Translational Modeling of Concurrent MASH and Atherosclerotic Cardiovascular Disease in Both Sexes
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Translational Modeling of Concurrent MASH and Atherosclerotic Cardiovascular Disease in Both Sexes
Posted on March, 2026 by Jia-yu Ke, Ph.D.
Keywords
D22052704 (ｍCDHFD:コリン欠乏高脂肪飼料) D22052703 (ｍMASHD：高脂肪高フルクトース飼料) ウェスタンダイエット 代謝異常関連脂肪肝炎(MASH) アテローム動脈硬化性心血管疾患（ASCVD） 肝障害 心疾患 スフィンガニン(sphinganine) Ldlr-/- mice
In metabolic research, MASH (liver disease) and ASCVD (heart disease) often occur together. While MASH drives liver damage, heart disease is the leading cause of death for these patients. Developing new treatments is difficult because traditional animal models rarely show both diseases at once, especially in females.
The Challenge: Physiological Relevance
Most MASH models use extreme dietary cholesterol (>1.25%). In Ldlr-/- mice, these levels cause unrealistic blood fat profiles that do not mirror human disease. The primary challenge is creating a single model that develops both MASH and ASCVD using human-like cholesterol levels (0.2%). Additionally, female mice are often resistant to MASH in standard models, creating a gap in sex-specific research.
To solve this, Dr. Oren Rom’s group (LSU Health Shreveport) established a 24-week study in Ldlr-/- mice. They used precision diets designed in collaboration with senior scientist Sridhar Radhakrishnan (Research Diets, Inc.) using a physiologically relevant 0.2% cholesterol concentration.
Establishing Robust Sex-Based Models
The study compared three dietary regimens:
• mCDHFD (#D22052704): A choline-deficient high-fat diet (45 kcal%, lard based), modified from widely
used D12451, designed to stress metabolic pathways without toxic cholesterol overloading. This was the most
robust model for inducing both MASH-fibrosis and atherosclerosis in both males and females.
• mMASHD (#D22052703):A modified MASH-inducing diet with 40 kcal% fat (palm oil based with trans fats)
and high fructose, specifically adapted for this study. It uniquely induced significant MASH-fibrosis in females,
while males showed a milder phenotype.
• Western Diet (WD):(Similar to Research Diets #D12079B): A high-fat (42 kcal%, butter based), sucrose-rich
diet commonly used in atherosclerosis studies. It was effective for males, but failed to induce MASH in females.
Multiomics Insights into Disease Mediators
Using integrated multiomics, the team identified sphinganine as a universal predictor of disease severity in both liver and plasma. Lipidomics revealed downregulated PUFA pathways alongside upregulated steryl esters and dihexosylceramides. Metabolomic data showed positive correlations between disease severity and itaconate/lactate, while glycine, carnitine, and thiamine pyrophosphate were negatively associated. Notably, the mouse models shared key inflammatory gene signatures with human MASH patients, specifically the upregulation of Trem2, Ccl2, and CD52.
Conclusion
This study establishes a validated framework for concurrent MASH and atherosclerosis research. By using realistic cholesterol levels, researchers can now study dual-organ pathology in both sexes. These models are essential for identifying new therapeutic targets and testing drugs that address the urgent clinical need for dual-target therapies.
Reference:
Das S, Kumar Anand S, McKinney MP, et al. Sex-based multiomics analysis uncovers metabolic and molecular mediators linking MASH and atherosclerosis. JHEP Rep. Published online 2025. doi:10.1016/j.jhepr.2025.101703
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