Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice

Matsumoto, Hitoshi; Tamura, Shinji; Kamada, Y.; Kiso, Shinichi; Fukushima, Juichi; Wada, Akira; Maeda, Norikazu; Kihara, Shinji; Funahashi, Tohru; Matsuzawa, Yūji; Shimomura, Iichiro; Hayashi, Norio

doi:10.3748/wjg.v12.i21.3352

Cited by 68 publications

(45 citation statements)

References 38 publications

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“…Similarly, pretreatment of mice with adiponectin protects from LPS-induced liver injury in KK-Ay obese mice by suppressing TNF-␣ expression (36). In contrast, adiponectin-deficient mice exhibit increased sensitivity to galactosamine/LPS-induced liver injury (37). Taken together, these studies in isolated cells and in vivo studies demonstrate the critical anti-inflammatory effects of adiponectin on macrophage function.…”

Section: Discussionmentioning

confidence: 86%

Short-term Treatment of RAW264.7 Macrophages with Adiponectin Increases Tumor Necrosis Factor-α (TNF-α) Expression via ERK1/2 Activation and Egr-1 Expression

Park

McMullen

Huang

et al. 2007

Journal of Biological Chemistry

144

145

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Adiponectin is an adipokine with potent anti-inflammatory properties. However, the mechanisms by which adiponectin suppresses macrophage function are not well understood. Treatment of RAW264.7 macrophages with adiponectin for 18 h decreased lipopolysaccharide (LPS)-stimulated tumor necrosis factor-␣ (TNF-␣) production. Here we demonstrate that globular adiponectin (gAcrp) initially increased TNF-␣ expression in RAW264.7 macrophages; this TNF-␣ then contributed to increased expression of interleukin-10, which in turn was required for the development of tolerance to subsequent LPS exposure. gAcrp-mediated increases in TNF-␣ mRNA accumulation were associated with increased TNF-␣ promoter activity. gAcrp increased the DNA binding activity of both Egr-1 and NFB; mutation of either the Egr-1 or NFB binding sites in the TNF-␣ promoter decreased gAcrp-stimulated promoter activity. Further, co-transfection with either dominant negative Egr-1 or the IB super-repressor prevented gAcrp-stimulated TNF-␣ promoter activity. gAcrp also increased Egr-1 promoter activity, mRNA accumulation, and DNA binding activity. Inhibition of ERK1/2 with U0126 potently suppressed gAcrp-stimulated Egr-1 promoter activity, as well as TNF-␣ promoter activity. In summary, these data demonstrate that adiponectin initially increases TNF-␣ production by macrophages via ERK1/ 23 Egr-1 and NFB-dependent mechanisms; these increases in TNF-␣ in turn lead to increased expression of interleukin-10 and an eventual dampening of LPS-mediated cytokine production in macrophages.

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Section: Discussionmentioning

confidence: 86%

Short-term Treatment of RAW264.7 Macrophages with Adiponectin Increases Tumor Necrosis Factor-α (TNF-α) Expression via ERK1/2 Activation and Egr-1 Expression

Park

McMullen

Huang

et al. 2007

Journal of Biological Chemistry

144

145

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“…Conversely, adiponectin has been shown to inhibit lipopolysaccharide induction of macrophage activation both in vitro and in vivo. 10,20 Because KK-A y mice present significant hypoadiponectinemia (Fig. 6B), it is reasonable that Kupffer cells in these animals are more susceptible to certain stimuli such as gut-derived endotoxin (lipopolysaccharide).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice #

et al. 2009

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Pathogenesis of metabolic syndrome-related nonalcoholic steatohepatitis (NASH) involves abnormal tissue-repairing responses in the liver. We investigated the effect of pioglitazone, a thiazolidinedione derivative (TZD), on hepatic regenerative responses in obese, diabetic KK-A y mice. Male KK-A y mice 9 weeks after birth underwent twothirds partial hepatectomy (PH) after repeated intragastric injections of pioglitazone (25 mg/kg) for 5 days. Almost half of the KK-A y mice died within 48 hours of PH; however, mortality was completely prevented in mice pretreated with pioglitazone. In KK-A y mice, bromodeoxyuridine (BrdU) incorporation to hepatocyte nuclei 48 hours after PH reached only 1%; however, pioglitazone pretreatment significantly increased BrdU-positive cells to 8%. Cyclin D1 was barely detectable in KK-A y mice within 48 hours after PH. In contrast, overt expression of cyclin D1 was observed 24 hours after PH in KK-A y mice pretreated with pioglitazone. Hepatic tumor necrosis factor alpha (TNF-␣) messenger RNA (mRNA) was tremendously increased 1 hour after PH in KK-A y mice, the levels reaching ninefold over C57Bl/6 given PH, whereas pioglitazone blunted this increase by almost three-fourths. Pioglitazone normalized hypoadiponectinemia in KK-A y mice almost completely. Serum interleukin (IL)-6 and leptin levels were elevated extensively 24 hours after PH in KK-A y mice, whereas the levels were largely decreased in KK-A y mice given pioglitazone. Indeed, pioglitazone prevented aberrant increases in signal transducers and activators of transcription (STAT)3 phosphorylation and suppressor of cytokine signaling (SOCS)-3 mRNA in the liver in KK-A y mice. Conclusion: These findings indicated that pioglitazone improved hepatic regeneration failure in KK-A y mice. The mechanism underlying the effect of pioglitazone on regeneration failure most likely involves normalization of expression pattern of adipokines and subsequent cytokine responses during the early stage of PH. (HEPATOLOGY 2009;

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“…However, gene knockout models of adiponectin deficiency have not consistently demonstrated anticipated inflammation-prone phenotypes and in some cases are protected from inflammatory stimuli [20]. Of three adiponectin knockout models described [1,2,4], that of Maeda et al [1] has been shown to have an inflammation-prone phenotype in the LPS-galactosamine model of hepatitis [18] and in the dextran sodium sulphate (DSS) colitis model [17]. Conversely, Pini et al [19] report that adiponectin null mice do not have exaggerated inflammatory responses to systemic LPS challenge, and Fayad et al [20] report that adiponectin null mice are protected from inflammation in the DSS-colitis model.…”

Section: Discussionmentioning

confidence: 99%

“…If this hypothesis is correct, adiponectin-deficient animal models would be expected to display inflammationprone phenotypes, and while this has been found to be true in some instances [16][17][18], it has not been a consistent finding [18][19][20], highlighting a significant degree of complexity in immunomodulatory actions of adiponectin.…”

Section: Introductionmentioning

confidence: 99%

Induction of TLR Tolerance in Human Macrophages by Adiponectin: Does LPS Play a Role?

et al. 2009

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Obesity is regarded as a pro‐inflammatory state. It is associated with low circulating levels of the adipokine, adiponectin, which is considered to be an anti‐inflammatory. However, adiponectin knockout mice do not consistently demonstrate pro‐inflammatory phenotypes, suggesting more complexity in the in vivo immunomodulatory effects of adiponectin than originally anticipated. Moreover, adiponectin exerts pro‐inflammatory effects in some experimental systems. This contradiction has been resolved by hypothesizing that adiponectin induces tolerance to inflammatory stimuli, notably Toll‐like receptor (TLR) ligands. We noticed that this effect resembled lipopolysaccharide (LPS) tolerance and therefore tested adiponectin from a variety of sources for LPS contamination. All adiponectin tested carried low levels of LPS in the range of 1–30 pg/μg of adiponectin, sufficient to produce final LPS concentrations in the pg/ml range under experimental conditions. We found that induction of tolerance to TLR ligands by adiponectin in human monocyte‐derived macrophages could be reproduced by such LPS concentrations. Moreover, the LPS antagonist, polymixin B, substantially inhibited induction of tolerance by adiponectin. Furthermore, polymixin B and a naturally occurring antagonist LPS were able to partially attenuate induction of tumour necrosis factor‐α and interleukin‐6 in human monocyte‐derived macrophages by adiponectin. Polymixin B also inhibited nuclear factor‐κB and mitogen‐activated protein kinase signalling elicited by adiponectin. We therefore propose that some of adiponectin’s immunomodulatory effects, in particular, its TLR‐tolerising actions in human monocyte‐derived macrophages, may be confounded by induction of tolerance by contaminating LPS.

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Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice

Abstract: Adiponectin supresses TNF-alpha production and induces IL-10 production by Kupffer cells in response to LPS stimulation, and a lack of adiponectin enhances LPS-induced liver injury.

Cited by 68 publications

References 38 publications

Short-term Treatment of RAW264.7 Macrophages with Adiponectin Increases Tumor Necrosis Factor-α (TNF-α) Expression via ERK1/2 Activation and Egr-1 Expression

Short-term Treatment of RAW264.7 Macrophages with Adiponectin Increases Tumor Necrosis Factor-α (TNF-α) Expression via ERK1/2 Activation and Egr-1 Expression

Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice #

Induction of TLR Tolerance in Human Macrophages by Adiponectin: Does LPS Play a Role?

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