Hepatic Expression Of MCP-1 Research Articles

Hepatic iron storage is related to body adiposity and hepatic inflammation

BackgroundObesity has been reported to be associated with iron deficiency. However, few studies have investigated iron status in low adiposity. To investigate whether body adiposity was associated with altered hepatic iron status, we compared liver iron levels and markers involved in inflammation and iron absorption in obese, control, and mildly calorie restricted mice.MethodsSeven week old C57BL/6 mice were fed control (10% kcal fat, Control) or high fat (60% kcal fat, HFD) diets, or reduced amount of control diet to achieve 15% calorie restriction (CR) for 16 weeks. Hepatic non-heme iron content and ferritin protein level, and hematocrit and hemoglobin levels were determined to assess iron status. Hepatic expression of Mcp-1 and Tnf-α were measured as hepatic inflammatory markers. Hepatic hepcidin (Hamp) and Bmp6, and duodenal Dmt1, Dcyt1b, hephaestin (Heph) and ferroportin mRNA levels were measured as factors involved in regulation of iron absorption.ResultsHepatic non-heme iron and ferritin protein levels were significantly higher in the CR group compared with the Control group, and significantly lower in the HFD group. These two iron status markers showed significantly negative correlations with the amount of white adipose tissue (r = -0.689 for hepatic non-heme iron and r = -0.740 for ferritin). Hepatic Mcp-1 and Tnf-α mRNA levels were significantly lower in the CR compared with the HFD (74 and 47% lower) and showed significantly negative correlations with hepatic non-heme iron levels (Mcp-1: r = -0.557, P < 0.05; Tnf-α: r = -0.464, P < 0.05). Hepatic Hamp mRNA levels were lower in the HFD and higher in the CR groups compared with the Control group, which could be a response to maintain iron homeostasis. Duodenal Dcyt1b mRNA levels were higher in the CR group compared with the HFD group and duodenal Heph mRNA levels were higher in the CR group than the Control group.ConclusionWe showed that body adiposity was inversely correlated with liver iron status. Low inflammation levels in hepatic milieu and enhanced expression of duodenal oxidoreductases induced by calorie restriction could have contributed to higher iron status.

Maternal Obesity Programs Offspring's Predisposition to Non‐Alcoholic Fatty Liver Disease and Steatohepatitis

Maternal obesity and unbalanced diets during pregnancy are key factors in determining the risk of obesity in later life. Non‐alcoholic fatty liver disease (NAFLD) is an important co‐morbidity associated with obesity and metabolic dysfunction and a precursor to steatohepatitis (NASH). However, the contributions of gestational and early neonatal influences on development of NAFLD and subsequent NASH remain poorly appreciated. Using a model of controlled overfeeding, we have previously demonstrated that in utero exposure to maternal obesity during pregnancy alone leads to metabolic programming of liver, characterized by metabolic inflexibility. Here we examine the hypothesis that maternal over‐nutrition via in utero exposure to high fat diet induces inflammation and leads to exacerbated hepatic responses to post‐natal high fat diets (HFD) and methionine choline deficient (MCD) diets in the offspring. Female C57BL6/J mice were fed diets with either low (10%) or HFD (45% of calories) for 12 wk starting at 5 wk of age. Dams were mated with males on control diets and provided access to respective diets during pregnancy and lactation. At weaning, offspring were weaned onto control and HFD, creating four groups (CC, CH, HC, HH, denoting maternal and offspring diets, respectively). Offspring of obese mice dams (HH n=7) gained greater body weight and fat mass when fed HFD, compared to offspring from lean dam (CH n=11). Serum cholesterol concentrations were higher in HH compared to CH groups. Global hepatic gene expression and microbial ecology of the cecal contents in offspring was studied using RNAseq and 16S rRNA sequencing. Hepatic expression of Mcp1 and MMP13 gene expression was higher in HH compared to CC and CH indicative of inflammation in response to maternal high fat diet. Analysis of microbial OTUs with Multivariate association with linear models (MaAsLin) and LeFSE showed higher abundance of Firmicutes and lower abundance of Bacteriodetes in HH as well as CH compared to CC. To assess the susceptibility of offspring to NASH, 8 wk old offspring in a separate study were challenged with either control or MCD diets for 4 wk. MCD diet led to significant weight reduction irrespective of maternal nutritional background. Serum ALT was modestly higher in offspring from obese dams (HFD/MCD) relative to lean dam cohorts. Offspring of HF dams showed similar inflammatory changes but greater pro‐fibrogenic alterations following MCD diet. MaAsLin and LeFSE analysis revealed association between serum ALT levels, Coprococcus and MCD treatment. Genome‐scale DNA methylation of livers showed alterations in CpGs associated with cell adhesion, cell communication and development with MCD challenge, including genes in the TGF‐β signaling pathways. Overall, our findings indicate that maternal obesity during gestation and lactation detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.Support or Funding InformationSupport USDA CRIS 6206‐51000‐010‐05S

Matrine Inhibits Infiltration of the InflammatoryGr1hiMonocyte Subset in Injured Mouse Liver through Inhibition of Monocyte Chemoattractant Protein-1

Matrine (Mat) is a major alkaloid extracted from Sophora flavescens Ait, an herb which is used in the traditional Chinese medicine for treatment of inflammation, cancer, and other diseases. The present study examined the impact of Mat on the CCl4-induced hepatic infiltration of Gr1hi monocytes to explore the possible mechanisms underlying its anti-inflammatory and antifibrotic effects. The results indicated that Mat protected mice from acute liver injury induced by single intraperitoneal injection of CCl4 and attenuated liver fibrosis induced by repeated CCl4 injection. Meanwhile, the infiltrations of Gr1hi monocytes in both acute and chronic injured livers were all inhibited, and the enhanced hepatic expression of MCP-1 was suppressed. Cellular experiments demonstrated that Mat directly inhibited MCP-1 production in both nonparenchymal cells and hepatic stellate cells derived from CCl4-injured livers. Transwell chemotaxis assays showed that Mat significantly inhibited the chemotactic activity of MCP-1. These results suggest that the anti-inflammatory and antifibrotic effects of Mat could be contributed, at least in part, to its prevention of Gr1hi monocyte infiltration into the injured livers and inhibition of MCP-1 production and activity. These findings extend our understanding of the mechanisms underlying the anti-inflammatory and antifibrotic effects of Mat.

Therapeutic administration of a direct thrombin inhibitor reduces hepatic inflammation in a mouse model of hypercholesterolemia

Deficiency in the thrombin receptor protease activated receptor‐1 reduces hepatic inflammation and steatosis in mice fed a Western diet. We tested the hypothesis that thrombin inhibition could reverse hepatic steatosis and inflammation in mice with established diet‐induced fatty liver disease. LDLr−/− mice were fed a control diet or a Western diet for 19 weeks. Mice were given either the direct thrombin inhibitor argatroban or its vehicle for the final 4 weeks. Argatroban administration reduced macrophage and neutrophil accumulation in livers of mice fed a Western diet. Similarly, in mice fed a Western diet, argatroban administration reduced hepatic expression of MCP‐1, ICAM‐1, and MIP‐2, three mediators that can contribute to hepatic macrophage and neutrophil accumulation. In addition, argatroban tended to reduce hepatic steatosis, as indicated by hepatic triglyceride levels. Argatroban completely reversed the increase in serum triglycerides and reduced total serum cholesterol levels in mice fed a Western diet. Argatroban also reduced the expression of profibrogenic genes encoding Type 1 collagen and TIMP‐1 in livers of mice fed a Western diet. Overall, this study indicates that therapeutic intervention with a thrombin inhibitor rapidly reduces several features of diet‐induced NAFLD in mice. This work was supported by AHA Grants 0835121G and 11POST7430043 and by NIH Grants R01 ES017537 and DK073566.

Elevated systemic monocyte chemoattractrant protein-1 levels in hepatic steatosis without significant hepatic inflammation

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and diabetes mellitus. It encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter develops upon pro-inflammatory cell infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine monocyte chemoattractant proteins (MCP-1) plays an important role in the progression of hepatic inflammation and fibrosis and increased hepatic expression has been described in NASH. The aim of the present study was to investigate MCP-1 expression simple hepatic steatosis. Methods and Results: A high-fat diet (HFD; 30% lard) was fed to male BALB/c mice for 20 weeks leading to a significant increase of body weight and fasting glucose serum levels. Further, HFD-fed mice revealed marked hepatic lipid accumulation in the absence of significant hepatic inflammation as evidenced by unaltered serum transaminases and hepatic TNF expression. However, HFD-fed mice had elevated hepatic MCP-1 expression and significantly higher MCP-1 serum levels compared to control mice fed standard chow. Moreover, we detected markedly increased MCP-1 expression in visceral adipose tissue of HFD-fed mice. In addition, we assessed MCP-1 in a cohort of patients with bland steatosis and observed significantly increased serum levels, which correlated with the body-mass index and serum glucose levels. Conclusion: Our data indicate both the liver and adipose tissue as cellular sources of elevated circulating MCP-1 levels already in the early phase of hepatic steatosis. Since MCP-1 derived from visceral adipose tissue reaches the liver via portal circulation at high concentrations it may significantly contribute to the progression of simple steatosis to NASH.

Expression of MCP-1 and TGF-β1 and its significance in early stage of obstructive jaundice in rats

Objective To investigate the expression of MCP-1 and TGF-β1 in early stage of ob-structive jaundice and explore its relation to liver correlated injury indexes in rats. Methods Fifty male Wistar rats were randomized into the control group, sham-operated group and biliary obstruction group. On day 10, serum ALT and BIL-T levels were determined in inferior caval blood and hepatic MDA was estimated in liver homogenates. Meanwhile, serum TGF-β1 level was measured by ELISA and the MCP-1 infiltration determined with immunohistochemistry. Results Serum ALT and BIL-T values were elevated. Meanwhile, the liver MDA content was increased. The positive expression of MCP-1 was augmented and serum TGF-β1 was over-expressed in the early stage after obstructive jaun-dice in rats. The hepatic MCP-1 expression had a positive correlation with the elevated ALT, BIL-T and MDA levels. However, the serum TGF-β1 content only had a positive correlation with ALT and BIL-T. Conclution Hepatic MCP-1 and serum TGF-β1 expression in the early stage after biliary tract obstruction is related to liver injury and extrahepatic cholestasis. Meanwhile, the hepatic MCP-1 ex-pression is correlated with hepatic oxidation stress. They have an important significance in liver injury in rats during the early period of obstructive jaundice. Key words: Cholestasis; MCP-1; TGF-β1

Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory changes have been poorly characterized. TLR4, a known receptor for LPS, is also a receptor for a variety of endogenous ligands and has been implicated in atheroma formation. Here, we specifically examined the early inflammatory response of the liver to the atherogenic (ATH) diet and the possible contribution of TLR4. Animals fed the high-cholesterol/cholate diet for 3 weeks developed a significant, predominantly mononuclear leukocyte infiltration in the liver, hepatic steatosis, elevated hepatic expression of MCP-1, RANTES, and MIP-2, and increased serum levels of liver enzymes. In TLR4-deleted animals, there was a 30% attenuation in the serum alanine transaminase levels and a 50% reduction in the leukocyte infiltration with a fourfold reduction in chemokine expression. In contrast, hepatic steatosis did not differ from wild-type controls. TLR2 deletion had no effect on diet-induced hepatitis but increased the amount of steatosis. We conclude that the early inflammatory liver injury but not hepatic lipid loading induced by the ATH diet in mice is mediated in part by TLR4.

Dietary cholesterol and differential monocyte chemoattractant protein-1 gene expression in aorta and liver of apo E-deficient mice

In humans, hypercholesterolemia, steatohepatitis, and risk for arteriosclerosis are associated. Apolipoprotein E-deficient mice, a widely used animal model, show both arteriosclerosis and steatohepatitis in response to high-fat and cholesterol diets. We have found a relationship between these conditions and a higher mRNA aortic and hepatic monocyte chemoattractant protein-1 ( mcp-1) gene expression. Both tissues respond in a similar way when dietary cholesterol is provided for a few weeks but differently if the conditions persist for a protracted period of time. After 8 months of treatment, the mcp-1 gene expression in the aorta continues increasing but in the liver decreases. This coincides with a significant increase in hepatic ppar- δ anti-inflammatory gene expression. Apparently, the arterial wall cannot prevent the deleterious effects of higher mcp-1 expression by increasing ppar- δ gene expression and the lesion progress. However, in the liver, the activation of anti-inflammatory genes may reduce the hepatic mcp-1 expression which significantly decreases the inflammatory response. This differential inflammatory gene expression in aorta and liver may support the idea that anti-inflammatory transcription factors are involved in the response to diet and inflammation. Therefore, the use of cholesterol-enriched diets should be carefully considered in the apolipoprotein E-deficient mice because they may trigger different stimuli and seriously hinder the interpretation of possible findings.