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A stem cell based in vitro model of NAFLD enables the analysis of patient specific individual metabolic adaptations in response to a high fat diet and AdipoRon interference

ABSTRACT: A stem cell based in vitro model of NAFLD enables the analysis of patient specific individual metabolic adaptations in response to a high fat diet and AdipoRon interference

PROVIDER: PRJNA683035 | ENA |

REPOSITORIES: ENA

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Project description:Since the first report of AdipoRon as an orally active adiponectin receptor (AdipoR1/2) agonist, several studies have investigated its protective, metabolic and anti-cancer effects in the liver, kidney, heart, central nervous system and ovaries. Despite that, the effects of AdipoRon on pancreatic -cell function are yet to be addressed. Furthermore, the various AdipoRon actions reported to date have only been assessed at a rather high oral dosage without attempts to enhance its affinity and/or bioavailability. To examine how structural modifications can affect AdipoRon-induced multifaceted actions, we describe a series of AdipoRon analogs that contain amphiphilic ethylene glycol chains. Among these, we propose AdipoRonPEG5 as a more potent derivative of AdipoRon in exerting pleiotropic actions in mice under insulinopenic and high fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells in a dose-dependent manner, only AdipoRonPEG5 treatment is accompanied by a marked expression of genes involved in maintaining the functional state of β-cells along with a significant reduction in ceramides. Similarly, AdipoRonPEG5 can induce a substantial reduction of pancreatic, hepatic and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases, and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in STZ-induced insulinopenic adiponectin null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing lipotoxicity in the pancreas and liver of HFD-fed mice than AdipoRon at 5 mg/Kg dosage and is consistent with adiponectin cytoprotective effect of β-cells. Additionally, these results indicate that the beneficial effects AdipoRonPEG5 can be partially attributed to improved pharmacokinetics compared to AdipoRon, thus providing the opportunity for further derivatization to achieve improved affinity and tissue-specific targeting.

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A stem cell based in vitro model of NAFLD enables the analysis of patient specific individual metabolic adaptations in response to a high fat diet and AdipoRon interference

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