Sex- and age-associated factors drive the pathophysiology of MASLD

转录组 代谢组 内科学 内分泌学 胰岛素抵抗 生物 脂肪肝 病理生理学 肥胖 代谢综合征 氧化应激 脂肪变性 甘油三酯 非酒精性脂肪肝 胆固醇 疾病 医学 基因表达 基因 代谢物 遗传学
作者
Ajay K. Yadav,Justin J. MacNeill,Aleksei Krylov,Nadia Ashrafi,Romana Ashrafi Mimi,Romil Saxena,Sheng Liu,Stewart F. Graham,Jun Wan,Núria Morral
出处
期刊:Hepatology communications [Wiley]
卷期号:8 (9)
标识
DOI:10.1097/hc9.0000000000000523
摘要

Background: Metabolic dysfunction–associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments. Methods: Young (7 wk) and aged (52 wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed. Results: Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes. Conclusions: Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.

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