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抑制 SCAP/SREBP 加剧了小鼠非酒精性脂肪性肝炎的肝损伤和癌变。

Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis.

机构信息

Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

出版信息

J Clin Invest. 2022 Jun 1;132(11). doi: 10.1172/JCI151895.

DOI:10.1172/JCI151895
PMID:35380992
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9151706/
Abstract

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment.

摘要

固醇调节元件结合蛋白 (SREBP) 介导的从头脂肪生成增强被认为与非酒精性脂肪性肝炎 (NASH) 的发病机制有关。在这项研究中，我们评估了 SREBP 抑制对 NASH 和肝癌发展的影响在小鼠模型中。出乎意料的是，尽管肝脂肪变性明显减少，但通过删除肝脏中的 SREBP 切割激活蛋白 (SCAP) 抑制 SREBP 会加剧肝损伤、纤维化和癌变。这些表型通过恢复 SREBP 功能得到改善。转录组和脂质组分析表明，SCAP/SREBP 通路抑制由于脂肪酸 (FA) 合成受损和通过下调溶血磷脂酰胆碱酰基转移酶 3 (LPCAT3) 使 FA 掺入磷脂酰胆碱紊乱，改变了磷脂酰胆碱的 FA 组成，导致内质网 (ER) 应激和肝细胞损伤。补充磷脂酰胆碱可显著改善由 SCAP 缺失引起的肝损伤和 ER 应激。发现 SCAP/SREBP/LPCAT3 轴的活性与人类 NASH 中肝纤维化严重程度呈负相关。SREBP 抑制还与受损的自噬协同作用引发肝损伤。因此，过度强烈和广泛的脂肪生成抑制对 NASH 治疗不利；这将对 NASH 治疗具有重要的临床意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/8fd3780c641e/jci-132-151895-g126.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/a4c22bd42577/jci-132-151895-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/1181aa99e323/jci-132-151895-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/e492e1c013be/jci-132-151895-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/34560f354774/jci-132-151895-g122.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/1a1e194c3489/jci-132-151895-g123.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/03e74fd73569/jci-132-151895-g124.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/d303e949fa33/jci-132-151895-g125.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/8fd3780c641e/jci-132-151895-g126.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/a4c22bd42577/jci-132-151895-g119.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/1181aa99e323/jci-132-151895-g120.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/e492e1c013be/jci-132-151895-g121.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/34560f354774/jci-132-151895-g122.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/1a1e194c3489/jci-132-151895-g123.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/03e74fd73569/jci-132-151895-g124.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/d303e949fa33/jci-132-151895-g125.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9860/9151706/8fd3780c641e/jci-132-151895-g126.jpg

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2
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Cancers (Basel). 2021 Jan 26;13(3):474. doi: 10.3390/cancers13030474.
3
Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis.
Biomedicines. 2025 Jul 3;13(7):1631. doi: 10.3390/biomedicines13071631.
4
SREBP1 deficiency aggravates vascular calcification via iASPP-triggered ferroptosis of vascular smooth muscle cells.固醇调节元件结合蛋白1缺乏通过iASPP引发的血管平滑肌细胞铁死亡加重血管钙化。
Cardiovasc Diabetol. 2025 Jun 3;24(1):236. doi: 10.1186/s12933-025-02797-3.
5
promotes lipid metabolism in hepatocellular carcinoma by regulating the signaling pathway through .通过……调节信号通路促进肝细胞癌中的脂质代谢。
Am J Transl Res. 2025 Apr 15;17(4):2527-2540. doi: 10.62347/ZTGP5030. eCollection 2025.
6
Lactate transporter MCT4 regulates the hub genes for lipid metabolism and inflammation to attenuate intracellular lipid accumulation in non-alcoholic fatty liver disease.乳酸转运体MCT4通过调节脂质代谢和炎症的枢纽基因来减轻非酒精性脂肪性肝病中的细胞内脂质积累。
Genes Dis. 2025 Feb 15;12(4):101554. doi: 10.1016/j.gendis.2025.101554. eCollection 2025 Jul.
7
Lipogenesis and MASLD: re-thinking the role of SREBPs.脂肪生成与代谢相关脂肪性肝病：重新审视固醇调节元件结合蛋白的作用
Arch Toxicol. 2025 May 6. doi: 10.1007/s00204-025-04052-w.
8
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4
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5
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Metabolites. 2020 Mar 6;10(3):95. doi: 10.3390/metabo10030095.
6
Pathogenesis of NASH: The Impact of Multiple Pathways.非酒精性脂肪性肝炎的发病机制：多种途径的影响
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7
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Sci Rep. 2019 Jul 23;9(1):10663. doi: 10.1038/s41598-019-47216-2.
8
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9
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