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.
Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
EMBO Rep. 2024 Jul;25(7):2878-2895. doi: 10.1038/s44319-024-00158-x. Epub 2024 May 20.
Vitamin A (retinol) is distributed via the blood bound to its specific carrier protein, retinol-binding protein 4 (RBP4). Retinol-loaded RBP4 is secreted into the circulation exclusively from hepatocytes, thereby mobilizing hepatic retinoid stores that represent the major vitamin A reserves in the body. The relevance of extrahepatic retinoid stores for circulating retinol and RBP4 levels that are usually kept within narrow physiological limits is unknown. Here, we show that fasting affects retinoid mobilization in a tissue-specific manner, and that hormone-sensitive lipase (HSL) in adipose tissue is required to maintain serum concentrations of retinol and RBP4 during fasting in mice. We found that extracellular retinol-free apo-RBP4 induces retinol release by adipocytes in an HSL-dependent manner. Consistently, global or adipocyte-specific HSL deficiency leads to an accumulation of retinoids in adipose tissue and a drop of serum retinol and RBP4 during fasting, which affects retinoid-responsive gene expression in eye and kidney and lowers renal retinoid content. These findings establish a novel crosstalk between liver and adipose tissue retinoid stores for the maintenance of systemic vitamin A homeostasis during fasting.
维生素 A（视黄醇）通过与特定载体蛋白视黄醇结合蛋白 4（RBP4）结合分布在血液中。载有视黄醇的 RBP4 仅从肝细胞分泌到循环中，从而动员肝脏类视黄醇储存，这是体内维生素 A 的主要储备。对于通常保持在狭窄生理范围内的循环视黄醇和 RBP4 水平，肝外类视黄醇储存的相关性尚不清楚。在这里，我们表明禁食以组织特异性的方式影响类视黄醇的动员，并且脂肪组织中的激素敏感脂肪酶（HSL）在禁食期间维持血清视黄醇和 RBP4 的浓度是必需的。我们发现细胞外无视黄醇的 apo-RBP4 以 HSL 依赖的方式诱导脂肪细胞释放视黄醇。一致地，全身性或脂肪细胞特异性 HSL 缺乏导致脂肪组织中类视黄醇的积累和禁食期间血清视黄醇和 RBP4 的下降，这影响了眼睛和肾脏中视黄醇反应性基因的表达，并降低了肾脏中的类视黄醇含量。这些发现确立了肝脏和脂肪组织类视黄醇储存之间的新的串扰，以维持禁食期间的全身维生素 A 稳态。
