Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis.
Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis.
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DOI：
10.1111/cts.12962
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Isoherranen N
中科院分区：
文献类型：
--
作者：
Czuba LC;Wu X;Huang W;Hollingshead N;Roberto JB;Kenerson HL;Yeung RS;Crispe IN;Isoherranen N
全反式维甲酸（atRA）是维生素A的活性代谢物，在体外和动物模型中具有抗纤维化特性。肝脏维生素A的稳态是通过细胞特异性酶活性维持的，包括在肝星状细胞（hsc）中的储存，从肝细胞分泌到循环中，以及atRA的形成和清除。在慢性肝损伤期间，HSC的激活与肝脏视黄酯和视黄醇浓度的降低有关。atRA是由视黄醇通过两个酶促步骤合成的，但尚不清楚类视黄醇储存的损失是否与atRA形成的变化有关，以及哪些细胞类型导致了代谢变化。本研究的目的是确定急性肝损伤中维生素A代谢通量是否受到干扰，以及atRA浓度的变化是否与HSC活化和胶原表达相关。在基础水平上，HSC和Kupffer细胞表达参与维生素A代谢的关键基因，而在急性肝损伤后，肝切片中观察到代谢通量的复杂变化。这些变化包括atRA组织浓度的可重复峰值，视黄醇酯和atRA形成速率的降低，以及代谢酶表达的时间依赖性变化。动力学模拟表明，氧化还原酶在肝损伤后决定类维生素a代谢通量中起重要作用。这些早期变化发生在HSC激活和促纤维化基因表达上调之前，这与atRA组织浓度呈负相关，表明HSC和Kupffer细胞是参与肝损伤后维生素A代谢通量和信号变化的关键细胞。目前关于这个主题的知识是什么？这项研究解决了什么问题？维生素A在肝脏中代谢为肝星状细胞（hsc）中的视黄酯或全反式视黄酸（atRA），这是一种具有抗纤维化特性的活性代谢物。慢性肝损伤后，维生素A代谢通量受到干扰，HSC激活导致类维甲酸储存减少。这项研究增加了我们的什么知识？维生素A代谢酶表达的变化能否解释急性肝损伤后atRA浓度的变化和纤维化的调节？这将如何改变临床药理学或转化科学？在健康的肝脏中，HSC和Kupffer细胞都可能介导维生素A的稳态。急性肝损伤后，代谢酶表达/活性的复杂变化改变了类维生素a的代谢通量，导致atRA浓度的短暂峰值。atRA浓度与促纤维化基因表达、HSC活化和胶原沉积呈负相关。对急性肝损伤中维生素A代谢通量改变的更好理解，可能有助于深入了解细胞特异性对维生素A损失的贡献，并导致肝纤维化的新干预措施。
All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? WHAT QUESTION DID THIS STUDY ADDRESS? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (atRA), an active metabolite with antifibrogenic properties. Following chronic liver injury, vitamin A metabolic flux is perturbed, and HSC activation leads to diminished retinoid stores. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Do changes in the expression of vitamin A metabolizing enzymes explain changes in atRA concentrations and the regulation of fibrosis following acute liver injury? HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The atRA concentrations are inversely correlated with profibrogenic gene expression, HSC activation, and collagen deposition. Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis.
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