Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Metabolomics Department, Corewell Health Research Institute, Royal Oak, Michigan, USA.
Hepatol Commun. 2024 Aug 26;8(9). doi: 10.1097/HC9.0000000000000523. eCollection 2024 Sep 1.
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.
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.
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.
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.
代谢功能障碍相关脂肪性肝病（MASLD）与肥胖密切相关。性别和年龄影响 MASLD 的患病率和病理生理学。使用喂食西式饮食的动物模型对于研究导致代谢失调的分子机制以及促进新的药物靶标识别至关重要。然而，代谢失调病理生理学的性别相关和年龄相关机制仍知之甚少。这一知识空白限制了针对特定性别和年龄的个体化药物治疗的发展。
年轻（7 周）和年老（52 周）雄性和雌性小鼠分别喂食高脂肪饮食（HFD）或低脂肪饮食。分析肝脏代谢组（>600 种分子）和转录组谱。
雄性和雌性 HFD 喂养的小鼠均发生肥胖、葡萄糖不耐受和肝脂肪变性。然而，HFD 喂养的雄性小鼠的空腹血糖、胰岛素和血清丙氨酸氨基转移酶水平更高，表明代谢疾病更为严重。此外，雄性小鼠的肝脏二酰甘油和糖基神经酰胺（已知的胰岛素抵抗和纤维化介质）显著增加，转录组发生更多变化：细胞外基质组织和促炎基因仅在雄性中升高。相比之下，HFD 喂养的雌性小鼠没有观察到主要的脂质损伤增加。然而，衰老对雌性肝脏的影响更大。酰基辅酶 A 水平显著降低，提示脂肪酸氧化发生变化，并且转录组发生广泛变化，包括氧化应激反应基因表达降低和脂质分配基因改变。
本研究表明雄性和雌性对 HFD 的反应存在明显差异。我们的研究强调了在药物靶标识别研究中需要同时使用雌雄两性，并对衰老动物中导致 MASLD 病理生理学的分子机制进行特征描述。
