Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

Abstract

Background Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for inter-species crosstalk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 family fember A1 (Aldh1a1) knock out adipocytes (KO) inhibits adipogenesis and increase thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures. Methods Murine wide type (WT) and KO preadipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes were detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray. Results Co-culture of encapsulated mouse KO vs. WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARγ activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression with WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4) and lipokalin 2 (LCN2) in KO vs WT adipocytes. Conclusion Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for reduction of obesity in dogs and a strategy for translation to patients.

Bioactive lipids in cancer stem cells

“…It was recently found that the prominent CSC marker aldehyde dehydrogenase (ALDH)1A1 modulates energy metabolism in adipocytes from several species[58]. In this study, retinoic acid deficiency in knock-out ALDH1A1 adipocytes inhibited adipogenesis and increased thermogenesis.…”

GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

“…The different effect of GLS1 and MYC inhibitors in cancer and BPH cells can be partially attributed to the significant upregulation of ALDH1A1 expression in BPH tissues in response to Gln starvation. Recent studies demonstrated that ALDH proteins are important for energy metabolism in tumor and normal tissues [57][58][59] , and that reduced nicotinamide adenine dinucleotide (NADH) produced by ALDH is essential for maintaining redox homeostasis 60,61 .…”

A comparative study on normal and obese mice indicates that the secretome of mesenchymal stromal cells is influenced by tissue environment and physiopathological conditions

“…Fstl3 BM-MSCs release factors involved in growth and differentiation of neural cells, such as glia maturation factor-β (GMFB) and mesencephalic astrocyte-derived neurotrophic factor (MANF) [39,40]. These cells also release proteins that regulate energy metabolism, such as Me1 (malic enzyme), Aldh1a2, and Aldh1a3 (aldehyde dehydrogenase) [41,42]. BM-MSCs also secrete many proteins associated with glycosaminoglycan formation and degradation.…”