IgG-mediated anaphylaxis occurs in mice and may contribute to human reactions to infused drugs. To distinguish IgE- from putative IgG-mediated human anaphylaxis, we developed blood markers for murine anaphylaxis and evaluated their human relevance. Both IgG- and IgE-mediated anaphylaxis were characterized by decreased basophil and monocyte percentages and an increased neutrophil percentage in mouse blood. IgE- but not IgG-mediated murine anaphylaxis was accompanied by large increases in IL-4 secretion, plasma soluble IL-4 receptor-α (IL-4Rα) concentration, and T-cell membrane IL-4Rα expression. T-cell IL-4Rα expression also increased when mice that express human Fcε receptor Iα were sensitized with IgG-depleted serum from a peanut-allergic individual and challenged with peanut extract. Increased T-cell IL-4Rα expression is likely to also be a marker for human IgE-mediated anaphylaxis, because IgE-activated human basophils secrete IL-4, and IL-4 increases human T-cell IL-4Rα expression in vitro. Murine IgG- but not IgE-mediated anaphylaxis was characterized by decreased neutrophil Fcγ receptor III (FcγRIII) expression that was observed even when the antigen dose was insufficient to induce shock. Human neutrophils cultured with IgG immune complexes also lost FcγRIII. These observations suggest that decreased blood neutrophil FcγRIII expression without increased IL-4Rα expression can be used to determine whether and when IgG-mediated anaphylaxis occurs in man.

Purpose of review About 15–25% of patients with simple steatosis of non-alcoholic fatty liver disease progresses to non-alcoholic steatohepatitis (NASH), and the underlying mechanism for this progression has not been elucidated. NASH ultimately could progress to cirrhosis, an irreversible condition. Recent findings Farnesoid X receptor (FXR) has been studied for its role in modulating inflammation, and the expression of FXR is down-regulated during NASH development. FXR deficiency has shown to progress and exacerbate NASH development, and FXR activation has been protective against liver inflammation associated with NASH. The expression of factors in both the adaptive and innate immune response in the liver are regulated in a FXR-dependent and -independent manner. Summary Therefore, understanding key signaling pathways of liver inflammation in NASH is important to determine essential components that predispose, progress, or exacerbate NASH. FXR has been identified as a therapeutic target for NASH to prevent liver inflammation.

PFOS is a chemical of nearly ubiquitous exposure in humans. Recent studies have associated PFOS exposure to adipose tissue-related effects. The present study was to determine whether PFOS alters the process of adipogenesis and regulates insulin-stimulated glucose uptake in mouse and human preadipocytes. In murine-derived 3T3-L1 preadipocytes, PFOS enhanced hormone-induced differentiation to adipocytes and adipogenic gene expression, increased insulin-stimulated glucose uptake at concentrations ranging from 10 to 100 µM, and enhanced Glucose transporter type 4 and Insulin receptor substrate-1 expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase, quinone 1 and Glutamate-cysteine ligase, catalytic subunit were significantly induced in 3T3-L1 cells treated with PFOS, along with a robust induction of Antioxidant Response Element (ARE) reporter in mouse embryonic fibroblasts isolated from ARE-hPAP transgenic mice by PFOS treatment. Chromatin immunoprecipitation assays further illustrated that PFOS increased Nrf2 binding to ARE sites in mouse Nqo1 promoter, suggesting that PFOS activated Nrf2 signaling in murine-derived preadipocytes. Additionally, PFOS administration in mice (100 µg/kg/day) induced adipogenic gene expression and activated Nrf2 signaling in epididymal white adipose tissue. Moreover, the treatment on human visceral preadipocytes illustrated that PFOS (5 and 50 µM) promoted adipogenesis and increased cellular lipid accumulation. It was observed that PFOS increased Nrf2 binding to ARE sites in association with Nrf2 signaling activation, induction of Peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α expression, and increased adipogenesis. This study points to a potential role PFOS in dysregulation of adipose tissue expandability, and warrants further investigations on the adverse effects of persistent pollutants on human health.

Farnesoid X receptor (FXR) induces fibroblast growth factor 15 (FGF15; human ortholog FGF19) in the gut to potently inhibit bile acid (BA) synthesis in the liver. FXR activation in hepatic stellate cells (HSCs) reduces liver fibrosis (LF). Fgf15–/– mice develop attenuated LF, but the underlying mechanisms for this protection are unclear. We hypothesized that FGF15/19 functions as a profibrotic mediator or mitogen to HSCs and increased BAs in Fgf15–/– mice leads to enhanced FXR activation in HSCs, subsequently reducing fibrogenesis. In this study, complimentary in vivo and in vitro approaches were used: (1) CCl4‐induced LF model in wild type (WT), Fgf15–/–, and Fgf15 transgenic (TG) mice with BA levels modulated by feeding cholestyramine‐ or cholic acid–containing diets; (2) analysis of primary HSCs isolated from WT and Fgf15–/– mice; and (3) treatment of a human HSC line, LX‐2, with FXR activators and/or recombinant FGF19 protein. The results showed that Fgf15–/– mice had lower basal collagen expression, which was increased by BA sequestration. CCl4 induced fibrosis with similar severity in all genotypes; however, cholestyramine increased fibrosis severity only in Fgf15–/– mice. HSCs from Fgf15–/– mice showed increased FXR activity and reduced expression of profibrotic mediators. In LX‐2 cells, FXR activation increased peroxisome proliferator‐activated receptor gamma activity and reduced proliferation. FGF19 activated both signal transducer and activator of transcription 3 and c‐Jun N‐terminal kinase pathways and reduced nuclear factor kappa‐light‐chain‐enhancer of activated B cells signaling without increasing fibrogenic gene expression or cell proliferation. Conclusion: FGF15/19 does not act as a direct profibrotic mediator or mitogen to HSCs in our models, and the protection against fibrosis by FGF15 deficiency may be mediated through increased BA activation of FXR in HSCs.

Recent studies have investigated the roles of FXR deficiency in the pathogenesis of alcoholic liver disease (ALD). However, the underlined molecular mechanisms remain unclear. In this study, FXR knockout (FXR −/−) and wild-type (WT) mice were subjected to chronic-plus-binge alcohol feeding to study the effect of FXR deficiency on ALD development. The degree of liver injury was greater in FXR −/− mice compared to WT mice. Ethanol feeding enhanced hepatic steatosis in FXR −/− mice, accompanied by decreased mRNA levels of Pparα and Srebp-1c. The expression of Lcn2 was increased by ethanol treatment, despite unchanged expression of pro-inflammatory cytokines Tnfα, II6 and II-1 β. Furthermore, ethanol treatment altered bile acid (BA) homeostasis to a greater extent in FXR −/− mice, as well as serum and hepatic BA pool composition. The mRNA levels of hepatic Cyp7a1 and Shp, as well as intestinal Fgf15, were decreased in WT mice with ethanol feeding, which were further reduced in FXR −/− mice. Levels of both primary and

No abstract

Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extra-hepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXR Int−/− ) mice following treatment with control or ethanol-containing diet. We found that FXR Int−/− mice were more susceptible to ethanol-induced liver steatosis and inflammation, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Deltamethrin, a type II pyrethroid, is a widely used insecticide. The purpose of this study was to determine whether perinatal deltamethrin exposure altered the expression of adipogenic and lipogenic genes in white adipose tissue (WAT) in adult pups. C57BL/6 pregnant mice were administered 0, 1, or 3 mg/kg of deltamethrin orally every 3 days throughout gestation and lactation. Offspring were weaned on postnatal day 25, and WAT was collected from 5-month-old male mice. Perinatal deltamethrin exposure decreased the mRNA expression of adipogenesis-related transcription factors Pparγ, Cebpα, and lipogenic genes Srebp1c, Acc-1, Cd36, Lpl, Scd-1; along with Nrf2 and target genes Nqo1 and Gclc at the 1 mg/kg treatment. Cytokine expression of Fas/Tnf-R and Cd209e at the 1 mg/kg treatment was significantly decreased, and expression of Tnf, Cd11c, and Fas/Tnf-R was decreased at the 3 mg/kg treatment. Developmental deltamethrin exposure did not overtly affect body weight or adipose weight, but decreased mRNA expression of specific genes that may poten tially disrupt normal adipogenesis and lipid and glucose metabolism if the offspring are challenged by changes in diet or environment.