with extracellular-related proteins accounting for the highest proportion (Figure 1C). KEGG enrichment analysis showed changes in the expression of proteins related to multiple biological pathways, with the highest number of proteins related to complement and coagulation cascade function (Figure 1D). Please refer to Supplementary Materials Tables S1 and S2 for the raw data of the proteomics diagram in Figure 1.

3.2. The 300-Day OCA Intervention Attenuates Platelet Activation and Atherosclerosis Progression After OVX in Mice

As the proteomic data show that OVX significantly alters complement and coagulation cascade-related protein levels in mouse plasma, considering the correlation between coagulation cascade and platelet activation rate [55,56,57], combined with clinical research findings indicating that platelet activation rates significantly increase after menopause [58], we speculate that platelet activation levels may be altered in OVX mice. Considering the view that OCA can inhibit platelet activation [44], we detected the platelet activation rate in mice after ovariectomy and administration of OCA. In the flow cytometry data, the horizontal axis and the vertical axis represent the PE fluorescence intensity of the CD61 antibody and the APC fluorescence intensity of the CD62p antibody, respectively (the same applies below). The data show that the platelet activation rate of mice significantly increased after OVX, while OCA intervention significantly reduced this increase in platelet activation rate (Figure 2A,B) and decreased plasma platelet-activating factor levels (Figure 2C).
To evaluate the impact of OCA on the risk of postmenopausal atherosclerosis, in this study, we first simulated the postmenopausal physiological state by constructing an OVX mouse model. The mice were treated with OCA by oral gavage for 300 consecutive days, following which lipid deposition at the aortic arch was detected through Oil Red O staining. The results showed that OVX significantly increased lipid deposition in the aortic arch, while OCA treatment significantly reduced lipid accumulation in the OVX mice (Figure 3A,B).
Menopause has been found to cause a decrease in estradiol levels [35]. In this study, plasma estradiol concentrations were measured in mice, and the data showed that OVX significantly reduced estradiol levels in mouse plasma, while OCA did not significantly alter the estradiol reduction caused by OVX (Figure 3C). Further detection revealed that OCA administration had no significant effect on the blood lipids of OVX mice (Figure 3D–G), suggesting that atherosclerosis progression in mice after OCA-reduced OVX may be influenced by factors other than blood lipids.

3.3. A 7-Day OCA Intervention Can Reduce the Platelet Activation Rate in Mice After Ovariectomy

To further confirm the effect of elevated platelet activation rate on atherosclerosis progression in mice after OVX, in this study, we conducted an intragastric administration of OCA in mice 8–14 days after OVX and measured their platelet activation rate. The results showed that the platelet activation rate significantly increased after 7 days of OVX, while OCA intervention significantly inhibited this phenomenon (Figure 4A,B).

3.4. The 300-Day OCA Intervention Enhances the Intestinal Barrier in OVX Mice

Menopause can lead to intestinal barrier damage [35], which in turn increases the level of LPS in the blood [59]. Because OCA can enhance the intestinal barrier, in this study, we further examined the intestinal morphology and barrier markers in each group of mice. HE staining showed the intestinal morphology of each group (Figure 5A), and plasma DAO detection (intestinal permeability index [60,61,62] showed that OCA significantly reduced the increase in DAO after 300 days of OVX (Figure 5B), indicating that OCA slowed down the intestinal barrier damage caused by OVX.
Intestinal barrier injury can lead to the invasion of gut microbiota into the bloodstream [59,63]. As a component of Gram-negative bacteria, LPS can enhance the platelet activation rate [64] and reflect bacterial levels in the blood [65]. Here, we further detected the LPS concentration in the plasma of each group of mice after 300 days of OVX. The data show that, at 300 days after OVX, the level of LPS in mouse plasma significantly increased, while OCA intervention significantly reduced these levels after OVX (Figure 5C).
To directly detect the effect of LPS on platelet activation, we detected the platelet activation rate in mice after intraperitoneal injection of LPS for 30 min, with the data showing that the platelet activation rate significantly increased (Figure 5D,E).

3.5. Chronic LPS Exposure Increases Platelet Activation and Atherosclerosis in Mice

To further examine the role of elevated plasma LPS in postmenopausal atherosclerosis, we embedded a slow-release pump into the abdominal cavity to keep LPS in the blood. After testing the blood lipids of mice 30 days later, it was found that intraperitoneal slow-release LPS did not significantly change the blood lipid level of mice (Figure 6A–D), but significantly increased the platelet activation rate (Figure 6E,F) and increased the development of atherosclerosis (Figure 7A,B).

4. Discussion

In this study, we detected changes in the plasma proteome of mice after OVX through proteome analysis, and the effects of OCA on atherosclerosis, blood lipids, intestinal barrier, platelet-activating factor, and platelet activation rate in mice after OVX through oral intervention with OCA. We also detected the effects of LPS on platelet activation rate in mice through intraperitoneal injection and intraperitoneal sustained release of LPS, and the effects of intraperitoneal sustained release of LPS on blood lipids and atherosclerosis progression in mice.
The data from this study showed that OVX leads to intestinal barrier dysfunction and increased platelet activation rate, which is consistent with clinical studies showing intestinal barrier damage [35,39,66] and elevated platelet activation rate in postmenopausal women [67]. Repairing the intestinal barrier can reduce excessive activation of platelets [68]; the data from this study show that continuous OCA administration enhanced the intestinal barrier of mice after OVX, reduced the platelet activation rate and atherosclerosis progression, in alleviating the progression of atherosclerosis, which is consistent with the research conclusion that OCA can alleviate vascular calcification in ApoE−/− mice [69].
At the same time, the level of LPS in the plasma of mice after OVX increased. The data show that LPS entering the bloodstream can increase the platelet activation rate, which is in agreement with multiple studies [70,71,72]. Continuous intraperitoneal sustained release of LPS can also increase the platelet activation rate in mice and promote the progression of atherosclerosis, which is consistent with the clinical observation of systemic endotoxemia and the risk of thrombosis [73,74]. Combined with the view that excessive activation of platelets can promote the progression of atherosclerosis [40,41], this study speculated that the increase in atherosclerosis induced by ovariectomy in mice may be related to the abnormal platelet overactivation after menopause.
Menopause not only increases the risk of atherosclerosis [75,76] but is also associated with multiple comorbidities, including anxiety [2], Alzheimer’s disease [77,78], osteoporosis [79,80,81], periodontitis [82], and sarcopenia [83,84], which are closely related to changes in intestinal microbiota composition [83,85,86,87,88]. The diversity of intestinal microorganisms changes in postmenopausal atherosclerosis patients [89]. Given that OCA modulates gut microbial diversity [49], its potential impact on postmenopause-related diseases deserves further investigation. The atherosclerosis formation mechanism is complex, and individual risk assessment is particularly important in women [90]. In addition to drug intervention, another important research direction to explore is reliable biomarkers [91] and effective diagnostic methods [92,93] for early detection of postmenopausal atherosclerosis.
Inflammation is an important risk factor for atherosclerosis [94,95], and postmenopausal women have elevated systemic inflammatory markers [96,97,98]; in this context, it has been reported that restoration of intestinal barrier function can reduce systemic inflammation [99,100]. In this study, we did not evaluate inflammatory cytokines, nor did we describe the detailed molecular pathways involved in OCA-mediated protection, which are significant limitations. This study found that the plasma protein expression in mice changed significantly after OVX, but no further research was conducted regarding the impacts of these protein expression changes on the risk of atherosclerosis. The sample size of this study, being relatively small, is a further limitation of this study. Although this study found that OCA can enhance the intestinal barrier of OVX mice and reduce the level of LPS in the plasma of OVX mice, it was not confirmed whether the increased LPS levels in the plasma of OVX mice come from the intestinal barrier. Furthermore, the data of this study showed that OCA significantly reduced the platelet activation rate and the progress of atherosclerosis in OVX mice, but we did not conduct in-depth research on platelet aggregation in atherosclerotic plaque, which is another limitation. Further research addressing the abovementioned limitations may provide new insights into the formation and prevention of atherosclerosis after menopause.

5. Conclusions

This study described the phenomenon of OCA being able to reduce the progression of atherosclerosis in mice after bilateral oophorectomy. However, this cannot be considered as definitive evidence of a fully established mechanism, and further research is still needed.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jgg74030017/s1, Table S1: KEGG annotation; Table S2: KEGG enrichmen.

Author Contributions

Conceptualization, J.S. and D.Q.; methodology, J.S., Y.Y. and Y.J.; validation, J.S. and Y.Y.; formal analysis, J.S.; investigation, J.S.; resources, J.S. and D.Q.; data curation, J.S., Y.Y. and Y.J.; writing—original draft preparation, J.S.; writing—review and editing, J.S. and D.Q.; visualization, J.S. and Y.Y.; supervision, project administration and funding acquisition, D.Q. All authors have read and agreed to the published version of the manuscript.

Funding

This research and the APC was funded by the Natural Science Foundation of Shandong Province (ZR2021QH254) support.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Qingdao University Medical College on 25 August 2021 (No. 20210825C573520220315179).

Informed Consent Statement

Not applicable.

Data Availability Statement

The author declares that all raw data for this study can be provided by contacting the corresponding author.

Acknowledgments

We would like to thank Meng Zhang, Yunlong Luo and Changcheng Li from Beijing Tsingke Biotech Co., Ltd. for them assistance in data interpretation.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
OCAObeticholic Acid
OVXBilateral ovariectomy
DAODiamine Oxidase
LPSLipopolysaccharide
HE stainingHematoxylin-eosin staining
FXRFarnesoid X Receptor

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Figure 1. At 300 days after OVX, the expression of proteins is significantly altered in mouse plasma. (A) The volcano plot shows the difference in expression levels of differentially expressed proteins between two groups of samples (the horizontal axis represents the logarithm of the difference multiplier with a base of 2, the vertical axis represents the logarithm of the p-value with a base of 10, and the red and green scatter dots represent the up- and downregulated differentially expressed proteins, respectively). (B) Cluster heatmap of differentially expressed proteins (rows represent differentially expressed proteins, columns represent samples, and shorter clustering branches indicate higher similarity). (C) Pie chart of differentially expressed protein subcellular localization results (different colors represent different subcellular structures; numbers outside parentheses represent the number of differentially expressed proteins annotated with corresponding subcellular structures, and the ratios of them to all differentially expressed proteins annotated with subcellular structures are inside parentheses). (D) KEGG enrichment analysis result bubble plot (selecting the 20 most significant pathway entries from the enrichment results and displaying them in the plot, with the vertical axis representing KEGG pathways and the horizontal axis representing enrichment factors, the ratio of the number of differentially expressed proteins enriched in this entry to the number of annotated proteins; the larger the enrichment factor, the higher the degree of differentially expressed protein enrichment, and the smaller the p-value, the more significant the enrichment).
Figure 1. At 300 days after OVX, the expression of proteins is significantly altered in mouse plasma. (A) The volcano plot shows the difference in expression levels of differentially expressed proteins between two groups of samples (the horizontal axis represents the logarithm of the difference multiplier with a base of 2, the vertical axis represents the logarithm of the p-value with a base of 10, and the red and green scatter dots represent the up- and downregulated differentially expressed proteins, respectively). (B) Cluster heatmap of differentially expressed proteins (rows represent differentially expressed proteins, columns represent samples, and shorter clustering branches indicate higher similarity). (C) Pie chart of differentially expressed protein subcellular localization results (different colors represent different subcellular structures; numbers outside parentheses represent the number of differentially expressed proteins annotated with corresponding subcellular structures, and the ratios of them to all differentially expressed proteins annotated with subcellular structures are inside parentheses). (D) KEGG enrichment analysis result bubble plot (selecting the 20 most significant pathway entries from the enrichment results and displaying them in the plot, with the vertical axis representing KEGG pathways and the horizontal axis representing enrichment factors, the ratio of the number of differentially expressed proteins enriched in this entry to the number of annotated proteins; the larger the enrichment factor, the higher the degree of differentially expressed protein enrichment, and the smaller the p-value, the more significant the enrichment).
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Figure 2. The 300-day OCA intervention reduces platelet activation in OVX mice. (A,B) Flow cytometric analysis of platelet activation rate in each group (the detection occurred 300 days after OCA administration). The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 21.04 and p = 0.0002), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.05), while there was no statistically significant difference between the sham group and the OVX + OCA group (p = 0.2721; differences were considered significant at p < 0.01). In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count. (C) Plasma platelet-activating factor levels in each group. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 19.78 and p = 0.2721), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.01), while there was no statistically significant difference between the sham group and the OVX + OCA group (p = 0.0873; differences were considered significant at p < 0.05).
Figure 2. The 300-day OCA intervention reduces platelet activation in OVX mice. (A,B) Flow cytometric analysis of platelet activation rate in each group (the detection occurred 300 days after OCA administration). The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 21.04 and p = 0.0002), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.05), while there was no statistically significant difference between the sham group and the OVX + OCA group (p = 0.2721; differences were considered significant at p < 0.01). In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count. (C) Plasma platelet-activating factor levels in each group. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 19.78 and p = 0.2721), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.01), while there was no statistically significant difference between the sham group and the OVX + OCA group (p = 0.0873; differences were considered significant at p < 0.05).
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Figure 3. The 300-day OCA intervention reduces atherosclerosis progression in OVX mice. (A,B) Oil Red O staining of the aortic arch showing atherosclerotic lesions in each group (the detection occurred 300 days after OCA administration, 100× magnification, the red area within the outer wall of the blood vessel divided by the total area within the outer wall is an indicator of lipid deposition progression). The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 14.33 and p = 0.0009), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.05), while there was no statistically significant difference between the sham group and the OVX + OCA group, (p = 0.1904; differences were considered significant at p < 0.05). (C) Plasma estradiol levels in sham group, OVX group, and OVX + OCA group. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 166.9, p < 0.0001), and post hoc tests showed that there was a statistically significant difference in the e-index between the sham group, OVX group, sham group, and OVX + OCA group (p < 0.0001). There was no statistically significant difference between the OVX group and the OVX + OCA group (p = 0.9475). (D–G) Plasma triglyceride, cholesterol, and high-density lipoprotein and low-density lipoprotein levels in each group. The one-way ANOVA results based on the triglyceride data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.1161 and p = 0.8915). The results of one-way ANOVA based on the triglyceride data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.7761 and p = 0.4838). The one-way ANOVA results based on the high-density lipoprotein data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.5721 and p = 0.5802). The one-way ANOVA results based on the low-density lipoprotein data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.3360 and p = 0.7217).
Figure 3. The 300-day OCA intervention reduces atherosclerosis progression in OVX mice. (A,B) Oil Red O staining of the aortic arch showing atherosclerotic lesions in each group (the detection occurred 300 days after OCA administration, 100× magnification, the red area within the outer wall of the blood vessel divided by the total area within the outer wall is an indicator of lipid deposition progression). The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 14.33 and p = 0.0009), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, as well as between the OVX group and the OVX + OCA group (p < 0.05), while there was no statistically significant difference between the sham group and the OVX + OCA group, (p = 0.1904; differences were considered significant at p < 0.05). (C) Plasma estradiol levels in sham group, OVX group, and OVX + OCA group. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 166.9, p < 0.0001), and post hoc tests showed that there was a statistically significant difference in the e-index between the sham group, OVX group, sham group, and OVX + OCA group (p < 0.0001). There was no statistically significant difference between the OVX group and the OVX + OCA group (p = 0.9475). (D–G) Plasma triglyceride, cholesterol, and high-density lipoprotein and low-density lipoprotein levels in each group. The one-way ANOVA results based on the triglyceride data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.1161 and p = 0.8915). The results of one-way ANOVA based on the triglyceride data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.7761 and p = 0.4838). The one-way ANOVA results based on the high-density lipoprotein data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.5721 and p = 0.5802). The one-way ANOVA results based on the low-density lipoprotein data of the sham group, OVX group, and OVX + OCA group showed that there was no statistically significant difference between the three groups (F = 0.3360 and p = 0.7217).
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Figure 4. A 7-day OCA intervention reduces platelet activation rate in OVX mice. (A,B) Flow cytometric analysis of the platelet activation rate in each group after 7 days of OCA intervention. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 12.60 and p = 0.0011), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, between the sham group and the OVX + OCA group, and between the OVX group and the OVX + OCA group (p < 0.05). (The detection occurred 7 days after the OCA intervention. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count, t-test; differences were considered significant at p < 0.05.).
Figure 4. A 7-day OCA intervention reduces platelet activation rate in OVX mice. (A,B) Flow cytometric analysis of the platelet activation rate in each group after 7 days of OCA intervention. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 12.60 and p = 0.0011), and post hoc tests showed that there was a statistically significant difference between the sham group and the OVX group, between the sham group and the OVX + OCA group, and between the OVX group and the OVX + OCA group (p < 0.05). (The detection occurred 7 days after the OCA intervention. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count, t-test; differences were considered significant at p < 0.05.).
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Figure 5. The 300-day OCA intervention enhances the intestinal barrier and reduces plasma LPS in OVX mice. (A) Representative HE staining images showing intestinal morphology in each group (the detection occurred 300 days after OCA administration, 100× magnification). (B) Plasma diamine oxidase (DAO) levels in different groups. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 18.94 and p < 0.0003), and post hoc tests showed that differences between the sham group and OVX group, sham group and OVX + OCA group, and OVX group and OVX + OCA group were statistically significant (p < 0.05). (C) LPS levels in different groups. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 16.54 and p = 0.0005), and the difference between the three groups was statistically significant; post hoc tests showed that differences between the sham group and OVX group, sham group and OVX + OCA group, and OVX group and OVX + OCA group were statistically significant (p < 0.05; differences were considered significant at p < 0.05). (D,E) Flow cytometric analysis of platelet activation rate. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count (the detection occurred 30 min after intraperitoneal injection of saline or LPS, t-test; differences were considered significant at p < 0.05).
Figure 5. The 300-day OCA intervention enhances the intestinal barrier and reduces plasma LPS in OVX mice. (A) Representative HE staining images showing intestinal morphology in each group (the detection occurred 300 days after OCA administration, 100× magnification). (B) Plasma diamine oxidase (DAO) levels in different groups. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 18.94 and p < 0.0003), and post hoc tests showed that differences between the sham group and OVX group, sham group and OVX + OCA group, and OVX group and OVX + OCA group were statistically significant (p < 0.05). (C) LPS levels in different groups. The one-way ANOVA results of the sham group, OVX group, and OVX + OCA group showed that there was a significant difference between the three groups (F = 16.54 and p = 0.0005), and the difference between the three groups was statistically significant; post hoc tests showed that differences between the sham group and OVX group, sham group and OVX + OCA group, and OVX group and OVX + OCA group were statistically significant (p < 0.05; differences were considered significant at p < 0.05). (D,E) Flow cytometric analysis of platelet activation rate. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count (the detection occurred 30 min after intraperitoneal injection of saline or LPS, t-test; differences were considered significant at p < 0.05).
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Figure 6. Chronic LPS release increases platelet activation rate without altering plasma lipid profiles in mice. (A–D) Plasma triglyceride, cholesterol, and high-density lipoprotein and low-density lipoprotein levels in each group (t-test, differences were considered significant at p < 0.05). (E,F) Flow cytometric analysis of platelet activation rate. (The detection occurred 30 days after continuous intraperitoneal LPS release. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count, t-test; differences were considered significant at p < 0.05).
Figure 6. Chronic LPS release increases platelet activation rate without altering plasma lipid profiles in mice. (A–D) Plasma triglyceride, cholesterol, and high-density lipoprotein and low-density lipoprotein levels in each group (t-test, differences were considered significant at p < 0.05). (E,F) Flow cytometric analysis of platelet activation rate. (The detection occurred 30 days after continuous intraperitoneal LPS release. In the flow cytometry data, the horizontal axis represents the fluorescence intensity and corresponding CD61 protein particle count, and the vertical axis represents the fluorescence intensity and corresponding CD62p protein particle count, t-test; differences were considered significant at p < 0.05).
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Figure 7. Chronic LPS release promotes atherosclerosis progression in mice. (A,B) Oil Red O staining of the aortic arch showing atherosclerotic lesion development in each group, 100× magnification; the red area within the outer wall of the blood vessel divided by the total area within the outer wall is an indicator of lipid deposition progression (the detection occurred 30 days after continuous intraperitoneal LPS release, t-test; differences were considered significant at p < 0.05).
Figure 7. Chronic LPS release promotes atherosclerosis progression in mice. (A,B) Oil Red O staining of the aortic arch showing atherosclerotic lesion development in each group, 100× magnification; the red area within the outer wall of the blood vessel divided by the total area within the outer wall is an indicator of lipid deposition progression (the detection occurred 30 days after continuous intraperitoneal LPS release, t-test; differences were considered significant at p < 0.05).
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MDPI and ACS Style

Sun, J.; Yin, Y.; Jiang, Y.; Qian, D. Obeticholic Acid Reduces Atherosclerosis Progression in Mice After Bilateral Ovariectomy. J. Gerontol. Geriatr. 2026, 74, 17. https://doi.org/10.3390/jgg74030017

AMA Style

Sun J, Yin Y, Jiang Y, Qian D. Obeticholic Acid Reduces Atherosclerosis Progression in Mice After Bilateral Ovariectomy. Journal of Gerontology and Geriatrics. 2026; 74(3):17. https://doi.org/10.3390/jgg74030017

Chicago/Turabian Style

Sun, Jiangdong, Yufeng Yin, Yu Jiang, and Dongmeng Qian. 2026. "Obeticholic Acid Reduces Atherosclerosis Progression in Mice After Bilateral Ovariectomy" Journal of Gerontology and Geriatrics 74, no. 3: 17. https://doi.org/10.3390/jgg74030017

APA Style

Sun, J., Yin, Y., Jiang, Y., & Qian, D. (2026). Obeticholic Acid Reduces Atherosclerosis Progression in Mice After Bilateral Ovariectomy. Journal of Gerontology and Geriatrics, 74(3), 17. https://doi.org/10.3390/jgg74030017

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