Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss
Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss
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DOI：
10.1096/fj.14-266296
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发表时间：
2015-09-01
期刊：
影响因子：
4.8
通讯作者：
Blaner, William S.
中科院分区：
文献类型：
--
作者：
Clugston, Robin D.;Huang, Li-Shin;Blaner, William S.
酒精诱导的肝类视黄醇储存耗竭与肝损伤的进展相关；然而，酒精作用的机制尚未完全阐明。我们的目标是获得酒精诱导的肝类视黄醇消耗的机制理解。野生型和突变型小鼠通过Lieber-DeCarli液体饮食连续喂食酒精，与之匹配的对照动物配对喂食等热量的无酒精饮食，以确保两组之间的营养和卡路里摄入量相等。系统分析组织视黄醇和视黄醇酯水平，辅以基因和蛋白质表达分析。我们的结果描述了酒精诱导的肝类维甲酸消耗的两个阶段。最初，大约15%的肝类视黄醇含量从肝脏转移，导致肝外组织类视黄醇水平升高。随后，肝类维甲酸含量急剧下降（约60%），周围没有进一步的类维甲酸积累。对突变小鼠的后续研究揭示了RBP、CRBP1和CD36在类视黄酮动员和肝外类视黄酮摄取中的作用，以及CYP2E1在肝类视黄酮分解代谢中的作用。总之，酒精对肝类视黄醇储存有两期影响，其特点是初始阶段迅速动员到肝外组织，随后在肝脏内广泛分解代谢。
The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol's effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, similar to 15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver.