Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model.
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.
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Jieyi
J
Li
Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Dipanjan
D
Chanda
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Patrick J
PJ
van Gorp
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Mike L J
ML
Jeurissen
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Tom
T
Houben
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Sofie M A
SM
Walenbergh
Department of Pharmacology, Maastricht University, Maastricht, The Netherlands.
Jacques
J
Debets
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Yvonne
Y
Oligschlaeger
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.|Department of Medical Biochemistry and Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Marion J J
MJ
Gijbels
Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Dietbert
D
Neumann
Department of Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Ronit
R
Shiri-Sverdlov
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