The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics.
The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics.
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DOI：
10.1038/s41420-023-01400-6
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发表时间：
2023-03-25
影响因子：
7
通讯作者：
Kunos, George
中科院分区：
文献类型：
--
作者：
Mukhopadhyay, Bani;Holovac, Kellie;Schuebel, Kornel;Mukhopadhyay, Partha;Cinar, Resat;Iyer, Sindhu;Marietta, Cheryl;Goldman, David;Kunos, George
肝祖细胞（HPCs）的增殖和分化在不同条件下驱动肝脏的稳态更新。肝脏再生与Axin2 + Cnr1 + HPCs的增加以及内源性大麻素花生四烯酸乙醇胺（AEA）水平的显著升高有关。但是，将AEA信号传导与HPC增殖和/或分化联系起来的分子机制尚未得到探索。在此，我们表明HPCs在体外暴露于AEA会引发细胞周期和分化，同时Cnr1、Krt19和Axin2的表达增加。从机制上讲，我们发现AEA促进转录因子β - 连环蛋白的核定位，随后诱导其下游靶标。对CRISPR介导的β - 连环蛋白调控的转录组敲除后的细胞进行系统分析表明，AEA调节β - 连环蛋白依赖性细胞周期和分化以及白细胞介素途径。此外，我们发现当氨基酸和葡萄糖作为底物容易获得时，AEA促进HPCs中的氧化磷酸化，但当细胞主要依赖脂肪酸氧化时，AEA会抑制它。因此，内源性大麻素系统通过β - 连环蛋白途径刺激Axin2 + Cnr1 + HPCs的增殖，同时调节其前体细胞的代谢活性，从而促进肝细胞的更新和成熟。
The proliferation and differentiation of hepatic progenitor cells (HPCs) drive the homeostatic renewal of the liver under diverse conditions. Liver regeneration is associated with an increase in Axin2+Cnr1+ HPCs, along with a marked increase in the levels of the endocannabinoid anandamide (AEA). But the molecular mechanism linking AEA signaling to HPC proliferation and/or differentiation has not been explored. Here, we show that in vitro exposure of HPCs to AEA triggers both cell cycling and differentiation along with increased expression of Cnr1, Krt19, and Axin2. Mechanistically, we found that AEA promotes the nuclear localization of the transcription factor β-catenin, with subsequent induction of its downstream targets. Systemic analyses of cells after CRISPR-mediated knockout of the β-catenin-regulated transcriptome revealed that AEA modulates β-catenin-dependent cell cycling and differentiation, as well as interleukin pathways. Further, we found that AEA promotes OXPHOS in HPCs when amino acids and glucose are readily available as substrates, but AEA inhibits it when the cells rely primarily on fatty acid oxidation. Thus, the endocannabinoid system promotes hepatocyte renewal and maturation by stimulating the proliferation of Axin2+Cnr1+ HPCs via the β-catenin pathways while modulating the metabolic activity of their precursor cells.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8
作者：
Cadoret, A;Ovejero, C;Perret, C
通讯作者：
Perret, C
影响因子：
4
作者：
Bikkavilli, Rama Kamesh;Feigin, Michael E.;Malbon, Craig C.
通讯作者：
Malbon, Craig C.
影响因子：
2.9
作者：
Cordi, Sabine;Godard, Cecile;Lemaigre, Frederic P.
通讯作者：
Lemaigre, Frederic P.