The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling

Uchimura, Kohei; Hayata, Manabu; Mizumoto, Teruhiko; Miyasato, Yoshikazu; Kakizoe, Yutaka; Morinaga, Jun; Onoue, Tomoaki; Yamazoe, Rika; Ueda, Miki; Adachi, Masataka; Miyoshi, Takuji; Shiraishi, Naoki; Ogawa, Wataru; Fukuda, Kazuki; Kondo, Tatsuya; Matsumura, Takeshi; Araki, Eiichi; Tomita, Kimio; Kitamura, Kenichiro

doi:10.1038/ncomms4428

Cited by 55 publications

(68 citation statements)

References 39 publications

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“…Consistent with our findings, Uchimura et al recently reported that hepatic Tlr4 plays an important role in regulating glucose metabolism and insulin sensitivity in mice 27 .…”

Section: Resultssupporting

confidence: 93%

Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

et al. 2014

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Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however which Tlr4 expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity, and ameliorated hepatic steatosis despite the development of obesity after a high fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.

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“…Consistent with our findings, Uchimura et al recently reported that hepatic Tlr4 plays an important role in regulating glucose metabolism and insulin sensitivity in mice 27 .…”

Section: Resultssupporting

confidence: 93%

Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

et al. 2014

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“…The reported sizes of TLR4 fragments were different, suggesting that different enzymes may be involved in this process. So far, neutrophil elastase and prostasin (a serine protease) have been identified to cleave the extracellular region of TLR4 [25, 26]. The present study clearly demonstrates that 1,25D 3 causes ectodomain shedding of TLR4.…”

Section: Discussionsupporting

confidence: 57%

“…As noted above, ADAM10-mediated ectodomain shedding of TLR4 resulted in a significant decrease in the response of cells to LPS in terms of p38 phosphorylation and ICAM-1 expression. In HepG2 cells [26], the ectodomain cleavage of TLR4 mediated by the serine protease prostasin was also shown to decrease the receptor activity. In contrast, the ectodomain cleavage of TLR4 mediated by neutrophil elastase in macrophage was accompanied by an increased production of inflammatory cytokines [25].…”

Section: Discussionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

Yang

Kim

Han

et al. 2017

Cell Physiol Biochem

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Background/Aims: We investigated how 1,25-dihydroxyvitamin D₃ (1,25D₃) inhibits the effects of lipopolysaccharide (LPS) in human aortic endothelial cells. Methods: Cellular signaling was explored by determination of protein abundance with Western blot, measurement of cytosolic Ca²⁺ concentration and immunofluorescence staining for a disintegrin and metalloprotease 10 (ADAM10). Results: LPS stimulated the expression of intercellular adhesion molecule 1 (ICAM-1) through toll-like receptor 4 (TLR4) and subsequent activation of p38 mitogen-activated protein kinase (p38 MAPK). Pretreatment with 1,25D₃ attenuated LPS-induced p38 MAPK activation and ICAM-1 expression by causing ectodomain shedding of TLR4. This effect of 1,25D₃ depended on its ability to induce a rapid extracellular Ca²⁺ influx through L-type calcium channels because the ectodomain shedding was prevented by the absence of extracellular Ca²⁺ or the presence of verapamil. TLR4 ectodomain shedding was also induced by Bay K8644 (L-type calcium channel agonist). Both 1,25D₃ and Bay K8644 caused extracellular Ca²⁺ influx-dependent ADAM10 translocation to the cell surface. Depletion of ADAM10 by siRNA transfection prevented 1,25D₃- and Bay K8644-induced ectodomain shedding of TLR4, and abolished the inhibitory effect of 1,25D₃ on LPS-induced ICAM-1 expression. Conclusion: 1,25D₃ causes ectodomain shedding of TLR4 and thereby decreases the responsiveness of cells to LPS. ADAM10, activated by extracellular Ca²⁺ influx, was implicated in the ectodomain cleavage of TLR4.

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“…This surprising finding is not in accordance with several other studies, suggesting that mice lacking MyD88 in the brain or in the gut are protected against both diet-induced obesity and insulin resistance. [11][12][13][14] Therefore, our data strongly suggest that MyD88 differentially contributes to the regulation of energy and glucose homeostasis depending on the targeted organ. This also partially explains the quantity of conflicting data existing when investigating whole-body Myd88 deletion and its impact of obesity and related disorders.…”

Section: Discussionmentioning

confidence: 60%

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Duparc

Plovier

Marrachelli

et al. 2016

Gut

139

112

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ObjectiveTo examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.DesignTo study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).ResultsHepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.ConclusionsOur study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.

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The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling

Cited by 55 publications

References 39 publications

Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

1,25-Dihydroxyvitamin D3 Attenuates the Effects of Lipopolysaccharide by Causing ADAM10-Dependent Ectodomain Shedding of Toll-Like Receptor 4

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

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