May 2024, Volume 2 Issue 6
    

  • Select all
  • Editorial
  • Research Highlight
    Lauren F. Uchiyama, Peter Tontonoz
  • Research Highlight
    Yuelong Yan, Boyi Gan
  • Review Article
    Qixiang Zhao, Jiayu Wu, Yong Ding, Yanli Pang, Changtao Jiang

    In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

  • Original Article
    Huan Chen, Ting Ling, Di Chen, Wenjuan Liu, Huan Qi, Tian Xia, Xiaolong Liu, Wen Wang, Xin Guo, Wuxiyar Otkur, Fangjun Wang, Zhaochao Xu, Jean-Claude Martinou, Hai-long Piao

    Pyruvate is an essential fuel for maintaining the tricarboxylic acid (TCA) cycle in the mitochondria. However, the precise molecular mechanism of pyruvate uptake by mitochondrial pyruvate carrier (MPC) is largely unknown. Here, we report that the DNA/RNA-binding protein Y-box binding protein 1 (YBX1) is localized to the mitochondrial inter-membrane space by its C-terminal domain (CTD) in cancer cells. In mitochondria, YBX1 inhibits pyruvate uptake by associating with MPC1/2, thereby suppressing pyruvate-dependent TCA cycle flux. This association, in turn, promotes MPC-mediated glutaminolysis and histone lactylation. Our findings reveal that the YBX1-MPC axis exhibits a positive correlation with metastatic potential, while does not affect cell proliferation in both cultured cells and tumor xenografts. Therefore, the restricted pyruvate uptake into mitochondria potentially represents a hallmark of metastatic capacity, suggesting that the YBX1-MPC axis is a therapeutic target for combating cancer metastasis.

  • Original Article
    Tiange Feng, Yuan Liang, Lijun Sun, Lu Feng, Jiajie Min, Michael W. Mulholland, Yue Yin, Weizhen Zhang

    The “gut-liver axis” is critical for the control of hepatic lipid homeostasis, where the intestine affects the liver through multiple pathways, such as nutrient uptake, gastrointestinal hormone release, and gut microbiota homeostasis. Whether intestine-originated exosomes mediate the gut’s influence on liver steatosis remains unknown. Here, we aimed to determine whether intestinal epithelium-derived exosomes (intExos) contribute to the regulation of hepatic lipid metabolism. We found that mouse intExos could be taken up by hepatic cells. Mice fed high-fat diet (HFD) received intExos showed strong resistance to liver steatosis. MicroRNA sequencing of intExos indicated the correlation between miR-21a-5p/miR-145a-5p and hepatic lipid metabolism. Both liver overexpression of miR-21a-5p and intExos containing miR-21a-5p alleviated hepatic steatosis in mice fed with HFD. Mechanistically, miR-21a-5p suppressed the expression of Ccl1 (C-C motif chemokine ligand 1) in macrophages, as well as lipid transport genes Cd36 (cluster of differentiation 36) and Fabp7 (fatty acid binding protein 7) in hepatocytes. Liver-specific inhibition of miR-145a-5p significantly reduced hepatic lipid accumulation in mice fed with HFD through negatively regulating the expression of Btg1 (BTG anti-proliferation factor 1), leading to an increase of stearoyl-CoA desaturase-1 and lipogenesis. Our study demonstrates that intExos regulate hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD) progression via miR-21a-5p and miR-145a-5p pathways, providing novel mediators for the gut-liver crosstalk and potential targets for regulating hepatic lipid metabolism.

  • Original Article
    Limin Xie, Wanyu Hu, Haowei Zhang, Yujin Ding, Qin Zeng, Xiyan Liao, Dandan Wang, Wanqin Xie, Hannah Xiaoyan Hui, Tuo Deng

    Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.

  • Letter
    Ningning Bai, Xuhong Lu, Yansu Wang, Xiaoya Li, Rong Zhang, Haoyong Yu, Cheng Hu, Xiaojing Ma, Yuqian Bao, Ying Yang
  • Letter
    Feng Li, Shubin Lin, Zhiyi Tan, Yanqing Pang, Shuai Wang
  • Letter
    Yawei Wang, Xin Feng, Wenjing Zhou, Runze Huang, Yating Hu, Hui Hui, Jie Tian, Xiao Wang, Xiao-Wei Chen