BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.
目的利用高效液相色谱质谱联用法(LC⁃MS/MS)检测不同时段血清尿苷水平并探讨其与代谢综合征(MS)的关系。方法选取2021年1月~12月在武汉大学人民医院内分泌科住院的MS患者107例(MS组)及同期体检时发现有甲状腺结节者68例(非MS组),收集两组受试者一般临床资料及实验室检查指标并分组进行比较。采用多元逐步回归分析评估MS的相关影响因素。采用Spearman相关分析评估血清尿苷水平与MS相关指标的相关性。结果MS组男性患者比例、腰围、BMI、肌酐(Cr)、尿酸(UA)、空腹C肽(CpS⁃0h)、餐后2 h C肽(CpS⁃2h)、胰岛素抵抗指数(HOMA⁃IR)及甘油三酯(TG)均高于非MS组,估算的肾小球滤过率(eGFR)及高密度脂蛋白胆固醇(HDL⁃C)均低于非MS组(P<0.05)。MS组空腹血清尿苷水平与非MS组比较差异无统计学意义(P=0.245),餐后血清尿苷水平显著低于非MS组(P=0.002)。多元逐步回归分析结果显示,BMI、TG、Cr为MS发生的相关因素(P<0.01)。Spearman相关分析结果显示,餐后血清尿苷与HOMA⁃IR呈负相关(r=-0.23,P=0.004)。结论餐后血清尿苷不是MS的生物标志物,其可能通过间接影响其他代谢性指标而与MS相关。
Carbohydrates have a protein sparing effect,but long-term feeding of a high-carbohydrate diet(HCD)leads to metabolic disorders due to the limited utilization efficiency of carbohydrates in fish.How to mitigate the negative effects induced by HCD is crucial for the rapid development of aquaculture.Uridine is a pyrimidine nucleoside that plays a vital role in regulating lipid and glucose metabolism,but whether uridine can alleviate metabolic syndromes induced by HCD remains unknown.In this study,a total of480 Nile tilapia(Oreochromis niloticus)(average initial weight 5.02±0.03 g)were fed with 4 diets,including a control diet(CON),HCD,HCD+500 mg/kg uridine(HCUL)and HCD+5,000 mg/kg uridine(HCUH),for 8 weeks.The results showed that addition of uridine decreased hepatic lipid,serum glucose,triglyceride and cholesterol(P<0.05).Further analysis indicated that higher concentration of uridine activated the sirtuin1(sirt1)/adenosine 5-monophosphate-activated protein kinase(AMPK)signaling pathway to increase lipid catabolism and glycolysis while decreasing lipogenesis(P<0.05).Besides,uridine increased the activity of glycogen synthesis-related enzymes(P<0.05).This study suggested that uridine could alleviate HCD-induced metabolic syndrome by activating the sirt1/AMPK signaling pathway and promoting glycogen synthesis.This finding reveals the function of uridine in fish metabolism and facilitates the development of new additives in aquatic feeds.
