scholarly journals Inhibition of sphingosine 1-phosphate signaling ameliorates murine nonalcoholic steatohepatitis

2017 ◽  
Vol 312 (3) ◽  
pp. G300-G313 ◽  
Author(s):  
Amy S. Mauer ◽  
Petra Hirsova ◽  
Jessica L. Maiers ◽  
Vijay H. Shah ◽  
Harmeet Malhi
Keyword(s):  
Liver Injury ◽  
Nonalcoholic Steatohepatitis ◽  
Smooth Muscle Actin ◽  
Myeloid Cells ◽  
Saturated Fat ◽  
Sphingosine 1 Phosphate ◽  
Macrophage Chemotaxis ◽  
Liver Triglycerides ◽  
Macrophage Accumulation

Nonalcoholic steatohepatitis (NASH) is a lipotoxic disorder, wherein proinflammatory lipids, such as ceramide and its derivative sphingosine 1-phosphate (S1P), contribute to macrophage-associated liver inflammation. For example, we have previously demonstrated a role for S1P in steatotic hepatocyte-derived S1P-enriched extracellular vesicles in macrophage chemotaxis in vitro. Therefore, we hypothesized that FTY720, an S1P antagonist, would ameliorate NASH by inhibiting proinflammatory monocyte chemotaxis. To test our hypothesis, NASH was established in C57BL/6 male mice by feeding a diet high in fructose, saturated fat, and cholesterol for 22 wk. Then mice received daily intraperitoneal injections of FTY720 for 2 wk before analysis of liver injury, inflammation, and fibrosis. FTY720-treated mice with NASH demonstrated improved liver histology with a significant reduction in hepatocyte ballooning and inflammatory foci. Hepatomegaly was reversed, and liver triglycerides were reduced following FTY720 administration to mice with NASH. Correspondingly, serum ALT levels, hepatic inflammatory macrophage accumulation, and the expression of Ly6C in recruited myeloid cells was reduced in FTY720-treated mice. Hepatic collagen accumulation and expression of α-smooth muscle actin were significantly lowered as well. Body composition, energy consumption and utilization, and hepatic sphingolipid composition remained unchanged following FTY720 administration. FTY720 ameliorates murine nonalcoholic steatohepatitis. Reduction in liver injury and inflammation is associated with a reduction in hepatic macrophage accumulation, likely due to dampened recruitment of circulating myeloid cells into the liver. Nonalcoholic steatohepatitis may be a novel indication for the therapeutic use of FTY720. NEW & NOTEWORTHY There are no approved pharmacologic therapies for nonalcoholic steatohepatitis (NASH), the leading cause of chronic liver disease worldwide. This study describes the use of FTY720, a novel small molecule, for the amelioration of NASH in a mouse model. We demonstrate that 2-wk administration of FTY720 to mice with NASH led to a reduction in liver injury, inflammation, and fibrosis. These data provide a preclinical rationale for studying this drug in human NASH.

scholarly journals Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity

2011 ◽  
Vol 212 (3) ◽  
pp. 343-351 ◽  
Author(s):  
Dario A Gutierrez ◽  
Alyssa H Hasty
Keyword(s):  
Adipose Tissue ◽  
Leptin Receptor ◽  
Double Knockout ◽  
Diet Induced Obesity ◽  
Insulin Tolerance ◽  
Long Form ◽  
Inflammatory State ◽  
Macrophage Chemotaxis ◽  
Macrophage Accumulation

The adipokine leptin is primarily produced by white adipose tissue (AT) and is a potent monocyte/macrophage chemoattractant in vitro. The long form of the leptin receptor (LepR) is required for monocyte/macrophage chemotaxis towards leptin. In this study, we examined the effects of haematopoietic LepR as well as LepR with C–C chemokine receptor 2 (CCR2) deficiency (double knockout (DKO)) on macrophage recruitment to AT after two different periods of high fat diet (HFD) feeding. Briefly, 8-week-old C57BL/6 mice were transplanted with bone marrow (BM) from Lepr+/+, Lepr−/− or DKO donors (groups named BM-Lepr+/+, BM-Lepr−/− and BM-DKO respectively), and were placed on an HFD for 6 or 12 weeks. At the end of the study, macrophage infiltration and the inflammatory state of AT were evaluated by real-time RT-PCR, histology and flow cytometry. In addition, glucose and insulin tolerance were assessed at both time points. Our results showed no differences in macrophage accumulation or AT inflammatory state between the BM-Lepr+/+ and BM-Lepr−/− mice after 6 or 12 weeks of HFD feeding; any effects observed in the BM-DKO were attributed to the haematopoietic deficiency of CCR2. In addition, no changes in glucose or insulin tolerance were observed between groups after either period of HFD feeding. Our findings suggest that although leptin is a potent chemoattractant in vitro, haematopoietic LepR deficiency does not affect macrophage accumulation in AT in early to moderate stages of diet-induced obesity.

scholarly journals Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury

2018 ◽  
Vol 314 (5) ◽  
pp. G597-G609 ◽  
Author(s):  
Melina M. Malinen ◽  
Izna Ali ◽  
Jacqueline Bezençon ◽  
James J. Beaudoin ◽  
Kim L. R. Brouwer
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Tissue ◽  
Primary Biliary Cholangitis ◽  
Drug Induced ◽  
Organic Solute Transporter ◽  
Organic Solute ◽  
Solute Transporter

The heteromeric steroid transporter organic solute transporter α/β (OSTα/β, SLC51A/B) was discovered over a decade ago, but its physiological significance in the liver remains uncertain. A major challenge has been the lack of suitable models expressing OSTα/β. Based on observations first reported here that hepatic OSTα/β is upregulated in nonalcoholic steatohepatitis, the aim of this research was to develop an in vitro model to evaluate OSTα/β function and interaction with drugs and bile acids. OSTα/β expression in human liver tissue was analyzed by quantitative RT-PCR, Western blotting, and immunofluorescence. Radiolabeled compounds were used to determine OSTα/β-mediated transport in the established in vitro model. The effect of bile acids and drugs, including those associated with cholestatic drug-induced liver injury, on OSTα/β-mediated transport was evaluated. Expression of OSTα/β was elevated in the liver of patients with nonalcoholic steatohepatitis and primary biliary cholangitis, whereas hepatocyte expression of OSTα/β was low in control liver tissue. Studies in the novel cell-based system showed rapid and linear OSTα/β-mediated transport for all tested compounds: dehydroepiandrosterone sulfate, digoxin, estrone sulfate, and taurocholate. The interaction study with 26 compounds revealed novel OSTα/β inhibitors: a biomarker for cholestasis, glycochenodeoxycholic acid; the major metabolite of troglitazone, troglitazone sulfate; and a macrocyclic antibiotic, fidaxomicin. Additionally, some drugs (e.g., digoxin) consistently stimulated taurocholate uptake in OSTα/β-overexpressing cells. Our findings demonstrate that OSTα/β is an important transporter in liver disease and imply a role for this transporter in bile acid-bile acid and drug-bile acid interactions, as well as cholestatic drug-induced liver injury. NEW & NOTEWORTHY The organic solute transporter OSTα/β is highly expressed in hepatocytes of liver tissue obtained from patients with nonalcoholic steatohepatitis and primary biliary cholangitis. OSTα/β substrates exhibit rapid, linear, and concentration-driven transport in an OSTα/β-overexpressing cell line. Drugs associated with hepatotoxicity modulate OSTα/β-mediated taurocholate transport. These data suggest that hepatic OSTα/β plays an essential role in patients with cholestasis and may have important clinical implications for bile acid and drug disposition.

scholarly journals MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

Gut ◽  
2017 ◽  
Vol 67 (2) ◽  
pp. 333-347 ◽  
Author(s):  
Evangelos Triantafyllou ◽  
Oltin T Pop ◽  
Lucia A Possamai ◽  
Annika Wilhelm ◽  
Evaggelia Liaskou ◽  
...  
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Acute Liver Injury ◽  
Myeloid Cells ◽  
Confocal Imaging ◽  
Macrophage Phenotype ◽  
Hla Dr ◽  
The Impact

ObjectiveAcute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.DesignFlow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.ResultsWe demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance.ConclusionsWe identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.

Astrocyte-Plexus Is Formed in the Neovascularization Induced by CD11b+ Cells From An Ischemic Hind-Limb Mouse Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3043-3043
Author(s):  
Jeong A. Kim ◽  
Oak Kee Hong ◽  
Jong Wook Hong ◽  
Hal E. Broxmeyer
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Vessel Wall ◽  
Cultured Cells ◽  
Conflicts Of Interest ◽  
Smooth Muscle Actin ◽  
Myeloid Cells ◽  
Artery Dissection

Abstract Abstract 3043 Poster Board II-1019 Angiogenic sprouting needs to navigate through tissues to establish a vascular branching pattern. Such angiogenic guidance is mainly inferred by nonrandom angiogenic sprouting in the developing central nervous system (CNS). In mammalian retina, a vascular plexus initially forms, superimposed on a preexisting astrocyte-plexus, and retinal astrocytes begin to express vascular endothelial growth factor (VEGF-A), which stimulates endothelial cells to sprout radially from the optic nerve head into the retinal periphery. However, there has been little investigation of the role of astrocyte-plexus in new vessel formation of other ischemic sites besides retina. We recently found that infiltrated CD11b+ cells in ischemic muscles differentiate into endothelial-like cells in vitro, and that direct-injection of muscle-derived CD11b+ cells enhances recovery of blood perfusion in ischemic hind-limbs of C57BL/6 mice. To study if the astrocytes are related to the neovascularization process in ischemic limbs, infiltrated CD11b+ myeloid-cells in ischemic muscles were isolated 4 days after femoral artery dissection, and then seeded at 0.5×105/cm2 onto Matrigel and cultured in EGM-2 medium. Under these conditions, we tested the following hypotheses: (1) cultured cells initially form an astrocyte-network in vitro, and (2) astrocytes are involved in the formation of vascular structure. Seven days after the cells were embedded in Matrigel, spindle shaped cells grew, spread-out radially from cell clusters to the periphery, and established a mesh-like network expressing glial fibrillary acidic protein (GFAP), a marker for astrocyte. These spindle shaped cells were also positive for pericyte markers: desmin, NG-2, and platelet-derived growth factor receptor (PDGFR)-β. Interestingly, proliferating endothelial cells were closely associated with astrocytes by extension of endothelial cell filopodia on astrocytes. This observation is consistent that astrocyte scaffold guides extension of endothelial cell filopodia. Two weeks after cells were embedded in Matrigel, CD11b+ cells expanded and were layered in the same way to form vessel wall-like structures consisting of hundreds of cells. Spindle shaped GFAP-positive cells gradually expressed smooth muscle-actin at the bottom of the culture plate, migrated to the vessel wall-like structures, and covered the surface of the walls like pericytes. Taken together with the novel finding of astrocyte-like cell differentiation from CD11b+ cells from Matrigel culture, mobilization of CD11b+ myeloid-cells to regions of muscle ischemia would appear to play an important role in neovascularization after ischemic injury. Disclosures No relevant conflicts of interest to declare.

scholarly journals Procyanidin B2 Reduces Vascular Calcification through Inactivation of ERK1/2-RUNX2 Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 916
Author(s):  
Yingquan Liang ◽  
Guilan Chen ◽  
Feng Zhang ◽  
Xiaoxiao Yang ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Calcification ◽  
Aortic Root ◽  
Smooth Muscle Actin ◽  
Bone Morphogenetic Protein 2 ◽  
Plaque Burden ◽  
Runx2 Expression ◽  
Plaque Instability ◽  
Related Transcription Factor

Vascular calcification is strongly associated with atherosclerotic plaque burden and plaque instability. The activation of extracellular signal-regulated kinase 1/2 (ERK1/2) increases runt related transcription factor 2 (RUNX2) expression to promote vascular calcification. Procyanidin B2 (PB2), a potent antioxidant, can inhibit ERK1/2 activation in human aortic smooth muscle cells (HASMCs). However, the effects and involved mechanisms of PB2 on atherosclerotic calcification remain unknown. In current study, we fed apoE-deficient (apoE−/−) mice a high-fat diet (HFD) while treating the animals with PB2 for 18 weeks. At the end of the study, we collected blood and aorta samples to determine atherosclerosis and vascular calcification. We found PB2 treatment decreased lesions in en face aorta, thoracic, and abdominal aortas by 21.4, 24.6, and 33.5%, respectively, and reduced sinus lesions in the aortic root by 17.1%. PB2 also increased α-smooth muscle actin expression and collagen content in lesion areas. In the aortic root, PB2 reduced atherosclerotic calcification areas by 75.8%. In vitro, PB2 inhibited inorganic phosphate-induced osteogenesis in HASMCs and aortic rings. Mechanistically, the expression of bone morphogenetic protein 2 and RUNX2 were markedly downregulated by PB2 treatment. Additionally, PB2 inhibited ERK1/2 phosphorylation in the aortic root plaques of apoE−/− mice and calcified HASMCs. Reciprocally, the activation of ERK1/2 phosphorylation by C2-MEK1-mut or epidermal growth factor can partially restore the PB2-inhibited RUNX2 expression or HASMC calcification. In conclusion, our study demonstrates that PB2 inhibits vascular calcification through the inactivation of the ERK1/2-RUNX2 pathway. Our study also suggests that PB2 can be a potential option for vascular calcification treatment.

scholarly journals Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis

2021 ◽  
Vol 22 (12) ◽  
pp. 6468
Author(s):  
Hana Lastuvkova ◽  
Fatemeh Alaei Faradonbeh ◽  
Jolana Schreiberova ◽  
Milos Hroch ◽  
Jaroslav Mokry ◽  
...  
Keyword(s):  
Bile Acid ◽  
Nonalcoholic Steatohepatitis ◽  
Plasma Concentrations ◽  
Liver Steatosis ◽  
Saturated Fat ◽  
Cardiovascular Complications ◽  
Biliary Secretion ◽  
Fecal Excretion ◽  
High Cholesterol Diet ◽  
Chow Diet

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

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