Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet-induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1and mTORC2-dependent pathways. BCAAs/branchedchain a-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome-dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/ BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.
Background Poor engraftment of intramyocardial stem cells limits their therapeutic efficiency against myocardial infarction ( MI )‐induced cardiac injury. Transglutaminase cross‐linked Gelatin (Col‐Tgel) is a tailorable collagen‐based hydrogel that is becoming an excellent biomaterial scaffold for cellular delivery in vivo. Here, we tested the hypothesis that Col‐Tgel increases retention of intramyocardially‐injected stem cells, and thereby reduces post‐ MI cardiac injury. Methods and Results Adipose‐derived mesenchymal stem cells ( ADSC s) were co‐cultured with Col‐Tgel in a 3‐dimensional system in vitro, and Col‐Tgel encapsulated ADSC s were observed using scanning electron microscopy and confocal microscopy. Vitality, proliferation, and migration of co‐cultured ADSC s were evaluated. In addition, mice were subjected to MI and were intramyocardially injected with ADSC s, Col‐Tgel, or a combination thereof. ADSC s engraftment, survival, cardiac function, and fibrosis were assessed. In vitro MTT and Cell Counting Kit‐8 assays demonstrated that ADSC s survive and proliferate up to 4 weeks in the Col‐Tgel. In addition, MTT and transwell assays showed that ADSC s migrate outside the edge of the Col‐Tgel sphere. Furthermore, when compared with ADSC s alone, Col‐Tgel‐encapsulated ADSC s significantly enhanced the long‐term retention and cardioprotective effect of ADSC s against MI ‐induced cardiac injury. Conclusions In the current study, we successfully established a 3‐dimensional co‐culture system using ADSC s and Col‐Tgel. The Col‐Tgel creates a suitable microenvironment for long‐term retention of ADSC s in an ischemic area, and thereby enhances their cardioprotective effects. Taken together, this study may provide an alternative biomaterial for stem cell‐based therapy to treat ischemic heart diseases.
Smooth muscle cells (SMCs), which form the walls of blood vessels, play an important role in vascular development and the pathogenic process of vascular remodeling. However, the molecular mechanisms governing SMC differentiation remain poorly understood. Glycoprotein M6B (GPM6B) is a four‐transmembrane protein that belongs to the proteolipid protein family and is widely expressed in neurons, oligodendrocytes, and astrocytes. Previous studies have revealed that GPM6B plays a role in neuronal differentiation, myelination, and osteoblast differentiation. In the present study, we found that the GPM6B gene and protein expression levels were significantly upregulated during transforming growth factor‐β1 (TGF‐β1)‐induced SMC differentiation. The knockdown of GPM6B resulted in the downregulation of SMC‐specific marker expression and repressed the activation of Smad2/3 signaling. Moreover, GPM6B regulates SMC Differentiation by Controlling TGF‐β‐Smad2/3 Signaling. Furthermore, we demonstrated that similar to p‐Smad2/3, GPM6B was profoundly expressed and coexpressed with SMC differentiation markers in embryonic SMCs. Moreover, GPM6B can regulate the tightness between TβRI, TβRII, or Smad2/3 by directly binding to TβRI to activate Smad2/3 signaling during SMC differentiation, and activation of TGF‐β‐Smad2/3 signaling also facilitate the expression of GPM6B. Taken together, these findings demonstrate that GPM6B plays a crucial role in SMC differentiation and regulates SMC differentiation through the activation of TGF‐β‐Smad2/3 signaling via direct interactions with TβRI. This finding indicates that GPM6B is a potential target for deriving SMCs from stem cells in cardiovascular regenerative medicine. Stem Cells 2018 Stem Cells 2019;37:190–201
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