The Chemical Chaperone 4-Phenylbutyric Acid Prevents Alcohol-Induced Liver Injury in Obese KK-A(y) Mice.
Co-occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA)-which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress-on chronic-plus-binge ethanol (EtOH)-induced liver injury in a mouse model of obesity.
Male KK-Ay mice (8 weeks old) were fed a Lieber-DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair-fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage.
Chronic-plus-binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic-plus-binge EtOH-induced up-regulation of ER stress-related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X-box-binding protein-1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic-plus-binge EtOH-induced expression of the oxidative stress marker heme oxygenase-1 (HO-1) and 4-hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO-1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH-induced hepatic activity of cytochrome P450 2E1.
Binge EtOH intake after chronic consumption induces massive ER stress-related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic-plus-binge EtOH-induced liver injury by reducing ER and oxidative stress after an EtOH binge.
Suzuki M
，Kon K
，Ikejima K
，Arai K
，Uchiyama A
，Aoyama T
，Yamashina S
，Ueno T
，Watanabe S
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Genetic Loss of Immunoglobulin A Does Not Influence Development of Alcoholic Steatohepatitis in Mice.
Chronic alcohol abuse is associated with intestinal dysbiosis and bacterial translocation. Translocated commensal bacteria contribute to alcoholic liver disease. Secretory immunoglobulin A (IgA) in the intestine binds bacteria and prevents bacterial translocation.
To investigate the functional role of IgA in ethanol (EtOH)-induced liver disease in mice, we subjected wild type (WT) and IgA-deficient littermate mice to Lieber-DeCarli models of chronic EtOH administration and the model of chronic and binge EtOH feeding (the NIAAA model).
Chronic EtOH feeding increased systemic levels of IgA, while fecal IgA was reduced in C57BL/6 WT mice. WT and Iga-/- littermate mice showed similar liver injury, steatosis, and inflammation following 4 weeks of EtOH feeding or chronic and binge EtOH feeding. IgA deficiency did not affect intestinal absorption or hepatic metabolism of EtOH. Pretreatment with ampicillin elevated intestinal IgA in WT littermate mice. Despite increased intestinal IgA, WT littermate mice exhibited a similar degree of liver disease compared with Iga-/- mice after 7 weeks of EtOH feeding. Interestingly, bacterial translocation to mesenteric lymph nodes was increased in Iga-/- mice fed an isocaloric diet, but was the same after EtOH feeding relative to WT littermate mice. The absence of intestinal IgA was associated with increased intestinal and plasma IgM in Iga-/- mice after EtOH feeding.
Our findings indicate that absence of IgA does not affect the development of alcoholic liver disease in mice. Loss of intestinal IgA is compensated by increased levels of intestinal IgM, which likely limits bacterial translocation after chronic EtOH administration.
Inamine T
，Yang AM
，Wang L
，Lee KC
，Llorente C
，Schnabl B
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New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism.
Intestinal dysbiosis has been shown to be associated with the pathogenesis of alcoholic liver disease (ALD), which includes changes in the microbiota composition and bacterial overgrowth, but an effective microbe-based therapy is lacking. Pediococcus pentosaceus (P. pentosaceus) CGMCC 7049 is a newly isolated strain of probiotic that has been shown to be resistant to ethanol and bile salts. However, further studies are needed to determine whether P. pentosaceus exerts a protective effect on ALD and to elucidate the potential mechanism.
To evaluate the protective effect of the probiotic P. pentosaceus on ethanol-induced liver injury in mice.
A new ethanol-resistant strain of P. pentosaceus CGMCC 7049 was isolated from healthy adults in our laboratory. The chronic plus binge model of experimental ALD was established to evaluate the protective effects. Twenty-eight C57BL/6 mice were randomly divided into three groups: The control group received a pair-fed control diet and oral gavage with sterile phosphate buffered saline, the EtOH group received a ten-day Lieber-DeCarli diet containing 5% ethanol and oral gavage with phosphate buffered saline, and the P. pentosaceus group received a 5% ethanol Lieber-DeCarli diet but was treated with P. pentosaceus. One dose of isocaloric maltose dextrin or ethanol was administered by oral gavage on day 11, and the mice were sacrificed nine hours later. Blood and tissue samples (liver and gut) were harvested to evaluate gut barrier function and liver injury-related parameters. Fresh cecal contents were collected, gas chromatography-mass spectrometry was used to measure short-chain fatty acid (SCFA) concentrations, and the microbiota composition was analyzed using 16S rRNA gene sequencing.
The P. pentosaceus treatment improved ethanol-induced liver injury, with lower alanine aminotransferase, aspartate transaminase and triglyceride levels and decreased neutrophil infiltration. These changes were accompanied by decreased levels of endotoxin and inflammatory cytokines, including interleukin-5, tumor necrosis factor-α, granulocyte colony-stimulating factor, keratinocyte-derived protein chemokine, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. Ethanol feeding resulted in intestinal dysbiosis and gut barrier disruption, increased relative abundance of potentially pathogenic Escherichia and Staphylococcus, and the depletion of SCFA-producing bacteria, such as Prevotella, Faecalibacterium, and Clostridium. In contrast, P. pentosaceus administration increased the microbial diversity, restored the relative abundance of Lactobacillus, Pediococcus, Prevotella, Clostridium and Akkermansia and increased propionic acid and butyric acid production by modifying SCFA-producing bacteria. Furthermore, the levels of the tight junction protein ZO-1, mucin proteins (mucin [MUC]-1, MUC-2 and MUC-4) and the antimicrobial peptide Reg3β were increased after probiotic supplementation.
Based on these results, the new strain of P. pentosaceus alleviated ethanol-induced liver injury by reversing gut microbiota dysbiosis, regulating intestinal SCFA metabolism, improving intestinal barrier function, and reducing circulating levels of endotoxin and proinflammatory cytokines and chemokines. Thus, this strain is a potential probiotic treatment for ALD.
Jiang XW
，Li YT
，Ye JZ
，Lv LX
，Yang LY
，Bian XY
，Wu WR
，Wu JJ
，Shi D
，Wang Q
，Fang DQ
，Wang KC
，Wang QQ
，Lu YM
，Xie JJ
，Li LJ
... -
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