Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis

This study addresses the critical need for an animal model that replicates both metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerotic cardiovascular disease, particularly in females, to facilitate therapeutic development. Using male and female <i>Ldlr</i> <sup>-/-</sup> mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectively modeling both diseases in both sexes, while a western diet is effective only in males. Multiomics analyses identified key metabolic and inflammatory pathways linking MASH and atherosclerosis that mirror transcriptomic signatures found in humans, and highlight circulating cholesterol, CCL2, and sphinganine as potential biomarkers. These findings establish a translational model and reveal sex-specific metabolic pathways that will advance our understanding of the shared pathophysiology of MASH and atherosclerosis, and facilitate the development of dual therapeutic approaches, addressing an urgent unmet clinical need.

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Publication Details

Journal
JHEP Reports
Published
2025-12-02
DOI
https://doi.org/10.1016/j.jhepr.2025.101703
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis

Sumit Kumar Anand, Lin Tan, A. Wayne Orr, Sumati Rohilla et al.
JHEP Reports
Liver Disease Diagnosis and Treatment
article

Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis

Sumit Kumar Anand, Lin Tan, A. Wayne Orr, Sumati Rohilla, Iqbal Mahmud, M. Peyton McKinney, Alia Ghrayeb, Arif Yurdagul, Xiaolu Zhang, Oren Rom, Rajan Pandit, Wanqing Liu, Nilesh Pandey, Fabio Arias, Francisco J. Schöpfer, Dhananjay Kumar, Sarah P. Thayer, Fei Chang, Cyrine Ben Dhaou, Philip L. Lorenzi, Sridhar Radhakrishnan, Sandeep Das, Nirav Dhanesha, Babak Razani, Bo Wei, Alexandra C Finney, Edward A. Fisher, Eyal Gottlieb, Harpreet Kaur, Zhipeng Liu, Bishuang Cai, Koral S. E. Richard
article en

Abstract

This study addresses the critical need for an animal model that replicates both metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerotic cardiovascular disease, particularly in females, to facilitate therapeutic development. Using male and female <i>Ldlr</i> <sup>-/-</sup> mice, we found that different diets containing equivalent physiological levels of cholesterol induce sex-specific responses, with a modified choline-deficient high-fat diet effectively modeling both diseases in both sexes, while a western diet is effective only in males. Multiomics analyses identified key metabolic and inflammatory pathways linking MASH and atherosclerosis that mirror transcriptomic signatures found in humans, and highlight circulating cholesterol, CCL2, and sphinganine as potential biomarkers. These findings establish a translational model and reveal sex-specific metabolic pathways that will advance our understanding of the shared pathophysiology of MASH and atherosclerosis, and facilitate the development of dual therapeutic approaches, addressing an urgent unmet clinical need.

JHEP ReportsVol. 8(3)
Rutgers, The State University of New Jersey (US), The University of Texas MD Anderson Cancer Center (US), University of Pittsburgh (US), Wayne State University (US), Purdue University West Lafayette (US), Louisiana State University in Shreveport (US), Los Angeles Medical Center (US), University of Pittsburgh Medical Center (US), New York University (US), Louisiana State University Health Sciences Center Shreveport (US)
National Science Foundation, American Heart Association, Purdue University, Wayne State University, University of Pittsburgh, Louisiana State University, Ochsner Health, National Institutes of Health, University of California, Los Angeles, University of Texas MD Anderson Cancer Center, Medical Center, University of Pittsburgh, NYU Grossman School of Medicine
Openalex Percentile: Top 51%
Liver Disease Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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