MSP is a negative regulator of inflammation and lipogenesis in ex vivo models of non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis (NASH), a metabolic disorder consisting of steatosis and inflammation, is considered the hepatic equivalent of metabolic syndrome and can result in irreversible liver damage. Macrophage-stimulating protein (MSP) is a hepatokine that potentially has a beneficial role in hepatic lipid and glucose metabolism via the activation of AMP-activated protein kinase (AMPK). In the current study, we investigated the regulatory role of MSP in the development of inflammation and lipid metabolism in various NASH models, both in vitro and ex vivo. We observed that MSP treatment activated the AMPK signaling pathway and inhibited lipopolysaccharide (LPS)- and palmitic acid (PA)-induced gene expression of pro-inflammatory cytokines in primary mouse hepatocytes. In addition, MSP treatment resulted in a significant reduction in PA-induced lipid accumulation and inhibited the gene expression of key lipogenic enzymes in HepG2 cells. Upon short hairpin RNA-induced knockdown of RON (the membrane-bound receptor for MSP), the anti-inflammatory and anti-lipogenic effects of MSP were markedly ablated. Finally, to mimic NASH ex vivo, we challenged bone marrow-derived macrophages with oxidized low-density lipoprotein (oxLDL) in combination with LPS. OxLDL+LPS exposure led to a marked inhibition of AMPK activity and a robust increase in inflammation. MSP treatment significantly reversed these effects by restoring AMPK activity and by suppressing pro-inflammatory cytokine gene expression and secretion under this condition. Taken together, these data suggest that MSP is an effective inhibitor of inflammation and lipid accumulation in the stressed liver, thereby indicating that MSP has a key regulatory role in NASH.
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.
Jieyi
J
Li
Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, 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.
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 Molecular Genetics, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Ronit
R
Shiri-Sverdlov
Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
Dietbert
0000-0002-4316-684X
D
Neumann
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002478:Cells, Cultured; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction
D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; C099252:oxidized low density lipoprotein; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases