Xu Kai, Corona-Avila Irene, Frutos María Dolores, Núñez-Sánchez María Ángeles, Makhanasa Dhruvi, Shah Pratham Viral, Guzman Grace, Ramos-Molina Bruno, Priyadarshini Medha, Khan Md Wasim
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, United States of America.
Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain.
Biochim Biophys Acta Mol Basis Dis. 2025 Apr;1871(4):167746. doi: 10.1016/j.bbadis.2025.167746. Epub 2025 Feb 27.
The global prevalence of Metabolic Dysfunction-Associated Steatohepatitis (MASH) has been rising sharply, closely mirroring the increasing rates of obesity and metabolic syndrome. MASH exhibits a strong sexual dimorphism where females are affected with more severe forms after menopause. Hexokinase domain-containing protein 1 (HKDC1) has recently been recognized for its role in liver diseases, where its expression is minimal under normal conditions but significantly increases in response to metabolic stressors like obesity and liver injury. This selective upregulation suggests HKDC1's potential specialization in hepatic glucose and lipid dysregulation, linking it closely to the progression of MASH. This study aims to clarify the role of HKDC1 in Western diet-induced MASH in female mice by examining its impact on hepatic glucose and lipid metabolism, offering insights into its potential as a therapeutic target and addressing the need for sex-specific research in liver disease. This study reveals that HKDC1 expression is elevated in obese women with MASH and correlates with liver pathology. In a mouse model, liver-specific HKDC1 knockout (HKDC1) protected against Western diet-induced obesity, glucose intolerance, and MASH features, including steatosis, inflammation, and fibrosis. Transcriptomic analysis showed that HKDC1 deletion reduced pro-inflammatory and pro-fibrotic gene expression, while gut microbiome analysis indicated a shift toward MASH-protective bacteria. These findings suggest that HKDC1 may exacerbate MASH progression through its role in metabolic and inflammatory pathways, making it a potential therapeutic target.
代谢功能障碍相关脂肪性肝炎（MASH）的全球患病率一直在急剧上升，与肥胖和代谢综合征的发病率上升密切相关。MASH表现出强烈的性别差异，女性在绝经后会受到更严重的影响。含己糖激酶结构域蛋白1（HKDC1）最近因其在肝脏疾病中的作用而受到认可，在正常情况下其表达极低，但在肥胖和肝损伤等代谢应激源的作用下会显著增加。这种选择性上调表明HKDC1在肝脏葡萄糖和脂质调节异常方面具有潜在的特异性，与MASH的进展密切相关。本研究旨在通过研究HKDC1对肝脏葡萄糖和脂质代谢的影响，阐明其在西方饮食诱导的雌性小鼠MASH中的作用，深入了解其作为治疗靶点的潜力，并满足肝脏疾病针对性别研究的需求。本研究表明，HKDC1在患有MASH的肥胖女性中表达升高，且与肝脏病理相关。在小鼠模型中，肝脏特异性HKDC1基因敲除（HKDC1）可预防西方饮食诱导的肥胖、葡萄糖不耐受以及MASH的特征，包括脂肪变性、炎症和纤维化。转录组分析表明，HKDC1缺失降低了促炎和促纤维化基因的表达，而肠道微生物组分析表明向具有MASH保护作用的细菌转变。这些发现表明，HKDC1可能通过其在代谢和炎症途径中的作用加剧MASH的进展，使其成为一个潜在的治疗靶点。
