ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Ying-Jia Chi, Zhen-Yu Bai, Guang-Li Feng, Xiao-Hong Lai, Yu-Feng Song
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引用次数: 0

Abstract

Background: Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver.

Methods: In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments.

Results: The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals.

Conclusions: The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

ER-线粒体接触点通过Ip3r-Grp75-Vdac复合体招募Seipin调节肝脏脂肪生成。
背景:线粒体和内质网(ER)接触点(MERCS)构成了ER和线粒体的功能性交流平台,在肝脏的脂质平衡中发挥着至关重要的作用。然而,MERCS对肝脏中性脂质合成的确切影响仍不清楚:本研究通过构建以黄颡鱼为基础的脂质代谢动物模型,探讨了 MERCS 在棕榈酸(PA)诱导的肝脏中性脂质失衡中的作用和机制。鉴于线粒体钙离子通道(si-mcu)不能破坏 MERCS 的结构完整性,在一些体外实验中,通过转染 si-mcu 阻断了 MERCS 在离体肝细胞中介导的 Ca2+ 信号传导:主要发现有(1)肝细胞MERCs亚蛋白组分析证实,通过激活Ip3r-Grp75-电压依赖性阴离子通道(Vdac)复合物,摄入过量膳食PA会增强肝脏MERCs。(2)膳食 PA 摄入会导致肝脏中性脂质通过 MERCs 招募 Seipin 沉积,从而促进脂滴的生物生成。(3)我们的研究结果首次证明,MERCs招募Seipin并控制肝脏脂质平衡,除了MERCs的结构完整性外,还取决于Ip3r-Grp75-Vdac控制的Ca2+信号传导。值得注意的是,我们的研究结果还证实了这些机制从鱼类到哺乳动物都是保守的:结论:本研究的结果提供了一个新的视角,揭示了 MERCS 募集的 SEIPIN 通过 Ip3r-Grp75-Vdac 复合物介导的 Ca2+ 信号在肝脏脂质合成中的调控作用,突出了 MERCS 在肝脏脂质稳态中的关键贡献。
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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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