interleukin-8 and Fatty-Liver

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF α and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

Topics: Apolipoprotein B-100; Atherosclerosis; Endocytosis; Erectile Dysfunction; Fatty Liver; Female; Fibrinolysis; Humans; Hydrogen Peroxide; Inflammation; Interleukin-8; Lipoproteins, LDL; Macrophages; Male; Oxygen; Peroxidase; Pulmonary Disease, Chronic Obstructive; Renal Dialysis; Sleep Wake Disorders; Tumor Necrosis Factor-alpha

Oxidative stress and inflammation are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bayberries contain high levels of polyphenols that possess antioxidative and anti-inflammatory properties in vitro. The purpose of this study was to investigate whether the consumption of bayberry juice beneficially alters the levels of oxidative, inflammatory, and apoptotic biomarkers in young individuals with features of NAFLD.. In this randomized, placebo-controlled, double-blind, crossover study, 44 participants (ages 18-25 y) were given 250 mL of either bayberry juice or placebo twice daily for 4 wk. Several anthropometric characteristics were measured, and fasting blood samples were drawn before and after each intervention period. The levels of plasma glucose, insulin, lipids, and some NAFLD-related biomarkers were determined.. No significant effects on the anthropometric parameters and the homeostasis model assessment for insulin resistance were observed. Compared with placebo, the consumption of bayberry juice significantly decreased the plasma levels of protein carbonyl groups (P = 0.038), tumor necrosis factor-α (P < 0.001), and interleukin-8 (P = 0.022). The apoptosis markers analysis revealed significant differences between the treatment and the placebo in the levels of tissue polypeptide-specific antigen (P < 0.001) and cytokeratin-18 fragment M30 (P < 0.001).. The consumption of bayberry juice for a period of 4 wk can protect against NAFLD in young adults by improving the plasma antioxidant status and inhibiting the inflammatory and apoptotic responses that are involved in this disease.

Topics: Adolescent; Adult; Anthropometry; Antioxidants; Apoptosis; Beverages; Biomarkers; Blood Glucose; Cross-Over Studies; Double-Blind Method; Fatty Liver; Female; Fruit; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-8; Male; Myrica; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Plant Extracts; Polyphenols; Tumor Necrosis Factor-alpha; Young Adult

We performed this study to examine the metabolic differences arising from higher liver fat accumulation in obese Hispanic adolescents, with a particular focus on circulating levels of adipocytokines and insulin resistance.. Forty-one obese Hispanic adolescents (15.3 ± 1.0 years, body mass index percentile: 97.0 ± 3.9) were assessed for: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and hepatic fat fraction (HFF) by magnetic resonance imaging; fasting measures of serum glucose, insulin and adipocytokines; homeostasis model assessment of insulin resistance (HOMA-IR); and insulin sensitivity (SI) and the acute insulin response to glucose (AIR) by intravenous glucose tolerance test. Subjects with normal levels of HFF (below 5%; n = 25) were compared to those with HFF > 5% (n = 16).. The two groups differing in HFF were similar for total body fat, VAT and SAT. The group with HFF > 5% had significantly (P < 0.05) higher interleukin-8 (IL-8) (6.1 ± 1.6 vs. 3.2 ± 0.4 pg mL(-1) ), NGF (30.2 ± 9.9 vs. 13.9 ± 1.6 pg mL(-1) ), HOMA-IR (8.8 ± 1.1 vs. 5.5 ± 0.5), AIR (1869 ± 206 vs. 1092 ± 165) and a tendency for lower SI (1.2 ± 0.4 vs. 2.1 ± 0.3; P = 0.06), with no significant differences in any of other factors measured.. These data suggest that elevated liver fat is most closely associated with elevated serum IL-8 and NGF levels as well as increased AIR and HOMA-IR. These elevated factors may play significant roles in the metabolic abnormalities associated with elevated liver fat in obese Hispanics.

Topics: Adipokines; Adolescent; Blood Glucose; Body Composition; California; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fatty Liver; Female; Glucose Tolerance Test; Hispanic or Latino; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-8; Male; Nerve Growth Factor; Non-alcoholic Fatty Liver Disease; Obesity; Patient Education as Topic

Non-alcoholic steatohepatitis (NASH) is the most common cause of cryptogenic cirrhosis, is becoming more prevalent in China. However, there is as yet no clearly established therapy for reversing fatty liver. Our aim is to explore the effect of traditional Chinese herbs QuYuHuaTanTongLuo Decoction (QYHTTLD) on non-alcoholic steatohepatitis. Sixty-nine non-alcoholic steatohepatitis patients were randomly divided into two groups. One group of 35 patients were treated by QYHTTLD, another group of 34 patients were treated by Ursodeoxycholic acid (UDCA). The TNF-alpha, IL-8, MDA level, SOD activity and liver function, as well as B ultrasonic image were detected before and after being treated. The results showed: after 6 months treatment, MBI of the treatment group was obviously decreased (p<0.05). The levels of TC, TG and LDL-C were significantly decreased whereas the level of HDL-C increased (p<0.01, p<0.05, p<0.05, and p<0.05, respectively) in the treatment group, the levels of TC, TG, LDL-C and HDL-C had no significant difference in the control group (p>0.05). The levels of TNF-alpha, IL-8 and MDA were significantly decreased whereas SOD activity was significantly increased (p<0.01, p<0.05, p<0.01, and p<0.01, respectively) in the treatment group, the level of MDA was significantly decreased in the control group (p<0.05). B ultrasonic images were ameliorated in different degree (p<0.01 and p<0.01, respectively). Both QYHTTLD and UDCA had the effect in improving the scores of symptoms and signs of patients, however, the difference value of the scores in treatment group were significantly higher than that in control group after being treated for 6 months (p<0.05).. QYHTTLD is effective for treating non-alcoholic steatohepatitis, and its effect seems to relate with the ways of QYHTTL down-regulating inflammation cytokine IL-8 level and relieving lipid peroxidation of liver.

Topics: Adolescent; Adult; Drugs, Chinese Herbal; Fatty Liver; Female; Humans; Interleukin-8; Lipids; Male; Middle Aged; Superoxide Dismutase; Tumor Necrosis Factors

Topics: Erythrocytes; Fatty Liver; Female; Hepatitis; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Receptors, Complement 3b; Thymosin; Tumor Necrosis Factor-alpha

There are few data evaluating plasma and/or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis (NASH). A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH. Biochemical assessment of liver function, lipid profiles, and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks. Plasma hyaluronic acid (HA) concentrations decreased in parallel with weight loss. Plasma tumor necrosis factor (TNF) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis (AH). Although plasma TNF, interleukin 8 (IL-8), and IL-6 concentrations were all significantly elevated compared with control values, only plasma IL-6 levels significantly decreased with therapy. Peripheral blood monocyte TNF, IL-8, and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease. Independent effects of vitamin E were not observed in this small sample. In conclusion, patients with NASH have dysregulated cytokine metabolism similar to, but less pronounced than abnormalities documented in AH. Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study. Lifestyle modifications (low-fat diet and exercise) were associated with improvement in liver enzymes, cholesterol, and plasma HA levels in patients with NASH, whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit.

Topics: Adult; Antioxidants; Cytokines; Exercise; Fatty Liver; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Pilot Projects; Risk Reduction Behavior; Tumor Necrosis Factor-alpha; Vitamin E; Weight Loss

Neutrophil infiltration is a hallmark of nonalcoholic steatohepatitis (NASH), but how this occurs during the progression from steatosis to NASH remains obscure. Human NASH features hepatic neutrophil infiltration and up-regulation of major neutrophil-recruiting chemokines (e.g., chemokine [C-X-C motif] ligand 1 [CXCL1] and interleukin [IL]-8). However, mice fed a high-fat diet (HFD) only develop fatty liver without significant neutrophil infiltration or elevation of chemokines. The aim of this study was to determine why mice are resistant to NASH development and the involvement of p38 mitogen-activated protein kinase (p38) activated by neutrophil-derived oxidative stress in the pathogenesis of NASH.. Inflamed human hepatocytes attracted neutrophils more effectively than inflamed mouse hepatocytes because of the greater induction of CXCL1 and IL-8 in human hepatocytes. Hepatic overexpression of Cxcl1 and/or IL-8 promoted steatosis-to-NASH progression in HFD-fed mice by inducing liver inflammation, injury, and p38 activation. Pharmacological inhibition of p38α/β or hepatocyte-specific deletion of p38a (a predominant form in the liver) attenuated liver injury and fibrosis in the HFD. Genetic ablation of hepatic p38a increases simple steatosis but ameliorates oxidative stress-driven NASH, indicating that p38α plays distinct roles depending on the disease stages, which may set the stage for investigating p38α as a therapeutic target for the treatment of NASH.

Topics: Animals; Chemokine CXCL1; Diet, High-Fat; Disease Models, Animal; Drug Discovery; Fatty Liver; Gene Deletion; Hepatocytes; Humans; Interleukin-8; Mice; Mitogen-Activated Protein Kinase 14; Neutrophil Infiltration; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Severity of Illness Index

Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver.. Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting.. In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic pre-adipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca. These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.

Topics: alpha-2-HS-Glycoprotein; Animals; Blotting, Western; Cells, Cultured; Chemokine CCL2; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Immunohistochemistry; Inflammation; Insulin; Insulin Secretion; Insulin-Secreting Cells; Interleukin-6; Interleukin-8; Mice; Palmitates; Pancreas; Toll-Like Receptor 4

Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis.Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal β-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression.

Topics: Acyl-CoA Oxidase; Animals; Antimetabolites, Antineoplastic; Blotting, Western; Cells, Cultured; Disease Models, Animal; Enzyme Activation; Fatty Liver; Female; Fluorouracil; Gene Expression; Heme Oxygenase-1; Hep G2 Cells; Hepatocytes; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Liver; Mice, Inbred C57BL; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides

To investigate the effects of JAZF1 overexpression on the pro-inflammatory cytokines in hepatic steatosis.. The model of hepatic steatosis was established by incubating hepatocytes with palmitic acid (PA) at 0, 0.125, 0.25, 0.5 and 1 mM dose and for 0, 6, 12, 24 and 48 hours, after which recombinant adenovirus expressing JAZF1 (Ad-JAZF1) was introduced to up-regulate expression. Triglyceride level was measured by GOD. Cell viability was detected by CCK-8. The mRNA and protein expression of TNF-alpha, MCP-1, IL-8 and JAZF1 was examined by RT-PCR, ELISA, and western blotting.. The PA-treated hepatocytes showed dose-dependent significant increases in TNF-alpha, MCP-1 and IL-8 mRNA expression for doses up to 0.25 mM; there were no significant increases for the highest doses of 0.5 and 1 mM. The 0.25 mM PA-treated hepatocytes showed time-dependent significant increases in TNF-alpha, MCP-1 and IL-8 mRNA expressions (FTNF-alpha = 26.51, FMCP-1 = 57.20, FIL-8 = 353.85, P less than 0.01), with the maximum level reached at 12 h and followed by a gradual decrease with longer treatment times. JAZF1 mRNA and protein expression was markedly increased in hepatocytes infected with Ad-JAZF1 (P less than 0.01). However, the AP-treated hepatocytes with JAZF1 overexpression showed down-regulation of TNF-alpha, MCP-1 and IL-8 mRNA expression (decreased by 89.69%, 77.68%, and 83.21%, respectively) and secretion (37%, 37% and 41%, respectively, P less than 0.01).. Stimulation of hepatocytes by the PA fatty acid in vitro promotes mRNA expression of TNF-alpha, MCP-1 and IL-8, but overexpression of JAZF1 inhibits the PA-induced expression and secretion of these factors.

Topics: Cell Survival; Chemokine CCL2; Co-Repressor Proteins; Cytokines; DNA-Binding Proteins; Fatty Liver; Hepatocytes; Humans; Interleukin-8; Neoplasm Proteins; Palmitic Acid; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation

The aim of this study was to assess whether physical performance correlates with metabolic and inflammatory measures in research subjects with chronic liver disease.. This is a prospective, descriptive cohort study correlating performance on a 6-min walk test with cardiorespiratory variables, metabolic measures (glucose [GLU], C-peptide insulin, and lipids), liver enzymes (aspartate aminotransferase and alanine aminotransferase), and the proinflammatory cytokine interleukin-8 (IL-8).. This study enrolled 51 subjects (18 women) with chronic liver disease: 41% (n = 21) with nonalcoholic fatty liver disease and 59% (n = 30) with hepatitis C virus. Age, resting heart rate, and fasting GLU correlated significantly with distance walked (P's < 0.05). First quartile "poor performers" (n = 14) and fourth quartile "high performers" (n = 14) showed differences in age, sex, fasting GLU, and IL-8 level (P's < 0.05). Combining the number of abnormal serum values (IL-8, C-peptide insulin, GLU, aspartate aminotransferase, alanine aminotransferase, high-density lipoprotein, triglyceride, and total cholesterol) did not correlate with distance walked (P > 0.90). However, in multiple regression analysis, a model that included sex, age, resting heart rate, IL-8 level, and fasting GLU level explained approximately 39% of the variance in the distance walked during the test.. Older age, female sex, abnormal levels of the proinflammatory cytokine IL-8, abnormalities of GLU metabolism, and high resting heart rate are associated with poor physical performance in subjects with chronic liver disease. Poor physical performance is associated with physiologic, metabolic, and inflammatory abnormalities in subjects with nonalcoholic fatty liver disease and hepatitis C virus.

Topics: Age Factors; Blood Glucose; Exercise Test; Fatty Liver; Female; Heart Rate; Hepatitis C, Chronic; Humans; Interleukin-8; Male; Middle Aged; Physical Fitness; Prospective Studies; Regression Analysis; Rest; Sex Factors; Walking

To explore lipocalin-2 (LCN-2) expression and its possible role and mechanism(s) of production in rat models of diet-inducible fatty liver.. Fatty liver was triggered in male Sprague-Dawley rats fed either with liquid Lieber-DeCarli (LDC) or LDC + 70% cal fructose (L-HFr) diet for 4 or 8 wk. Chow-nourished animals served as controls. Hepatic expression of LCN-2 and other metabolic and inflammatory mediators was assessed by quantitative reverse transcription polymerase chain reaction and Western blotting. Serum LCN-2, fasting leptin, and lipid profile were evaluated via Enzyme-Linked Immunosorbent Assay, Radioimmunoassay, and colorimetric assays, respectively. The localization of LCN-2 in the liver was detected by using immunofluorescence staining. Furthermore, HE stain was used to evaluate hepatic fat degeneration and inflammation.. Both LDC-fed and L-HFr-fed rat histologically featured fatty liver. In the liver, mRNA transcriptions of Mcp-1, a2-m, Il-8 and Glut5 were increased in the L-HFr group at both time points (P < 0.001), while the transcription of Tlr4, Inos, and Tnf-α was significantly up-regulated at week 4. Interestingly, hepatic Lcn-2 expression was 90-fold at week 4 and 507-fold at week 8 higher in L-HFr-subjected rats vs control (P < 0.001). In contrast to HDL-cholesterol, systemic levels of LCN-2, fasting leptin and triglycerides were elevated in the L-HFr regimen (P < 0.001). Moreover, protein expression of hepatic LCN-2, CD14, phospho-MAPK, caspase-9, cytochrome c and 4-hydroxynonenal was increased in the L-HFr group. Conversely, the hepatic expression of PGC-1α (a mitochondrial-biogenic protein) was reduced in the L-HFr category at week 8. The localization of LCN-2 in the liver was predominantly restricted to MPO⁺ granulocytes.. Fructose diet up-regulates hepatic LCN-2 expression, which correlates with the increased indicators of oxidative stress and mitochondrial dysfunction. The LCN-2 may be involved in liver protection.

Topics: Animal Feed; Animals; Apoptosis; Chemokine CCL2; Colorimetry; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Fructose; Gene Expression Regulation; Glucose Transporter Type 5; Inflammation; Interleukin-8; Leptin; Lipid Peroxidation; Lipocalin-2; Lipocalins; Liver; Male; Oxidative Stress; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4

As an inhibitor of the nuclear receptor subfamily 2, group C, member 2 signaling pathway, juxtaposed with another zinc finger gene 1 (JAZF1) has been shown to be involved in gluconeogenesis, lipid metabolism, and insulin sensitivity. However, its role in hepatic lipogenesis and chronic low-grade inflammation leading to nonalcoholic fatty liver disease remains unknown. The aim of this study was to examine whether JAZF1 overexpression in vivo or in vitro can protect against palmitic acid (PA)-induced and high-fat diet (HFD)-induced systemic inflammatory responses, and the potential mechanism of this process. JAZF1 overexpression vector was transfected into PA-treated IAR-20 hepatocytes. The mRNA expression levels of proinflammatory cytokines were measured by real-time quantitative PCR, and stress-activated protein kinase activities were measured by immunoblotting. For in vivo studies, JAZF1 transgenic mice were fed an HFD for 12 weeks. Liver tissue was obtained for histological examination, real-time RT-PCR, and western blot analysis. PA significantly increased the expression levels of tumor necrosis factor-α, monocyte chemotactic protein-1 and interleukin-8 mRNA in IAR-20 hepatocytes in a dose-dependent and time-dependent manner. Treatment with JAZF1 or stress-activated protein kinase inhibitors inhibited PA-induced tumor necrosis factor-α, monocyte chemotactic protein-1 and interleukin-8 expression in these cells. In JAZF1-treated cells, the decreased expression of proinflammatory cytokines was accompanied by decreased p38 mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation and increased nuclear factor-κB inhibitor-α protein levels, similarly to the role of signaling inhibitors. In vivo, HFD-induced expression of proinflammatory cytokines was markedly attenuated in JAZF1-Tg mice as compared with controls. This attenuation was accompanied by decreased activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB. These data provide evidence for the important role of JAZF1 in preventing lipogenesis and systemic inflammation-related disease.

Topics: Animals; Chemokine CCL2; Co-Repressor Proteins; Cytokines; Diet, High-Fat; DNA-Binding Proteins; Fatty Liver; Interleukin-8; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Proteins; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Proteins; Signal Transduction; Tumor Necrosis Factor-alpha

Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD.

Topics: Adult; Chemokine CCL4; Chemokines; Cytokines; Fatty Liver; Female; Gastric Mucosa; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-8; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Receptors, CCR5; Receptors, Interleukin-8B; Stomach

Experimental and clinical studies suggest an association between small intestinal bacterial overgrowth (SIBO) and nonalcoholic steatohepatitis (NASH). Liver injury and fibrosis could be related to exposure to bacterial products of intestinal origin and, most notably, endotoxin, including lipopolysaccharide (LPS).. To compare the prevalence of SIBO and its relationships to LPS receptor levels and systemic cytokines in NASH patients and healthy control subjects.. Eighteen NASH patients (eight males) and 16 age-matched and gender-matched healthy volunteers were studied. SIBO was assessed by the lactulose breath hydrogen test (LHBT), plasma lipopolysaccharide binding protein (LBP) levels by ELISA, and expression (as a percentage) of TLR-2 and 4 on CD14-positive cells by flow cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) were measured in plasma.. SIBO was more common in NASH patients than control subjects (77.78% vs. 31.25%; P < 0.0001). LBP levels and TLR-2 expression were similar in both groups, TLR-4/MD-2 expression on CD14 positive cells was higher among NASH patients: expression, mean ± SEM, NASH vs. control: 20.95 ± 2.91% vs. 12.73 ± 2.29%, P < 0.05. Among the examined cytokines, only IL-8 levels were significantly higher in patients than control (P = 0.04) and correlated positively with TLR-4 expression (r = 0.5123, P = 0.036).. NASH patients have a higher prevalence of small intestinal bacterial overgrowth which is associated with enhanced expression of TLR-4 and release of IL-8. SIBO may have an important role in NASH through interactions with TLR-4 and induction of the pro-inflammatory cytokine, IL-8.

Topics: Acute-Phase Proteins; Adult; Breath Tests; Carrier Proteins; Fatty Liver; Female; Gene Expression Regulation; Humans; Interleukin-8; Intestine, Small; Lactulose; Male; Membrane Glycoproteins; Middle Aged; Toll-Like Receptor 4

Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohn's disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P < 0.001) and PSC (P < 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P < 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody-mediated gastrointestinal inflammatory diseases.

Topics: Adult; Aged; Antibodies, Antinuclear; Biomarkers; Cholangitis, Sclerosing; Disease Progression; Fatty Liver; Gene Expression Regulation; Hepatitis; Humans; Immune Tolerance; Inflammation Mediators; Inflammatory Bowel Diseases; Interleukin-6; Interleukin-8; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Resistin

Several adipocytokines have been implicated in the pathogenesis non-alcoholic fatty liver disease (NAFLD).. To assess adipocytokines in NAFLD patients and controls.. A total of 95 patients (26 non-alcoholic steatohepatitis (NASH), 19 simple steatosis (SS), 38 obese controls and 12 non-obese controls) were included. Fasting serum insulin, glucose, visfatin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and IL-6 were determined. Univariate and multivariate analyses were used to compare groups and determine associations.. Serum TNF-alpha and IL-8 were higher in NAFLD patients when compared with both obese and non-obese controls. Analysis involving all patients revealed a significant correlation between serum TNF-alpha and IL-8 (P < 6.319e-08), and between IL-6 and IL-8 (P < 5.271e-15). Homeostatic model assessment scores negatively correlated with adiponectin in NAFLD (P < 0.0032). Serum visfatin was higher in all three obese groups than in non-obese controls (P < 0.02, P < 0.002 and P < 0.008). Visfatin in NASH patients was lower than SS and obese controls. Although TNF-alpha was associated with NAFLD (P < 0.02), it was interdependent on visfatin. In comparison to SS, four factors were independently associated with NASH: age, alanine aminotransferase, IL-8 and adiponectin (P < 0.05). Multivariate analysis indicated that TNF-alpha was the only independent predictor of fibrosis in NASH (P < 0.0004).. These findings support a complex interaction between adipocytokines and the pathogenesis of NAFLD.

Topics: Adipokines; Adiponectin; Adult; Aged; Biopsy; Blood Glucose; Case-Control Studies; Cohort Studies; Cytokines; Fasting; Fatty Liver; Female; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Interleukin-6; Interleukin-8; Linear Models; Liver; Liver Cirrhosis; Male; Middle Aged; Multivariate Analysis; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Tumor Necrosis Factor-alpha

Obesity and the metabolic syndrome are closely correlated with hepatic steatosis. Simple hepatic steatosis in nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), which can be a precursor to more serious liver diseases, such as cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms underlying progression of steatosis to NASH remain unclear; however, inflammation, proinflammatory cytokines, and oxidative stress have been postulated to play key roles. We previously reported that patients with NASH have elevated serum levels of proinflammatory cytokines, such as interleukin-8 (IL-8), which are likely to contribute to hepatic injury. This study specifically examines the effect of hepatic steatosis on IL-8 production. We induced lipid accumulation in hepatocytes (HepG2, rat primary hepatocytes, and human primary hepatocytes) by exposing them to pathophysiologically relevant concentrations of palmitic acid to simulate the excessive influx of fatty acids into hepatocytes. Significant fat accumulation was documented morphologically by Oil Red O staining in cells exposed to palmitic acid, and it was accompanied by an increase in intracellular triglyceride levels. Importantly, palmitic acid was found to induce significantly elevated levels of biologically active neutrophil chemoattractant, IL-8, from steatotic hepatocytes. Incubation of the cells with palmitate led to increased IL-8 gene expression and secretion (both mRNA and protein) through mechanisms involving activation of nuclear factor kappaB (NF-kappaB) and c-Jun N-terminal kinase/activator protein-1.. These data demonstrate for the first time that lipid accumulation in hepatocytes can stimulate IL-8 production, thereby potentially contributing to hepatic inflammation and consequent liver injury.

Topics: Cell Line, Tumor; Chemokines, CXC; Cytokines; Fatty Liver; Hepatocytes; Humans; Interleukin-8; Lipids; MAP Kinase Kinase 4; NF-kappa B; Palmitic Acid; RNA, Messenger; Transcription Factor AP-1; Triglycerides

Non-alcoholic steatohepatitis (NASH) is a form of chronic hepatitis. The pathogenesis of NASH has been dealt with in only a few studies and so it has not been clearly identified yet. The purpose of this study was to investigate the roles of TNF-alpha, TGF-beta, IL-6, IL-8, malondialdehyde (MDA), nitric oxide (NO) and the expression of Bcl-2 and Bax in the pathogenesis of NASH.. The study included 92 patients, 57 of whom were diagnosed with biopsy-proven NASH, 13 with biopsy-proven hepatosteatosis and 22 with ultrasonography-diagnosed hepatosteatosis. Serum levels of TNF-alpha, TGF-beta, IL-6 and IL-8 were measured using the ELISA method. The plasma levels of NO were studied using the Griess method. Expressions of Bcl-2 and Bax were examined in paraffin blocks of liver biopsy materials by means of immunohistochemical-staining. MDA levels were measured using the thiobarbituric acid method.. No significant difference was found in the levels of TNF-alpha, TGF-beta, IL-6 or NO between the three groups (p>0.05). No difference was found in expression of Bcl-2 and expression of Bax between the biopsy-proven NASH and biopsy-proven hepatosteatosis groups (p>0.05). In the NASH group, the levels of IL-8 and MDA were found to be higher than those in the hepatosteatosis groups (p<0.05).. The elevated levels of MDA may indicate the relationship between oxidative stress and NASH. Furthermore, IL-8 was found to be higher in the NASH group than in the hepatosteatosis group, demonstrating the importance of inflammation in the pathogenesis of NASH.

Topics: Adult; Aged; bcl-2-Associated X Protein; Biomarkers; Biopsy; Cytokines; Fatty Liver; Female; Fibrosis; Humans; Interleukin-6; Interleukin-8; Liver Function Tests; Male; Malondialdehyde; Middle Aged; Nitric Oxide; Oxidative Stress; Prospective Studies; Proto-Oncogene Proteins c-bcl-2; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

We immunohistologically studied the hepatic tissue sections in cases with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome; n = 2) and acute fatty liver of pregnancy (AFLP; n = 2) compared to necropsy controls. Unlike in the AFLP cases, a marked infiltration of neutrophils in liver tissues was found in both cases of the HELLP syndrome. Immunostaining with the antihuman (polyclonal) TNF-alpha, IL-1 beta, IL-8 and antihuman neutrophil elastase (monoclonal antibody) was performed in paraffin-embedded hepatic tissue sections. Liver tissues in HELLP syndrome patients were stained strongly with TNF-alpha and neutrophil elastase antibody. The strongest staining pattern was observed in the eclamptic case, whereas in the AFLP cases, as in the necropsy controls, a very weak staining for anti-TNF-alpha and elastase antibody was found. The liver sections of the HELLP syndrome cases were moderately stained with polyclonal IL-1 beta and IL-8 antibodies whereas AFLP and controls had a very faint staining. Significant correlations were found between the numbers of necrotic hepatocytes and elastase dots in the same microscopic fields (randomly selected) of liver sections from two cases of HELLP syndrome (r2 = 0.63; p < 0.0001), which might suggest a neutrophil-mediated tissue damage in such a disease. This study suggests that a cytokine- and neutrophil-mediated liver injury occurs in the HELLP syndrome but not in AFLP.

Topics: Adult; Cytokines; Fatty Liver; Female; HELLP Syndrome; Humans; Immunohistochemistry; Interleukin-1; Interleukin-8; Leukocyte Elastase; Liver; Necrosis; Neutrophils; Pregnancy; Pregnancy Complications; Tumor Necrosis Factor-alpha