Hepatocyte-specific RAP1B deficiency ameliorates high-fat diet-induced obesity and liver inflammation in mice

IF 5.4 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-03-13 DOI:10.1111/dom.16309

Yinxu Fu PhD, Pingyi Hu MMed, Yanyang Hu MMed, Yu Fang MMed, Yaping Zhou MMed, Yu Shi MMed, Kaiqiang Yang MMed, Ting Fu MMed, Weijia Li PhD, Evgeniy Rostislavovich Gritskevitch PhD, Liqin Jin PhD, Jianxin Lyu PhD, Qiongya Zhao PhD

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引用次数: 0

Abstract

Aim

This study investigated the role of RAP1B in hepatic lipid metabolism and its implications in obesity and associated metabolic disorders, focusing on the molecular mechanisms through which RAP1B influences lipid accumulation, inflammation and oxidative stress in liver tissues and hepatocyte cell lines.

Materials and Methods

Liver-specific RAP1B-knockout (LKO) and overexpression (OE) mice were generated and fed a high-fat diet for 18 weeks to evaluate systemic and hepatic metabolic changes. Comprehensive metabolic phenotyping included measurements of body weight, body fat content, activity levels, energy expenditure (EE), respiratory exchange ratio (RER), glucose tolerance test and insulin tolerance test. RAP1B-knockdown AML12 hepatocytes were used for in vitro studies. Comprehensive transcriptome and metabolome analyses identified differentially expressed genes and key metabolic shifts. Biochemical and histological analyses were performed to assess lipid accumulation, oxidative stress and inflammatory markers.

Results

We found that LKO mice exhibited significant reductions in body weight, fat pad size and liver mass, along with decreased hepatic lipid accumulation due to enhanced lipid breakdown. These mice demonstrated improved glucose tolerance and insulin sensitivity without changes in food intake. Liver histology showed reduced F4/80-positive macrophage infiltration, indicating decreased inflammatory cell recruitment. Additionally, markers of oxidative stress were significantly lower, and molecular analysis revealed downregulation of the MAPK(p38) and NF-κB signaling pathways, further supporting an anti-inflammatory hepatic environment. In contrast, OE mice showed increased liver weight, aggravated hepatic lipid accumulation driven by enhanced lipogenesis, worsened insulin resistance and elevated inflammation.

Conclusions

This study highlights RAP1B's pivotal role in hepatic metabolism and positions it as a potential therapeutic target for obesity and related metabolic disorders.

查看原文本刊更多论文

肝细胞特异性RAP1B缺乏改善小鼠高脂肪饮食诱导的肥胖和肝脏炎症。

目的：本研究探讨RAP1B在肝脏脂质代谢中的作用及其在肥胖及相关代谢紊乱中的意义，重点探讨RAP1B影响肝组织和肝细胞细胞系脂质积累、炎症和氧化应激的分子机制。材料和方法：制备肝脏特异性rap1b敲除（LKO）和过表达（OE）小鼠，饲喂高脂饲料18周，评估全身和肝脏代谢变化。综合代谢表型包括体重、体脂含量、活动水平、能量消耗（EE）、呼吸交换比（RER）、葡萄糖耐量试验和胰岛素耐量试验。rap1b敲低的AML12肝细胞用于体外研究。综合转录组和代谢组分析确定了差异表达的基因和关键的代谢转变。进行生化和组织学分析以评估脂质积累、氧化应激和炎症标志物。结果：我们发现LKO小鼠的体重、脂肪垫大小和肝脏质量显著降低，同时由于脂质分解增强，肝脏脂质积累减少。这些小鼠在不改变食物摄入量的情况下表现出葡萄糖耐量和胰岛素敏感性的改善。肝脏组织学显示f4 /80阳性巨噬细胞浸润减少，表明炎症细胞募集减少。此外，氧化应激标志物显著降低，分子分析显示MAPK（p38）和NF-κB信号通路下调，进一步支持抗炎肝环境。相反，OE小鼠表现出肝脏重量增加，脂肪生成增强导致肝脏脂质积累加剧，胰岛素抵抗恶化和炎症升高。结论：本研究强调了RAP1B在肝脏代谢中的关键作用，并将其定位为肥胖及相关代谢疾病的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.