New Amphiphilic Squalene Derivative Improves Metabolism of Adipocytes Differentiated From Diabetic Adipose-Derived Stem Cells and Prevents Excessive Lipogenesis

Abstract

Squalene (Sq) is a natural compound, found in various plant oils, algae, and larger quantity in deep-sea shark liver. It is also known as an intermediate of cholesterol synthesis in plants and animals including humans. Although evidences demonstrated its antioxidant, anticancer, hypolipidemic, and hepatoprotective and cardioprotective effects, its biological effects in cellular function might have been underestimated because of the water-insoluble property. To overcome this hydrophobicity, we synthesized new amphiphilic Sq derivative (HH-Sq). On the other hand, adipose-derived stem cells (ASCs) are a valuable source in regenerative medicine for its ease of accessibility and multilineage differentiation potential. Nevertheless, impaired cellular functions of ASCs derived from diabetic donor have still been debated controversially. In this study, we explored the effect of the HH-Sq in comparison to Sq on the adipocyte differentiation of ASCs obtained from subjects with type 2 diabetes. Gene expression profile by microarray analysis at 14 days of adipogenic differentiation revealed that HH-Sq induced more genes involved in intracellular signaling processes, whereas Sq activated more transmembrane receptor pathway-related genes. In addition, more important number of down-regulated and up-regulated genes by Sq and HH-Sq were not overlapped, suggesting the compounds might not only have difference in their chemical property but also potentially exert different biological effects. Both Sq and HH-Sq improved metabolism of adipocytes by enhancing genes associated with energy homeostasis and insulin sensitivity, SIRT1 , PRKAA2 , and IRS1 . Interestingly, Sq increased significantly early adipogenic markers and lipogenic gene expression such as PPARG , SREBF1 , and CEBPA , but not HH-Sq. As a consequence, smaller and fewer lipid droplet formation was observed in HH-Sq-treated adipocytes. Based on our findings, we report that both Sq and HH-Sq improved adipocyte metabolism, but only HH-Sq prevented excessive lipogenesis without abrogating adipocyte differentiation. The beneficial effect of HH-Sq provides an importance of synthesized derivatives from a natural compound with therapeutic potentials in the application of cell therapies.

Qualitative Detection of Triterpenes and Quantification of Betulinic Acid from Hexane Extract of Simarouba glauca Leaves by Gas Chromatography-Mass Spectrometry and High-Performance Thin Layer Chromatography

“…Studies have reported the anticancer property of squalene [26] . Ganbold et al [27] reported a new amphiphilic squalene derivative improves metabolism of adipocytes differentiated from diabetic adipose-derived stem cells and prevents excessive lipogenesis.…”

Effect of metabolically divergent pig breeds and tissues on mesenchymal stem cell expression patterns during adipogenesis

“…Adipogenesis, a developmental process to form fat tissue as energy storage tissue in which excess energy is stored in the form of lipids in adipocytes, is controlled by a complex cascade of adipocyte-specific transcription factors such as peroxisome proliferator-activated receptor γ (Pparg), CCAAT/enhancer-binding protein α (Cebpa), perilipin 2 (Plin2), fatty acid synthase (Fasn) and sterol regulatory element binding transcription protein 1 (Srebp1) [ 27 , 28 ]. Furthermore, the specific regulation of cellular interactions in conjunction with many differentiation factors and extracellular matrix components are essential for the adipogenic differentiation process, such as signaling pathways, adhesion molecules and transcription factors [ 23 , 29 , 30 ].…”

Epigenome wide association study in peripheral blood of pregnant women identifies potential metabolic pathways related to gestational diabetes

“…In our study, CpGs of MTOR were hypermethylated in the body region, which could involve a higher expression of this gene. PRKAA2 was associated with glucose levels after OGTT, and this gene seems to be related to insulin sensitivity [ 44 ] and some polymorphisms have been associated with T2DM [ 45 ]. Furthermore, PRKAA2 is closely related to MTOR regulation, i.e., downregulation of PRKAA2 induces MTOR expression and an increase in protein synthesis and insulin resistance in rats [ 46 ].…”