Zhao Yue, Nie Hong-Yu, Jiang Shan, Zhao Meng-Fei, Sun Peng, Zhang Jing-Zi, Wang Xiao-Chen, Tang Yi-Ping, Zou Ming-Jie, Yuan Xian-Wen, Sun Xi-Tai, Shan Xiao-Dong, He Jian, Liu Jiang-Huai, Bi Yan, Fang Lei, Han Xiao, Li Chao-Jun
The State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Medical School of Nanjing University, Nanjing, Jiangsu Province, China.
State Key Laboratory of Reproductive Medicine and China International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Cell Mol Gastroenterol Hepatol. 2025 May 29;19(9):101546. doi: 10.1016/j.jcmgh.2025.101546.
BACKGROUND & AIMS: Metabolically unhealthy obesity (MUO) is characterized by hepatic steatosis and type 2 diabetes (T2D), distinct from metabolically healthy obesity (MHO). This study aimed to identify the key regulator responsible for MUO.
Metabolomics analysis was conducted to compare hepatic metabolite profiles between individuals with MUO and MHO and mice. Geranylgeranyl pyrophosphate (GGPP) levels and its synthetase geranylgeranyl diphosphate synthase (GGPPS) were quantified in human and murine liver tissues. Hepatocyte-specific Ggpps knockout mice (LKO) were generated to evaluate the effects of GGPP deficiency on MUO-associated phenotypes. Mechanistic studies focused on GGPP-dependent prenylation of the lipid droplet-associated protein Perilipin4 and its role in lipid droplet formation. The therapeutic potential of DGBP, a GGPPS inhibitor, was also tested in MUO models.
GGPP and GGPPS protein expression were significantly elevated in the livers of patients with MUO and mice compared with counterparts with MHO. Hepatocyte-specific Ggpps knockout (LKO) mice exhibited reduced hepatic lipid accumulation, smaller lipid droplets, and improved insulin sensitivity, demonstrating GGPP's critical role in MUO pathogenesis. Mechanistically, GGPP promoted Perilipin4 prenylation, which enhanced large lipid droplet formation and exacerbated hepatic steatosis and insulin resistance. Pharmacologic inhibition of GGPPS with DGBP effectively attenuated MUO phenotypes, highlighting its therapeutic potential.
Hepatic GGPP drives MUO progression by facilitating Perilipin4 prenylation, thereby promoting pathological lipid droplet expansion and insulin resistance. Targeting GGPP with inhibitors of GGPPS like DGBP represents a promising strategy for treating MUO. These findings provide novel insights into the metabolic heterogeneity of obesity and potential therapeutic interventions for MUO-related complications.
代谢不健康型肥胖（MUO）的特征为肝脂肪变性和2型糖尿病（T2D），有别于代谢健康型肥胖（MHO）。本研究旨在确定导致MUO的关键调节因子。
进行代谢组学分析，以比较MUO个体与MHO个体及小鼠之间的肝脏代谢物谱。对人和小鼠肝脏组织中的香叶基香叶基焦磷酸（GGPP）水平及其合成酶香叶基香叶基二磷酸合成酶（GGPPS）进行定量。构建肝细胞特异性Ggpps基因敲除小鼠（LKO），以评估GGPP缺乏对MUO相关表型的影响。机制研究聚焦于GGPP依赖的脂滴相关蛋白Perilipin4的异戊二烯化及其在脂滴形成中的作用。还在MUO模型中测试了GGPPS抑制剂DGBP的治疗潜力。
与MHO的对应个体相比，MUO患者肝脏和小鼠肝脏中的GGPP和GGPPS蛋白表达显著升高。肝细胞特异性Ggpps基因敲除（LKO）小鼠的肝脏脂质积累减少、脂滴变小且胰岛素敏感性提高，表明GGPP在MUO发病机制中起关键作用。机制上，GGPP促进Perilipin4的异戊二烯化，增强大脂滴形成，加剧肝脂肪变性和胰岛素抵抗。用DGBP对GGPPS进行药理抑制可有效减轻MUO表型，突出了其治疗潜力。
肝脏GGPP通过促进Perilipin4的异戊二烯化驱动MUO进展，从而促进病理性脂滴扩张和胰岛素抵抗。用DGBP等GGPPS抑制剂靶向GGPP是治疗MUO的一种有前景的策略。这些发现为肥胖的代谢异质性及MUO相关并发症的潜在治疗干预提供了新见解。
