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抑制O-GlcNAc转移酶减轻自发性肥胖小鼠肝脏病理变化

张紫扬, 龙新宇, 张佳怡, 李晓双, 寇乐乐, 杨沛凇, 张博熙, 徐彬, 李士泽^*

黑龙江八一农垦大学动物科技学院，农业农村部东北寒区牛病防治重点实验室，大庆 163319

摘要

本研究旨在探究抑制O-GlcNAc转移酶(O-GlcNAc transferase, OGT)对自发性肥胖小鼠肝脏病理变化的作用及其机制。将6 周龄雄性ob/ob 小鼠随机分为对照组和给药组(腹腔注射OGT抑制剂OSMI-1)。处理60 天后，采集小鼠肝脏组织和血清样本，用蛋白质免疫印记检测肝脏OGT和脂肪分解相关蛋白的表达水平，用全自动生化分析仪检测血清生化指标，用试剂盒检测血清高密度脂蛋白胆固醇(high-density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(low-densitylipoprotein cholesterol, LDL-C)，用HE染色、油红O染色、糖原染色和马松染色检测肝脏病理变化。结果显示，与对照组相比，给药组小鼠体重和肝脏质量显著下降，肝脏OGT蛋白表达水平和O-GlcNAc 糖基化修饰水平显著下调，血清天门冬氨酸氨基转移酶(aspartate aminotransferase, AST)、丙氨酸氨基转移酶(alanine aminotransferase, ALT)、总胆汁酸(total bile acid,TBA)、乳酸脱氢酶(lactate dehydrogenase, LDH)、总胆固醇(total cholesterol, TCHO)、甘油三酯(triglyceride, TRIG)水平显著下降，血清HDL-C 和LDL-C 水平显著下降，脂肪分解相关蛋白肉毒碱棕榈酰基转移酶1A (carnitine palmitoyltransferase 1A,CPT1A)、CPT2、酰基辅酶A氧化酶1 (acyl-CoA oxidase 1, ACOX1)和过氧化物酶体增殖物激活受体α (peroxisome proliferatoractivated-receptor α, PPARα)蛋白表达水平显著下调，肝脏脂滴数量显著下降，肝脏组织多细胞核、少空泡，糖原含量显著下降，胶原纤维含量显著增多。以上结果表明，抑制OGT可改善自发性肥胖小鼠血清指标异常及肝脏脂肪异常堆积，从而减轻肝脏病理变化。

关键词： OSMI-1; O-GlcNAc糖基化; 肝脏; 脂质分解

Inhibition of O-GlcNAc transferase alleviates liver pathological changes in spontaneously obese mice

ZHANG Zi-Yang, LONG Xin-Yu, ZHANG Jia-Yi, LI Xiao-Shuang, KOU Le-Le, YANG Pei-Song, ZHANG Bo-Xi, XU Bin, LI Shi-Ze^*

Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China

Abstract

This study was to explore the effects of O-GlcNAc transferase (OGT) inhibition on the liver pathological changes in spontaneously obese mice. Ten 6-week-old male ob/ob mice were randomly divided into a control group and a drug-treated group (receiving intraperitoneal injection of the OGT inhibitor OSMI-1). After 60 days of treatment, mouse liver tissue and serum samples were collected, and the expression levels of liver OGT and lipolysis-related proteins were detected by Western blot. Serum biochemical indexes were detected by full-automatic biochemical analyzer, and serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected by corresponding kits. Liver pathological changes were detected by HE staining, oil red O staining, glycogen staining, and Masson staining. The results showed that compared with the control group, the body weight and liver mass of mice in the drug-treated group were significantly reduced. The levels of OGT protein expression and O-GlcNAc glycosylation modification in the liver were significantly down-regulated. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bile acid (TBA), lactate dehydrogenase (LDH), total cholesterol (TCHO), and triglycerides (TRIG) were significantly decreased. The levels of serum HDL-C and LDL-C were significantly reduced, and the expression levels of lipolysis-related proteins, including carnitine palmitoyltransferase 1A (CPT1A), CPT2, acyl-CoA oxidase 1 (ACOX1), and peroxisome proliferator-activated receptor α (PPARα) were significantly down-regulated. The number of hepatic lipid droplets was decreased significantly, the liver tissue had multiple nuclei and fewer vacuoles, the glycogen content was decreased significantly, and the collagen fiber content was increased significantly. These results suggest that OGT inhibition can improve abnormal serum indicators and accumulation of liver fat in spontaneously obese mice, thereby reducing liver pathological changes.

Key words: OSMI-1; O-GlcNAc glycosylation; liver; lipolysis

收稿日期：　　录用日期：

通讯作者：李士泽　　E-mail:

DOI: 10.13294/j.aps.2025.0095

引用本文：

张紫扬, 龙新宇, 张佳怡, 李晓双, 寇乐乐, 杨沛凇, 张博熙, 徐彬, 李士泽. 抑制O-GlcNAc转移酶减轻自发性肥胖小鼠肝脏病理变化[J]. 生理学报 2025; 77 (6): 1201-1209.

ZHANG Zi-Yang, LONG Xin-Yu, ZHANG Jia-Yi, LI Xiao-Shuang, KOU Le-Le, YANG Pei-Song, ZHANG Bo-Xi, XU Bin, LI Shi-Ze. Inhibition of O-GlcNAc transferase alleviates liver pathological changes in spontaneously obese mice. Acta Physiol Sin 2025; 77 (6): 1201-1209 (in Chinese with English abstract).