Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

Abstract

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.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

“…Inflammation is the main reason for the pathogenesis of NASH [24,25]. Quantitative real-time PCR and Western blot analysis showed that the combination of blueberry juice and probiotic bacteria had a significant inhibitory effect on inflammatory cytokines IL-6 and TNF-α.…”

“…Some data suggested that NASH patients could receive antioxidant therapies according to the oxidative stresses in their serum [23]. Inflammation is another important factor causing NASH because NASH is mainly characterized by hepatic lipid accumulation and is associated with progressive inflammatory liver disease [24,25]. The liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid and complications are associated with inflammation in animal NASH models [26].…”

Effects of nutraceutical intervention on serum proteins in aged rats

“…This protein has been speculated to have protective effects and to be a necessary regulator of metabolic activity (Li et al 2015). However, recent studies have shown that MST1/MSP/HGFL increases pro-inflammatory cytokine production in the liver and lungs (Li et al 2016;Wang et al 2015). Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by inflammation accumulation of lipids in the liver.…”

“…Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by inflammation accumulation of lipids in the liver. NASH model mice treated with MSP were found to have significantly higher levels of tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand 2 (Ccl2), intracellular adhesion molecule 1 (Icam1), interleukin 1beta (IL-1β), interferon gamma (IFNγ), B cell lymphoma 2 (Bcl2), macrophage markers F4/80, and cluster of differentiation 68 (CD68) (Li et al 2016). Wang et al exposed rats to combustion smoke in order to create a model of smoke-induced airway inflammation and found that MST1/MSP/HGFL and its receptor, RON, stimulated production of pro-inflammatory cytokines TNF-α, IL-8, IL-1β, and IL-10 (Wang et al 2015).…”

“…Some studies have pointed to MSP as a negative regulator of inflammation and a key protein in maintaining metabolic homeostatis (Li et al 2015). However, there is evidence that MST1/ MSP activation increases pro-inflammatory cytokine production in the liver and lungs (Li et al 2016;Wang et al 2015). In the CNS, it has been found that there are receptors for MSP on microglia (Ron) and that MSP activation results in increased mRNA expression of proinflammatory cytokines (Suzuki et al 2008).…”