Wagner Carina, Košić Kristina, Bulfon Dominik, Breithofer Johannes, Jamnik Alina, Zitta Clara, Horvat Paula, Bilweis Kim, Schupp Michael, Zimmermann Robert, Taschler Ulrike, Lass Achim
Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular-Metabolic-Renal Research, Berlin, Germany.
Liver Int. 2025 Sep;45(9):e70213. doi: 10.1111/liv.70213.
Advanced liver disease leads to liver fibrosis that is characterised by the activation of non-parenchymal stellate cells, accumulation of extracellular matrix proteins, and the loss of hepatic vitamin A stores. To date, the molecular mechanisms and enzymes mediating the loss of hepatic vitamin A stores are incompletely understood.
Using a fibrosis mouse model induced by the hepatotoxin carbon tetrachloride (CCl), we investigated which cellular processes in the liver mediate the loss of hepatic retinyl ester stores. We found that repeated CCl injections into mice over six weeks led to a biphasic change in plasma retinol levels that were increased after three and decreased after six weeks as compared to control mice. As expected, livers of mice receiving CCl injections showed increased expression of pro-fibrogenic genes that were accompanied by decreased hepatic retinoid content, which was mainly due to loss of retinoids in non-parenchymal cells (NPCs). In the liver and NPCs, decreased retinyl ester levels correlated with reduced gene expression of lecithin:retinol acyltransferase and reduced hepatic ex vivo retinol acyltransferase activity. Conversely, gene expression of lipases known to exhibit retinyl ester hydrolase activity (REHA) remained unchanged or was decreased, consistent with decreased neutral REHA in homogenates of respective livers and lysates of isolated NPCs, respectively. Albeit hepatic expression levels of marker proteins for autophagosomal and lysosomal membranes were increased, gene expression of the major acidic retinyl ester hydrolase, lysosomal acid lipase, as well as ex vivo acidic REHA were reduced in NPC lysates.
Together, these results indicate that the loss of hepatic retinyl ester stores upon liver injury and stellate cell activation is rather a consequence of reduced retinol esterification than neutral or acidic hydrolysis.
晚期肝病会导致肝纤维化，其特征为非实质星状细胞活化、细胞外基质蛋白积聚以及肝脏维生素A储备丧失。迄今为止，介导肝脏维生素A储备丧失的分子机制和酶尚未完全明确。
利用由肝毒素四氯化碳（CCl）诱导的纤维化小鼠模型，我们研究了肝脏中哪些细胞过程介导了肝脏视黄酯储备的丧失。我们发现，在六周内对小鼠重复注射CCl导致血浆视黄醇水平出现双相变化，与对照小鼠相比，三周后升高，六周后降低。正如预期的那样，接受CCl注射的小鼠肝脏中促纤维化基因的表达增加，同时肝脏类视黄醇含量降低，这主要是由于非实质细胞（NPC）中类视黄醇的丧失。在肝脏和NPC中，视黄酯水平降低与卵磷脂：视黄醇酰基转移酶的基因表达减少以及肝脏体外视黄醇酰基转移酶活性降低相关。相反，已知具有视黄酯水解酶活性（REHA）的脂肪酶的基因表达保持不变或降低，分别与相应肝脏匀浆和分离的NPC裂解物中中性REHA降低一致。尽管自噬体和溶酶体膜的标记蛋白的肝脏表达水平升高，但NPC裂解物中主要酸性视黄酯水解酶、溶酶体酸性脂肪酶的基因表达以及体外酸性REHA均降低。
总之，这些结果表明，肝损伤和星状细胞活化后肝脏视黄酯储备的丧失更多是视黄醇酯化减少的结果，而非中性或酸性水解的结果。
