Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD).
Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD).
复制标题
DOI：
10.3390/nu10010029
复制
发表时间：
2017-12-29
期刊：
影响因子：
5.9
通讯作者：
Faber KN
中科院分区：
文献类型：
--
作者：
Saeed A;Dullaart RPF;Schreuder TCMA;Blokzijl H;Faber KN
维生素A是重要的生理过程所必需的，包括胚胎发生、视觉、细胞增殖和分化、免疫调节以及葡萄糖和脂质代谢。维生素A的许多功能是通过视黄酸来执行的，视黄酸激活由视黄酸受体（RAR）和类维生素A X受体（RXR）控制的转录网络。肝脏在维生素A代谢中起着核心作用：（1）它产生胆汁，支持脂溶性营养物质如维生素A的有效肠道吸收;（2）它产生视黄醇结合蛋白4（RBP 4），其将维生素A作为视黄醇分配到外周组织;和（3）它在肝星状细胞（HSC）中具有维生素A的最大体内供应，主要作为视黄酯。在饮食摄入不足的时候，肝脏维持稳定的循环视黄醇水平约2 μmol/L，足以为身体提供这种维生素数月。肝脏疾病，特别是那些导致纤维化和肝硬化的疾病，与维生素A稳态受损有关，并可能导致维生素A缺乏症。肝损伤触发HSC转分化为肌成纤维细胞，肌成纤维细胞产生过量的细胞外基质，导致纤维化。HSC在此过程中失去视黄酯储存，最终导致维生素A缺乏。非酒精性脂肪性肝病（NAFLD）是代谢综合征的肝脏表现，是一系列从良性肝脂肪变性到非酒精性脂肪性肝炎（NASH）的疾病;它可能进展为肝硬化和肝癌。NASH预计在不久的将来成为肝衰竭的主要原因。视黄酸是肝脏和脂肪组织中葡萄糖和脂质代谢的关键调节剂，但维生素A稳态受损是否有助于或抑制NAFLD的发展尚不清楚。马铃薯糖样磷脂酶结构域3（PNPLA 3-I148 M）的遗传变异是与NAFLD相关的最突出的遗传因素。有趣的是，PNPLA 3具有视黄酯水解酶活性，PNPLA 3-I148 M与低血清视黄醇水平相关，但与NAFLD患者肝脏中的视黄酯增强相关。因此，NAFLD中低循环视黄醇可能并不反映真正的“维生素A缺乏”，而是维生素A代谢紊乱。在这里，我们总结了目前关于NAFLD中维生素A代谢的知识及其在肝病进展中的假定作用，以及维生素A代谢物的治疗潜力。
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.