Laboratory of Molecular Biology, Nutrition and Biotechnology, Universitat de les Illes Balears, Palma de Mallorca and CIBER de Fisiopatología de la Obesidad y Nutrición, Spain.
Int J Biochem Cell Biol. 2012 Nov;44(11):2019-27. doi: 10.1016/j.biocel.2012.07.026. Epub 2012 Jul 31.
The vitamin A derivative retinoic acid (RA) is an important regulator of mammalian adiposity and lipid metabolism, primarily acting at the gene expression level through nuclear receptors of the RA receptor (RAR) and retinoid X receptor (RXR) subfamilies. Here, we studied cell-autonomous effects of RA on fatty acid metabolism, particularly fatty acid oxidation, in human hepatoma HepG2 cells. Exposure to all-trans RA (ATRA) up-regulated the expression of carnitine palmitoyl transferase-1 (CPT1-L) in HepG2 cells in a dose- and time-dependent manner, and increased cellular oxidation rate of exogenously added radiolabeled palmitate. The effect of ATRA on gene expression of CPT1-L was: dependent on ongoing transcription, reproduced by both 9-cis RA and a pan-RXR agonist (but not a pan-RAR agonist) and abolished following RXRα partial siRNA-mediated silencing. CPT1-L gene expression was synergistically induced in HepG2 cells simultaneously exposed to ATRA and a selective peroxisome proliferator-activated receptor α agonist. We conclude that ATRA treatment enhances fatty acid catabolism in hepatocytes through RXR-mediated mechanisms that likely involve the transactivation of the PPARα:RXR heterodimer. Knowledge of agents and nutrient-derivatives capable of enhancing substrate oxidation systemically and specifically in liver, and their mechanisms of action, may contribute to new avenues of prevention and treatment of fatty liver, obesity and other metabolic syndrome-related disorders.
维生素 A 衍生物视黄酸（RA）是哺乳动物肥胖和脂质代谢的重要调节剂，主要通过 RA 受体（RAR）和视黄醇 X 受体（RXR）亚家族的核受体在基因表达水平上发挥作用。在这里，我们研究了 RA 对脂肪酸代谢，特别是脂肪酸氧化的细胞自主作用，特别是在人肝癌 HepG2 细胞中。全反式 RA（ATRA）暴露以剂量和时间依赖的方式上调 HepG2 细胞中肉碱棕榈酰基转移酶-1（CPT1-L）的表达，并增加外源性添加的放射性标记棕榈酸的细胞氧化率。ATRA 对 CPT1-L 基因表达的影响：依赖于正在进行的转录，9-顺式 RA 和泛 RXR 激动剂（但不是泛 RAR 激动剂）可重现，并且在 RXRα 部分 siRNA 介导的沉默后被消除。同时暴露于 ATRA 和选择性过氧化物酶体增殖物激活受体α激动剂的 HepG2 细胞中，CPT1-L 基因表达协同诱导。我们得出结论，ATRA 治疗通过 RXR 介导的机制增强肝细胞中的脂肪酸分解代谢，这些机制可能涉及 PPARα：RXR 异二聚体的反式激活。了解能够全身性和特异性地增强肝脏中底物氧化的试剂和营养衍生剂及其作用机制，可能有助于为脂肪肝、肥胖症和其他代谢综合征相关疾病开辟新的预防和治疗途径。
