Adrenal lipoma formation via PI(3,4,5)P <sub>3</sub> /AKT-dependent transdifferentiation of adrenocortical cells into adipocytes
Abstract
Adrenal lipomas are benign tumors containing ectopic adipose tissue in the adrenal gland, an organ that normally lacks both adipocytes and their progenitors. The origin of this ectopic fat remains enigmatic, and the absence of a genetic animal model has hindered its investigation. Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], a key signaling lipid that regulates cellular growth and differentiation, is tightly regulated by the lipid phosphatases PTEN (phosphatase and tensin homolog) and SHIP2 (SH2-containing inositol phosphatase 2). Here, we demonstrate that simultaneous loss of Pten and Ship2 in the adrenal cortex induces adrenal lipoma formation in mice. These lipomatous cells display both adipocyte-like morphology and adipocyte-specific gene expression. Lineage tracing revealed that these lipomas originate from the adrenal cortex. Mechanistically, PI(3,4,5)P 3 hyperaccumulation in the adrenal cortex activates AKT (AKT8 virus oncogene cellular homolog), leading to ectopic PPARγ (peroxisome proliferator activated receptor gamma) expression, a key driver of adipocyte differentiation. This study suggests that the PI(3,4,5)P 3 /AKT-driven transdifferentiation of adrenocortical cells may represent a central mechanism underlying adrenal lipoma formation, thereby providing insights into lipoma pathogenesis and cellular reprogramming in vivo.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Shogo Yanai
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Junko Sasaki
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Hyeon-Cheol Lee-Okada
Department of Biochemistry, Juntendo University Graduate School of Medicine
Fumiya Takahashi
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University
Yuto Kikuchi
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Shin Morioka
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Toshiyoshi Yamamoto
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Katsuya Yuguchi
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Miko Oikawa
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Hiroaki Kajiho
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo
Takashi Baba
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University
Chikako Yokoyama
Department of Chemistry and Bioengineering, Graduate School of Engineering, Osaka Metropolitan University
Ken-Ichirou Morohashi
Department of Internal Medicine, Kurume University School of Medicine
Akira Suzuki
Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine
Takehiko Yokomizo
Department of Biochemistry, Juntendo University Graduate School of Medicine
Takehiko Sasaki
Department of Biochemical Pathophysiology, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo