Adipocyte HSL is required for maintaining circulating vitamin A and RBP4 levels during fasting

• Published in: EMBO reports Vol. 25; no. 7; pp. 2878 - 2895
• Main Authors: Steinhoff, Julia S, Wagner, Carina, Dähnhardt, Henriette E, Košić, Kristina, Meng, Yueming, Taschler, Ulrike, Pajed, Laura, Yang, Na, Wulff, Sascha, Kiefer, Marie F, Petricek, Konstantin M, Flores, Roberto E, Li, Chen, Dittrich, Sarah, Sommerfeld, Manuela, Guillou, Hervé, Henze, Andrea, Raila, Jens, Wowro, Sylvia J, Schoiswohl, Gabriele, Lass, Achim, Schupp, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.07.2024; EMBO Press
• Subjects: Adipocytes; Adipocytes - metabolism; Adipose Tissue; Adipose Tissue - metabolism; Animals; Biochemistry, Molecular Biology; Biomedical and Life Sciences; EMBO21; Fasting; Fasting - metabolism; Food and Nutrition; Life Sciences; Liver; Liver - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Retinol-Binding Proteins, Plasma; Retinol-Binding Proteins, Plasma - genetics; Retinol-Binding Proteins, Plasma - metabolism; Sterol Esterase; Sterol Esterase - genetics; Sterol Esterase - metabolism; Vitamin A; Vitamin A - blood; Vitamin A - metabolism; HSL; Vitamin A; RBP4; Fasting; Retinol
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00158-x

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. Synopsis Fasting levels of retinol and its transport protein RBP4 in the circulation depend on the presence of HSL in adipocytes, uncovering a crosstalk between adipose tissue and systemic retinoid homeostasis. Fasting reduces hepatic retinyl ester hydrolase activity and induces an accumulation of RBP4 protein in liver in mice. Expression and secretion of RBP4 in hepatocytes are regulated by FOXO1 and cAMP. Global- or adipocyte-specific deletion of hormone-sensitive lipase (HSL) results in reduced circulating retinol and RBP4 levels during fasting. Adipocytes release retinol to extracellular retinol-free apo-RBP4 in an HSL-dependent manner. Adipocyte-specific deletion of HSL affects fasted retinoid homeostasis in peripheral organs like the kidney. Fasting levels of retinol and its transport protein RBP4 in the circulation depend on the presence of HSL in adipocytes, uncovering a crosstalk between adipose tissue and systemic retinoid homeostasis.