Scholarlink

Background and aims <p>RNF186, which encodes a ring-finger domain-containing E3 ubiquitin-protein ligase, has previously been implicated in the regulation of lipid metabolic disorders associated with metabolic dysfunction-related fatty liver disease (MAFLD). However, the precise mechanism by which RNF186 influences glucose metabolism in the context of MAFLD remains unclear. In this study, we aimed to elucidate the role of RNF186 in the regulation of glucose metabolism, with a particular focus on skeletal muscle.</p> Methods <p>In vitro, we treated skeletal myocytes and hepatocytes with high glucose concentrations to study the expression of RNF186 and its effects on glucose uptake and insulin signaling. In vivo, we developed a MAFLD model through long-term high-fat feeding and assessed the impact of RNF186 deficiency on glucose metabolism in skeletal muscle, liver and adipose tissue using Western blotting, quantitative PCR (qPCR), and immunofluorescence.</p> Results <p>Our findings demonstrate that RNF186 is regulated by glucose concentration in skeletal muscle cells and hepatocytes and is sensitive to insulin in a high-glucose environment. The deletion of RNF186 increases glucose metabolism and alleviates insulin signaling disruption in the MAFLD model, affecting skeletal muscle, liver, and adipose tissue. Furthermore, in skeletal muscle, RNF186 deficiency reduces the ER stress-mediated unfolded protein response (UPR) by preventing the ubiquitination of ATF6, leading to increased transcription of GLUT4. Additionally, RNF186 deficiency promotes the membrane translocation of GLUT4 via the AKT/TBC1D4 signaling pathway. In contrast, overexpression of RNF186 decreases AKT signaling and GLUT4 expression, resulting in exacerbated disruption of glucose metabolism in MAFLD.</p> Conclusions <p>RNF186 regulates glucose metabolism across multiple tissues in MAFLD, notably by playing a dual role in modulating the transcription and translocation of GLUT4 in skeletal muscle. These findings suggest that targeting the expression of RNF186 could be a potential therapeutic strategy for treating MAFLD and related metabolic disorders.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

RNF186 controls glucose metabolism in metabolic dysfunction-associated fatty liver disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月28日

查看全文
  • Jiang Du,
  • Qizhang Du,
  • Yuxuan Zhang,
  • Jingwen Gao,
  • Chiheng Wang,
  • Beilin Kou,
  • Yan Jiang,
  • Dunyong Zhao,
  • Juntang Lin

摘要

Background and aims

RNF186, which encodes a ring-finger domain-containing E3 ubiquitin-protein ligase, has previously been implicated in the regulation of lipid metabolic disorders associated with metabolic dysfunction-related fatty liver disease (MAFLD). However, the precise mechanism by which RNF186 influences glucose metabolism in the context of MAFLD remains unclear. In this study, we aimed to elucidate the role of RNF186 in the regulation of glucose metabolism, with a particular focus on skeletal muscle.

Methods

In vitro, we treated skeletal myocytes and hepatocytes with high glucose concentrations to study the expression of RNF186 and its effects on glucose uptake and insulin signaling. In vivo, we developed a MAFLD model through long-term high-fat feeding and assessed the impact of RNF186 deficiency on glucose metabolism in skeletal muscle, liver and adipose tissue using Western blotting, quantitative PCR (qPCR), and immunofluorescence.

Results

Our findings demonstrate that RNF186 is regulated by glucose concentration in skeletal muscle cells and hepatocytes and is sensitive to insulin in a high-glucose environment. The deletion of RNF186 increases glucose metabolism and alleviates insulin signaling disruption in the MAFLD model, affecting skeletal muscle, liver, and adipose tissue. Furthermore, in skeletal muscle, RNF186 deficiency reduces the ER stress-mediated unfolded protein response (UPR) by preventing the ubiquitination of ATF6, leading to increased transcription of GLUT4. Additionally, RNF186 deficiency promotes the membrane translocation of GLUT4 via the AKT/TBC1D4 signaling pathway. In contrast, overexpression of RNF186 decreases AKT signaling and GLUT4 expression, resulting in exacerbated disruption of glucose metabolism in MAFLD.

Conclusions

RNF186 regulates glucose metabolism across multiple tissues in MAFLD, notably by playing a dual role in modulating the transcription and translocation of GLUT4 in skeletal muscle. These findings suggest that targeting the expression of RNF186 could be a potential therapeutic strategy for treating MAFLD and related metabolic disorders.