Carbohydrate Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
J Hepatol. 2023 Sep;79(3):605-617. doi: 10.1016/j.jhep.2023.05.011. Epub 2023 May 20.
BACKGROUND & AIMS: Disturbed hepatic metabolism frequently results in excessive lipid accumulation in the adipose tissue. However, the specific role of the liver-adipose axis in maintaining lipid homeostasis, as well as the underlying mechanism, has not yet been fully elucidated. In this study, we investigated the role of hepatic glucuronyl C5-epimerase (Glce) in the progression of obesity.
We determined the association between the expression of hepatic Glce and body mass index (BMI) in obese patients. Obesity models were established in hepatic Glce-knockout and wild-type mice fed a high-fat diet (HFD) to understand the effect of Glce on obesity development. The role of Glce in the progression of disrupted hepatokine secretion was examined via secretome analysis.
Hepatic Glce expression was inversely correlated with BMI in obese patients. Moreover, Glce level was found to be decreased in the liver of a HFD murine model. Hepatic Glce deficiency led to impaired thermogenesis in adipose tissue and exacerbated HFD-induced obesity. Interestingly, decreased level of growth differentiation factor 15 (GDF15) was observed in the culture medium of Glce-knockout mouse hepatocytes. Treatment with recombinant GDF15 obstructed obesity progression derived from the absence of hepatic Glce, similar to the effect of Glce or its inactive mutant overexpressed both in vitro and in vivo. Furthermore, liver Glce deficiency led to diminished production and increased degradation of mature GDF15, resulting in reduced hepatic GDF15 secretion.
Hepatic Glce deficiency facilitated obesity development, and decreased Glce expression further reduced hepatic secretion of GDF15, thereby perturbing lipid homeostasis in vivo. Therefore, the novel Glce-GDF15 axis plays an important role in maintaining energy balance and may act as a potential target for combating obesity.
Evidence suggests that GDF15 plays a key role in hepatic metabolism; however, the molecular mechanism for regulating its expression and secretion is largely unknown. Our work observes that hepatic Glce, as a key Golgi-localised epimerase, may work on the maturation and post-translational regulation of GDF15. Hepatic Glce deficiency reduces the production of mature GDF15 protein and facilitates its ubiquitination, resulting in the aggravation of obesity development. This study sheds light on the new function and mechanism of the Glce-GDF15 axis in lipid metabolism and provides a potential therapeutic target against obesity.
肝脏代谢紊乱常导致脂肪组织中脂质过度积累。然而，肝-脂肪轴在维持脂质稳态中的具体作用及其潜在机制尚未完全阐明。在本研究中，我们研究了肝糖醛酸 C5-差向异构酶（Glce）在肥胖进展中的作用。
我们确定了肥胖患者肝 Glce 表达与体重指数（BMI）之间的相关性。通过高脂饮食（HFD）喂养肝 Glce 敲除和野生型小鼠建立肥胖模型，以了解 Glce 对肥胖发展的影响。通过分泌组分析研究了 Glce 在破坏的肝细胞因子分泌进展中的作用。
肝 Glce 表达与肥胖患者的 BMI 呈负相关。此外，在 HFD 小鼠模型的肝脏中发现 Glce 水平降低。肝 Glce 缺乏导致脂肪组织产热受损，并加剧 HFD 诱导的肥胖。有趣的是，在 Glce 敲除鼠肝细胞的培养物中观察到生长分化因子 15（GDF15）水平降低。用重组 GDF15 处理可阻断源自肝 Glce 缺失的肥胖进展，类似于体外和体内过表达 Glce 或其无活性突变体的效果。此外，肝 Glce 缺乏导致成熟 GDF15 的产生减少和降解增加，导致肝 GDF15 分泌减少。
肝 Glce 缺乏促进肥胖发展，而 Glce 表达降低进一步减少肝 GDF15 分泌，从而扰乱体内脂质稳态。因此，新的 Glce-GDF15 轴在维持能量平衡中起重要作用，可能成为治疗肥胖的潜在靶点。
有证据表明 GDF15 在肝脏代谢中起关键作用；然而，调节其表达和分泌的分子机制在很大程度上尚不清楚。我们的工作观察到，肝 Glce 作为一种关键的高尔基定位差向异构酶，可能作用于 GDF15 的成熟和翻译后调节。肝 Glce 缺乏会降低成熟 GDF15 蛋白的产生，并促进其泛素化，从而加剧肥胖的发展。本研究揭示了 Glce-GDF15 轴在脂质代谢中的新功能和机制，并为肥胖的治疗提供了潜在的靶点。
