ROS induces CHOP-mediated Akr1A1 gene expression regulating the adipose-osteogenic lineage differentiation of MSCs through the SIRT1-dependent pathway

The Aldo-keto reductase family 1 member A1 (Akr1A1) is an enzyme that relies on NADPH to reduce aldehyde groups into alcohols. We extracted mesenchymal stem cells (MSCs) from human bone marrow and Wharton’s jelly to study the varying expression of Akr1A1 during the differentiation of MSCs into osteoblasts and adipocytes. We observed decreased Akr1A1 expression during osteogenesis and increased during adipogenesis. This variation in expression correlated with changes in intracellular reactive oxygen species (ROS) levels and C/EBP homology protein (CHOP) in cells committed to adipogenic and osteogenic lineages. Interestingly, our experiments involving the silencing and overexpression of the Akr1A1 gene showed that the levels of Akr1A1 expression influenced the differentiation of MSCs into specific lineages without altering ROS production and CHOP expression. When Akr1A1 was knocked down, adipogenesis was reduced, and osteoblastogenesis was promoted, increasing the protein levels of SIRT1, PGC-1α, TAZ, and other transcription factors favoring osteoblast differentiation. Conversely, overexpression of Akr1A1 resulted in the downregulation of SIRT1, PGC-1α, and TAZ, which led to an increase in adipogenesis and a decrease in osteogenesis. These results suggest that Akr1A1 is a downstream ROS/CHOP-induced target. We confirmed this using an oxidative stress cell model induced by D-galactose, which showed that increased ROS triggers CHOP-mediated Akr1A1 expression. This controls the preferential differentiation of MSCs into adipocytes over osteoblasts. Our findings indicate that the expression of Akr1A1, induced by CHOP in response to elevated intracellular ROS, may regulate the commitment of MSCs to adipogenic and osteogenic lineages through the SIRT1-mediated pathway. This understanding of the cellular mechanisms may pave the way for developing new treatments to prevent bone loss and too much fat buildup in conditions like metabolic and age-related osteoporosis. Supported by the Grant NSTC, 112-2314-B-005-004 -; the Grant MOE-113-S-0023-A; the Grant CYCH-NCHULS, 111-003 and Grant CYCH-NCHULS, 112-003, the Grant NCHU-CCH,11205. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.