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靶向 eIF6 驱动的翻译诱导代谢重排，从而减少非酒精性脂肪性肝病（NAFLD）及其向肝细胞癌的发展。

Targeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma.

机构信息

Istituto Nazionale di Genetica Molecolare, INGM, "Romeo ed Enrica Invernizzi", Milan, Italy.

Department of Biosciences, University of Milan, Milan, Italy.

出版信息

Nat Commun. 2021 Aug 12;12(1):4878. doi: 10.1038/s41467-021-25195-1.

DOI:10.1038/s41467-021-25195-1
PMID:34385447
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8361022/
Abstract

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPβ, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.

摘要

翻译后文本

在肝脏中，真核起始因子 6（eIF6）介导的翻译会在后肠期增加。其对脂肪变性和疾病的贡献尚不清楚。在这项研究中，我们研究了 eIF6 驱动的翻译是否有助于疾病的进展。eIF6 水平在从非酒精性脂肪性肝病（NAFLD）到肝细胞癌的进展过程中增加。降低 eIF6 水平可保护肝脏免受疾病进展的影响。eIF6 耗竭可减轻脂肪堆积，增加脂肪酸氧化（FAO）并减少体外致癌转化。此外，eIF6 耗竭可延迟从非酒精性脂肪性肝病到肝细胞癌的进展，在体内。从机制上讲，eIF6 耗竭会降低转录因子 C/EBPβ的翻译，从而降低与非酒精性脂肪性肝病向肝细胞癌进展相关的生物标志物的水平，并由于维持了替代的 mTORC1-eIF4F 翻译分支，从而保持线粒体呼吸，该分支增加转录因子 YY1 的表达。我们提供了概念验证，表明体外药理学抑制 eIF6 活性可再现 eIF6 耗竭的保护作用。我们假设存在一种可靶向的、进化上保守的翻译电路，该电路针对脂质积累和肿瘤进展进行了优化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/8d57b7f012a1/41467_2021_25195_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/cd78831191a1/41467_2021_25195_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/d9c83b2a9518/41467_2021_25195_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/a3e002a5dfca/41467_2021_25195_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/45e08e535676/41467_2021_25195_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/9628230068a8/41467_2021_25195_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/7ccb5d88e83f/41467_2021_25195_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/8d57b7f012a1/41467_2021_25195_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/cd78831191a1/41467_2021_25195_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/d9c83b2a9518/41467_2021_25195_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/083a559658bc/41467_2021_25195_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/a3e002a5dfca/41467_2021_25195_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/45e08e535676/41467_2021_25195_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/9628230068a8/41467_2021_25195_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/7ccb5d88e83f/41467_2021_25195_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5475/8361022/8d57b7f012a1/41467_2021_25195_Fig8_HTML.jpg

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