Activation of SIRT1 by SRT1720 alleviates dyslipidemia, improves insulin sensitivity and exhibits liver-protective effects in diabetic rats on a high-fat diet: New insights into the SIRT1/Nrf2/NFκB signaling pathway
Elsayed A. Elmorsy , Hossam A. Elsisi , Abdullah S. Alkhamiss , Norah Suliman Alsoqih , Mostafa M. Khodeir , Abdulaziz A. Alsalloom , Ahmad A. Almeman , Sahar R. Elghandour , Eman Hassan Nadwa , Amira Karam khalifa , Bahaa Eldin Ali Khaled , Asmaa Ramadan , Manal M. Kamal , Thamir Saad Alsaeed , Mariam S. Alharbi , Abdel-Moneim Hafez Abdel-Moneim , Abousree T. Ellethy , Sameh Saber
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引用次数: 0
Abstract
Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720’s protective role improved liver function and histology and prolonged rats’ survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.
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