Hepatic TLR4 signaling is activated by LPS from digestive tract during SARA, and epigenetic mechanisms contribute to enforced TLR4 expression

Chang, Guangjun; Zhuang, Songlin; Seyfert, Hans‐Martin; Zhang, Kai; Xu, Tianle; Jin, Di; Guo, Junfei; Shen, Xiang

doi:10.18632/oncotarget.6161

Cited by 44 publications

(45 citation statements)

References 47 publications

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“…Taken together, the distinctive base of above mentioned facts firmly suggests that LPS triggered the activation of TLR4 signaling, resulting in an inflammatory response in the uterus of goats suffering from SARA. Overwhelmingly, the data in the current study indicate that LPS triggers the TLR4-NF-κB signaling pathway, in accord with an earlier study (Chang et al, 2015). The present study found that SARA increased the mRNA expression and protein concentrations of NF-κB in the uterus of TG goats.…”

Section: Fig 3: Uterine Gene Expression Profile Analysis With Qrt-pcrsupporting

confidence: 92%

“…Moreover, it was observed that high concentrate feeding increased the free LPS level in the rumen; LPS subsequently translocated into the blood stream with the possible major site of LPS translocation into the blood stream being the intestines (Khafipour et al, 2009). Recently, Chang et al (2015) reported that a harmful feature of high grain diet-induced SARA is the induction of liver inflammation. The high rise in circulating LPS triggers inflammation that in turn stimulates extensive TLR4 signaling and ultimately elevates the expressions of innate immune genes and enhances the secretion of pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

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High Grain Diet Triggers Inflammation in the Goat Uterus: A Comprehensive Regulation Diet Modulates the Immune Response

Bilal¹,

Abaker²,

Aabdin³

et al. 2017

IJAB

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The aim of the present study was to explore the causal association between the increase in circulating subacute ruminal acidosis (SARA)-induced lipopolysaccharide (LPS) levels and uterine inflammation; moreover this study sought to evaluate the role of a comprehensive regulation diet in combating the inflammatory effects of a high grain diet. Twelve dairy goats were randomly assigned to two groups. One group was provided a high-concentrate buffered diet as the comprehensive regulation group (RG) control while, only a high concentrate powdered diet was fed to the treatment group (TG). The LPS concentrations in the rumen fluid were 428702±34505.6 and 255027±39756.2 EU/mL, in the TG and RG goats, respectively, while, the LPS levels in the peripheral plasma were 0.032±0.003 and 0.012±0.003 EU/mL in the TG and RG goats, respectively. The concentration of TNF-α, IL-1β and IL-6 was significantly higher, and there was enhanced expression of the inflammatory genes TLR4, MyD88, TRAF-6, NF-κB, IL-1β and IL-6 in the uteri of TG goats. SARA increased the NF-κB expression and level of its phosphorylated form in TG goats. The uteri of TG goats showed higher mRNA levels of proinflammatory genes than the RG goats, indicating the presence of inflammation. Thus, SARA-induced LPS derived from a high concentrate diet triggers inflammation in the goat uterus by reinforcing TLR4 signaling.

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Section: Fig 3: Uterine Gene Expression Profile Analysis With Qrt-pcrsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

High Grain Diet Triggers Inflammation in the Goat Uterus: A Comprehensive Regulation Diet Modulates the Immune Response

Bilal¹,

Abaker²,

Aabdin³

et al. 2017

IJAB

Self Cite

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“…According to our results, the increased expression of TLR4 indicated that TLR4 recognized the LPS and triggered the inflammatory pathway [9, 38]. Identification of inflammatory-stimuli by the innate immune system is organized by PPR that identify external stimuli for example pathogen associated molecular patterns (PAMPs) [39].…”

Section: Discussionmentioning

confidence: 99%

“…The persistent consumption of a HC diet by dairy animals enhances the production of organic acids and significantly results in a decline in pH values of the rumen and intestine [5–7]. This decrease in pH due to excessive high concentrate diet [8] may affect the alterations of the type of fermentation [9] and the structure of the microbes in the rumen [10, 11]. Moreover, the decline in pH also perturbs the balance of microbial population in the rumen causing substantial release of free endotoxin (lipopolysaccharide, LPS) from gram-negative bacteria [12].…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide derived from the digestive tract triggers an inflammatory response in the uterus of mid-lactating dairy cows during SARA

et al. 2016

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BackgroundThe aims of the current study were to evaluate the inflammatory response in cow uterus and to explore the molecular mechanism triggered by high concentrate-induced subacute ruminal acidosis (SARA) in mid-lactating dairy cows. Twelve mid-lactating Holstein cows with an average weight of 455 kg were allocated into two groups subjected to two diets for 18-weeks either a low-concentrate (LC) group containing 4:6 (NDF: NFC) and a high-concentrate (HC) group containing 6:4 (non-forage carbohydrates, NFC): (neutral detergent fiber, NDF) ratio based on dry matter.ResultsThe HC group showed lower ruminal pH and higher lipopolysaccharide (LPS) concentrations in both the rumen and peripheral plasma compared to the LC group. The LPS concentrations in the rumen fluid and the peripheral plasma were found significantly increased in the HC group compared to the LC group. The concentrations of IL-1β, TNF-α and IL-6 were significantly higher in the HC group compared to the LC group. The uterus of SARA cows revealed elevated mRNA concentrations of nuclear transcription factors and pro-inflammatory cytokines, which confirmed the presence of inflammation. The occurrence of uterine inflammation was further validated by the increased protein expression of NF-κB-p65 and its active phosphorylated variant in the uterus of SARA cows. Similarly, the inflammatory genes TLR4, LBP, MyD88, TRAF-6, NF-κB, IL-6, IL-8, TNF-α and IL-1β were significantly upregulated in the uterus of the HC versus the LC group.ConclusionTherefore, the results indicated that LPS derived from the rumen triggered the genes associated with inflammation in the uterus of mid-lactating dairy cows fed a high-concentrate diet, causing endometritis.

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“…Generally known for its proinflammatory properties, NF-κB is also an important antiapoptotic factor (48,49). LPS activation and TNF collectively lead to increased TLR4 expression, proinflammatory cytokine production, and inflammation, on the one hand, and NF-κB activation and cytoprotection on the other (48).…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 99%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

154

130

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Hepatic TLR4 signaling is activated by LPS from digestive tract during SARA, and epigenetic mechanisms contribute to enforced TLR4 expression

Cited by 44 publications

References 47 publications

High Grain Diet Triggers Inflammation in the Goat Uterus: A Comprehensive Regulation Diet Modulates the Immune Response

High Grain Diet Triggers Inflammation in the Goat Uterus: A Comprehensive Regulation Diet Modulates the Immune Response

Lipopolysaccharide derived from the digestive tract triggers an inflammatory response in the uterus of mid-lactating dairy cows during SARA

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

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