β-catenin抑制的LKB1 Sumoylation修饰和脂肪酸代谢对肾脏纤维化至关重要

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Shuangqin Chen, Jiemei Li, Ye Liang, Meijia Zhang, Ziqi Qiu, Sirui Liu, HaoRan Wang, Ye Zhu, Shicong Song, Xiaotao Hou, Canzhen Liu, Qinyu Wu, Mingsheng Zhu, Weiwei Shen, Jinhua Miao, Fan Fan Hou, Youhua Liu, Cheng Wang, Lili Zhou
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引用次数: 0

摘要

肝激酶 B1(LKB1)是一种控制细胞稳态的丝氨酸/苏氨酸激酶。在翻译后修饰中,苏木酰化对 LKB1 激活 5'- 磷酸腺苷(AMP)激活的蛋白激酶(AMPK)至关重要,而 AMPK 是能量代谢的关键调节因子。值得注意的是,AMPK 调节的脂肪酸代谢与维持正常肾功能密切相关。然而,LKB1 Sumoylation 的调控机制仍然难以捉摸。在这项研究中,我们证实了肾脏纤维化中臭名昭著的信号--β-catenin抑制了LKB1的Sumoylation,从而破坏了肾小管细胞中的脂肪酸氧化,引发了肾脏纤维化。从机理上讲,我们发现Sumo3是肾小管细胞中LKB1 Sumoylation的关键介质,而LKB1的转录受到β-catenin/转录因子4(TCF4)信号的抑制。过表达Sumo3(而非Sumo1或Sumo2)可恢复被β-catenin破坏的脂肪酸代谢,并延缓肾脏中的脂质积累和纤维化。在体内,有条件地敲除肾小管细胞中的β-catenin,可通过维持LKB1 Sumoylation和AMPK活化,有效地保护脂肪酸氧化和阻止脂质积累。此外,在单侧缺血再灌注小鼠中,Sumo3的异位表达能强烈抑制Wnt1加重的脂质积累和纤维化。在慢性肾脏病患者中,我们发现了 Sumo3 的表达缺失,而且与 LKB1 的抑制高度相关。这导致脂肪酸代谢紊乱和脂质积累,从而导致肾脏纤维化。总之,我们的研究揭示了脂肪酸代谢障碍的新机制,并为调控肾脏纤维化中的Sumo修饰提供了新的治疗靶点途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis.

Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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