Abstract
AimTo investigate the effects of tacrolimus (TC) and everolimus (EV) on non-alcoholic steatohepatitis (NASH) induced by high fat, high cholesterol and fructose (fast food) diet in C57BL/6J mice.Materials and MethodsC57BL/6J mice were divided into four groups (n=8). 1) Standard Chow (SC); 2) Fast food (FF) diet; 3) FF + Tacrolimus (TC, 1mg/kg) and; 4) FF + Everolimus (EV, 1mg/kg) and treated for 16 weeks. Serum and tissue samples were analyzed for evidence of inflammation, fibrosis, lipogenesis, and apoptosis.ResultsTC and EV treatments significantly reduced the hepatic lipid accumulation, improved liver-body weight ratio, blood biochemistry, and insulin resistance in mice fed with FF diet. However, inflammation, enlarged portal tracts, and fibrosis were pronounced in EV treated group. The lipogenic parameters, Peroxisome proliferator-activated receptor gamma (PPAR-γ), Sterol regulatory element-binding protein 1(SREBP-1), mammalian target of rapamycin (m-TOR), Stearoyl-CoA desaturase-1 (SCD-1) and fatty acid translocase (CD36) were significantly down-regulated in livers of TC and EV treated groups as compared to FF group. TC improved Bcl2/Bax ratio, decreased apoptosis, CYP2E1 protein expression and liver fibrosis levels, however, EV offered no such protection. Further, in an In-vitro model of lipotoxicity using the mouse hepatocyte (AML-12) cell line, treatment with TC and EV significantly reduced lipid accumulation and lipogenic and apoptotic markers induced with palmitic acid.ConclusionIn FF diet induced model of NASH, both TC and EV inhibited hepatic lipid accumulation and improved metabolic parameters such as insulin resistance and dyslipidemia. However, mice administered with EV exhibited inflammatory and fibrotic responses despite reduced hepatic steatosis.
Highlights
Metabolic derangements such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and related comorbidities, collectively referred to as metabolic syndrome (MS), create significant socio-economic health burden and is shaping into a global epidemic threat
The controversial background of everolimus and tacrolimus in the prevention of Non-alcoholic Fatty Liver Disease (NAFLD), the present study investigated the role of these two drugs i.e. tacrolimus and everolimus in a mouse model of non-alcoholic Steatohepatitis (NASH) (C57BL/6J mice fed with High Cholesterol/High Fat Diet + High Fructose Corn Syrup {fast food (FF), diet})
Average liver weight of mice in FF group (1.67±0.15g) was significantly higher than standard chow (SC) group (1.08±0.06g), (p
Summary
Metabolic derangements such as obesity, type 2 diabetes mellitus (T2DM), dyslipidemia, and related comorbidities, collectively referred to as metabolic syndrome (MS), create significant socio-economic health burden and is shaping into a global epidemic threat. A major consequent of MS is Non-alcoholic Fatty Liver Disease (NAFLD), whose prevalence has been increasing over the last decade [1]. NAFLD pathogenesis is associated with perturbances in several cellular pathways viz phosphoinositide 3-kinase-phosphatase and tensin homolog (PI3K-PTEN), hedgehogg signaling, and mammalian target of rapamycin (m-TOR). The m-TOR signaling pathway is critically being implicated in senescence, metabolic disorders, aging, cell proliferation and cellular growth [4, 5]. It is recognized as key regulator of lipid homeostasis, its role in the pathogenesis of NAFLD is quite controversial. Mammalian target of rapamycin complex 1 (mTORC1), a key component of m-TOR pathway is reported to be involved in the activation of many lipogenic transcriptional factors and proteins, like sterol regulatory element-binding protein 1 (SREBP1), an activator of stearoyl-CoA desaturase-1 (SCD-1) (Figure 1) [6]
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