Hepatocyte size fractionation allows dissection of human liver zonation,Journal of Cellular Physiology

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Hepatocyte size fractionation allows dissection of human liver zonation
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-01-16 , DOI: 10.1002/jcp.30273
Magnus Ölander ₁ , Christine Wegler _{1,

2} , Inken Flörkemeier ₁ , Andrea Treyer ₁ , Niklas Handin ₁ , Jenny M Pedersen ₁ , Anna Vildhede ₁ , André Mateus ₁ , Edward L LeCluyse ₃ , Jozef Urdzik ₄ , Per Artursson _{1,

5}

Affiliation

Human hepatocytes show marked differences in cell size, gene expression, and function throughout the liver lobules, an arrangement termed liver zonation. However, it is not clear if these zonal size differences, and the associated phenotypic differences, are retained in isolated human hepatocytes, the “gold standard” for in vitro studies of human liver function. Here, we therefore explored size differences among isolated human hepatocytes and investigated whether separation by size can be used to study liver zonation in vitro. We used counterflow centrifugal elutriation to separate cells into different size fractions and analyzed them with label‐free quantitative proteomics, which revealed an enrichment of 151 and 758 proteins (out of 5163) in small and large hepatocytes, respectively. Further analysis showed that protein abundances in different hepatocyte size fractions recapitulated the in vivo expression patterns of previously described zonal markers and biological processes. We also found that the expression of zone‐specific cytochrome P450 enzymes correlated with their metabolic activity in the different fractions. In summary, our results show that differences in hepatocyte size matches zonal expression patterns, and that our size fractionation approach can be used to study zone‐specific liver functions in vitro.

中文翻译：

肝细胞大小分级允许解剖人类肝脏分区

人类肝细胞在整个肝小叶的细胞大小、基因表达和功能方面表现出显着差异，这种排列称为肝分区。然而，尚不清楚这些区域大小差异以及相关的表型差异是否保留在分离的人类肝细胞中，这是人类肝功能体外研究的“金标准”。在这里，我们因此探索了分离的人类肝细胞之间的大小差异，并研究了按大小分离是否可用于研究体外肝分区。我们使用逆流离心淘析将细胞分成不同大小的部分，并用无标记定量蛋白质组学分析它们，结果分别显示小肝细胞和大肝细胞中分别富集了 151 和 758 种蛋白质（共 5163 种）。进一步的分析表明，不同肝细胞大小部分的蛋白质丰度概括了先前描述的带状标记和生物过程的体内表达模式。我们还发现区域特异性细胞色素 P450 酶的表达与其在不同组分中的代谢活性相关。总之，我们的结果表明肝细胞大小的差异与区域表达模式相匹配，并且我们的大小分级方法可用于体外研究区域特异性肝功能。

更新日期：2021-01-16

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