Sodium butyrate protects against lipopolysaccharide-induced liver injury partially via the GPR43/ β-arrestin-2/NF-κB network

Abstract

Background Butyrate acts as a regulator in multiple inflammatory organ injuries. However, the role of butyrate in acute liver injury has not yet been fully explored. In the present study, we aimed to investigate the association between butyrate and lipopolysaccharide (LPS)-induced acute liver injury and the signaling pathways involved. Methods LPS-induced acute liver injury was induced by intraperitoneal injection of LPS (5 mg/kg) in G-protein-coupled receptor 43 (GPR43)-knockout (KO) and wild-type female C57BL/6 mice. Sodium butyrate (500 mg/kg) was administered intraperitoneally 30 min prior to LPS exposure. Liver injury was detected by serum markers, tissue morphology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Pro-inflammatory-factor levels were detected by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (RT-PCR). Cell models were first treated with sodium butyrate (4 μmol/mL), followed by LPS (1 μg/mL) half an hour later in GPR43 small interfering RNA (siRNA)-transfected or control RAW264.7 cells. Cell-inflammation status was evaluated through detecting pro-inflammatory-factor expression by RT-PCR and also through checking toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB)-element levels including TLR4, TRAF6, IKKβ, IкBα, phospho-IкBα, p65, and phospho-p65 by Western blot. The interaction between GPR43 and β-arrestin-2 was tested by co-immunoprecipitation. Results Sodium butyrate reversed the LPS-induced tissue-morphology changes and high levels of serum alanine aminotransferase, aspartate transaminase, myeloperoxidase, TUNEL, and pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The ameliorating effect of sodium butyrate was weakened in GPR43-KO mice and GPR43 siRNA RAW264.7 cells, compared with those of GPR43-positive controls. Sodium butyrate downregulated some elements of the TLR4/NF-κB pathway, including phospho-IκBα and phospho-p65, in RAW264.7 cells. Increased interactions between GPR43 and β-arrestin-2, and between β-arrestin-2 and IкBα were observed. Conclusion Sodium butyrate significantly attenuated LPS-induced liver injury by reducing the inflammatory response partially via the GPR43/β-arrestin-2/NF-κB signaling pathway.

Amelioratory Effect of Resistant Starch on Non-alcoholic Fatty Liver Disease via the Gut-Liver Axis

“…It has been demonstrated that the uptake of butyrate and its synthetic derivative, N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), in the liver can enhance fatty acid oxidation by activating AMPK-acetyl-CoA carboxylase against fatty liver ( 84 ). In addition, butyrate exerts protective effects by activating the GPR43/β-arrestin-2/NF-κB network against LPS-induced liver injury in a mouse model ( 85 ).…”

Extracts with anti-inflammatory activities from Acanthopanax trifoliatus (L.) Merr. by inhibiting LPS-induced expression of iNOS and COX-2

“…LPS, a main component of outer cell membrane of Gram-negative bacteria, has been recognized as one of the most potent microbial initiators of inflammation (Li et al, 2019;Ko et al, 2019). Upon stimulation with LPS, RAW 264.7 macrophages cells could trigger the secretion of numerous inflammatory cytokines and mediators such as NO, TNF-α, IL-6 and so on (Luo et al, 2020). NO is a vital cellular signaling and defensing molecule involved in inflammation.…”

Intestinal Flora: A Potential New Regulator of Cardiovascular Disease

“…SCFA also activate GPR109A to stimulate the production of IL-18, promoting intestinal homeostasis and preventing colitis [ 50 ]. GPR43-deficient mice showed increased sensitivity to dextran sodium sulfate-induced colitis [ 51 ]. In recent studies, SCFA have been shown not only to exert its anti-inflammatory and protective properties in the intestines but also to reach the circulatory system, directly affecting the adipose tissue, brain, and liver and producing beneficial metabolic effects [ 52 ].…”