The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice

Pinto, Livia de Fraia; Compri, Cecília Melleti; Fornari, João Victor; Bartchewsky, Waldemar; Cintra, Dennys E.; Trevisan, Miriam Aparecida da Silva; Carvalho, Patrícia de Oliveira; Ribeiro, Marcelo Lima; Velloso, Lı́cio A.; Saad, Mário José Abdalla; Pedrazzoli, José; Gambero, Alessandra

doi:10.1111/j.1478-3231.2009.02200.x

Cited by 37 publications

(8 citation statements)

References 33 publications

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“…MCP-1, a chemoattractant protein that recruits immune cells to sites of inflammation, and TNF-α, a pro-inflammatory cytokine that inhibits insulin secretion and induces apoptosis of β-cells [35], also play pivotal roles in the development of insulin resistance and hepatic steatosis [36]. In a recent study, inhibition of C-C chemokine receptor 2, the MCP-1 receptor, ameliorated insulin resistance and hepatic steatosis by regulating hepatic lipid homeostasis in type 2 diabetic model mice [37], and anti-TNF-α treatment improved hepatic steatosis and insulin resistance [38,39]. In the present study, we demonstrated that hepatic inflammation was increased in HFD/STZ-induced type 2 diabetic mice as evidenced by the upregulation of TLR4, MCP-1, and TNF-α mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Kim

Jung

2020

IJMS

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To test the hypothesis that myricitrin (MYR) improves type 2 diabetes, we examined the effect of MYR on hyperglycemia, glucose intolerance, hepatic steatosis, and inflammation in high-fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice. Male C57BL/6J mice were randomly divided into three groups: non-diabetic, diabetic control, and MYR (0.005%, w/w)-supplemented diabetic groups. Diabetes was induced by HFD and STZ, and MYR was administered orally for 5 weeks. Myricitrin exerted no significant effects on food intake, body weight, fat weight, or plasma lipids levels. However, MYR significantly decreased fasting blood glucose levels, improved glucose intolerance, and increased pancreatic β-cell mass compared to the diabetic control group. Myricitrin administration also markedly increased glucokinase mRNA expression and activity as well as lowered glucose-6-phosphatase and phosphoenolpyruvate carboxykinase mRNA expression and activity in the liver. In addition, liver weight, hepatic triglyceride content, and lipid droplet accumulation were markedly decreased following MYR administration. These changes were seemingly attributable to the suppression of the hepatic lipogenic enzymes—fatty acid synthase and phosphatidate phosphohydrolase. Myricitrin also significantly lowered plasma MCP-1 and TNF-α levels and the mRNA expression of hepatic pro-inflammatory genes. These results suggest that MYR has anti-diabetic potential.

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Section: Discussionmentioning

confidence: 99%

Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Kim

Jung

2020

IJMS

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“…Thalidomide, an immunosuppressant with anti-TNFα properties, has also been shown to reduce the inflammatory profile induced in a murine NAFLD model. 45 Furthermore, NAFLD patients receiving etanercept, an antibody to TNF, have significant reductions in the AST/ALT ratio and serum C-reactive protein levels. 46 …”

Section: Discussionmentioning

confidence: 99%

Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

Luther

Garber

Khalili

et al. 2015

Cellular and Molecular Gastroenterology and Hepatology

231

180

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BACKGROUND & AIMSEmerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism.METHODSA meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells.RESULTSNonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)–induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury.CONCLUSIONSOur clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.

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“…In the current study, we observed increased expression of several pro-inflammatory genes in the livers of mice affected with NASH. TNFα has been shown to be a key factor in the development of NAFLD and NASH [ 21 , 22 ]. Since Kupffer cells, the liver’s residential macrophages, are the first responding cells to hepatocyte injuries, the increased release of TNFα from these cells is one of the most common characters of early phase of NASH in mouse model.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

Chanda

Gorp

et al. 2016

PLoS ONE

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Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)—a serum protein mainly secreted by liver—was shown to inhibit oxidized low-density lipoprotein (OxLDL)/lipopolysaccharides (LPS)-induced inflammation in mouse macrophages. Additionally, MSP could reduce palmitic acid (PA)-induced lipid accumulation and lipogenesis in the HepG2 cell line. Altogether, these data suggest MSP as a suppressor for metabolic inflammation. However, so far the potential of MSP to be used as a treatment for NASH was not investigated. We hypothesized that MSP reduces lipid accumulation and hepatic inflammation. To investigate the effects of MSP in the early stage of NASH, low-density lipoprotein receptor (Ldlr-/-) mice were fed either a regular chow or a high fat, high cholesterol (HFC) diet for 7 days. Recombinant MSP or saline (control) was administrated to the mice by utilizing subcutaneously-implanted osmotic mini-pumps for the last 4 days. As expected, mice fed an HFC diet showed increased plasma and hepatic lipid accumulation, as well as enhanced hepatic inflammation, compared with chow-fed controls. Upon MSP administration, the rise in cholesterol and triglyceride levels after an HFC diet remained unaltered. Surprisingly, while hepatic macrophage and neutrophil infiltration was similar between the groups, MSP-treated mice showed increased gene expression of pro-inflammatory and pro-apoptotic mediators in the liver, compared with saline-treated controls. Contrary to our expectations, MSP did not ameliorate NASH. Observed changes in inflammatory gene expression suggest that further research is needed to clarify the long-term effects of MSP.

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The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice

Abstract: We suggest that immunosuppressant drugs that target TNF-alpha and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.

Cited by 37 publications

References 33 publications

Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Myricitrin Ameliorates Hyperglycemia, Glucose Intolerance, Hepatic Steatosis, and Inflammation in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability

Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

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