Liu Lin, Zhang Yuntao, Wang Xuanyang, Meng Hongxue, He Yan, Xu Xiaoqing, Xu Huan, Wei Chunbo, Yan Xuemin, Tao Xinmiao, Dang Keke, Ma Pingnan, Guo Xiaoyu, Yang Sen, Wang Jiemei, Li Ying
Department of Nutrition and Food Hygiene, the National Key Discipline, School of Public Health, Harbin Medical University, Harbin, China.
Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China.
JHEP Rep. 2024 Mar 9;6(8):101060. doi: 10.1016/j.jhepr.2024.101060. eCollection 2024 Aug.
BACKGROUND & AIMS: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms.
The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders.
After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; -trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, 0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet.
Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine.
Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport . These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.
目前尚无研究调查黄嘌呤氧化酶（XO）升高对脂质代谢紊乱的直接影响。在此，我们旨在通过一项前瞻性队列研究阐明XO在脂质代谢中的作用，并阐明其潜在机制。
在一个基于人群的队列中，对3358名基线时年龄在20 - 75岁的参与者，采用Cox比例风险模型检验血清XO活性与代谢相关脂肪性肝病（MASLD）之间的关联。此外，使用小鼠模型研究XO过表达与脂质代谢紊乱之间关联的潜在机制。
经过平均5.8年的随访，我们发现血清XO活性升高与发生MASLD的风险增加相关（风险比[HR]：2.08；95%置信区间：1.44 - 3.01；-趋势<0.001）。此外，血清XO活性与血清甘油三酯水平显著相关（r = 0.68，P<0.001）。我们证明MASLD患者肝脏样本中肝XO表达增加。使用组织特异性敲入小鼠，我们观察到在高脂饮食而非正常饮食条件下脂质代谢迅速紊乱。我们发现XO过表达促进小肠对过量膳食脂肪的吸收。抑制XO也显著降低了高脂饮食喂养小鼠的脂肪吸收。
我们的研究在一项大型基于人群的前瞻性队列研究中阐明了血清XO活性水平与MASLD发生之间的关联。此外，我们的小鼠模型表明XO过表达通过涉及小肠过度吸收脂肪的机制促进脂质积累。
通过基于人群的前瞻性队列和各种动物模型，我们确定了黄嘌呤氧化酶调节脂质代谢的新机制。我们的研究结果表明，黄嘌呤氧化酶过表达通过增加过量膳食脂肪的吸收并可能促进脂质转运来促进脂质积累。这些结果对于开发治疗与脂质代谢紊乱相关疾病的疗法可能具有重要意义。
