MicroRNAs are fine tuners of diverse biological responses and expressed in various cell types the liver. Here we hypothesized that circulating microRNAs (miRNAs) may serve as biomarkers liver damage inflammation. We studied miRNA-122, which is abundant hepatocytes, miR-155, -146a, -125b, regulate inflammation immune cells mouse models alcoholic disease (ALD), drug (acetaminophen, APAP)-induced injury (DILI), Toll-like receptor (TLR) 9+4 ligand-induced inflammatory cell-mediated damage. found...

The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response–domain-containing adaptor inducing interferon (IFN)-β. MyD88 pathway induces proinflammatory cytokine activation, critical mediator ALD. Here we evaluated role alcohol-induced injury wild-type,...

Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNFα production has a central role the pathogenesis alcoholic liver disease. Micro-RNA (miR)-125b, miR-146a, miR-155 can regulate inflammatory responses to LPS. Here we evaluated involvement miRs alcohol-induced macrophage activation. Chronic alcohol treatment vitro resulted time-dependent but not miR-125b or miR-146a levels RAW 264.7 macrophages. Furthermore,...

It has been well documented that alcohol and its metabolites induce injury inflammation in the liver. However, there is no potential biomarker to monitor extent of liver alcoholic hepatitis patients. MicroRNAs (miRNAs) are a class non-coding RNAs involved various physiologic pathologic processes. In circulation, great proportion miRNAs associated with extracellular vesicles (EVs)/exosomes. Here, we hypothesized exosome-associated can be used as biomarkers (AH). Exosomes were isolated from...

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic use results in gut permeability serum endotoxin levels contribute to many effects alcohol, including alcoholic liver disease. In this study, we evaluated acute binge drinking healthy adults on levels. We found resulted a rapid increase 16S rDNA, marker bacterial translocation from...

Abstract The importance of chemokines in alcoholic liver injury has been implicated. role the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated patients with disease is not yet understood. Here, we evaluated pathophysiological significance MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), injury. Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo vitro assays...

Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, expression C-C chemokine receptor type 2 (Ccr2) 5 (Ccr5) the livers patients with ALD, circulating chemokines, ligand types (CCL2), (CCL5) hepatitis. hypothesized that inhibition CCL2 signaling dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model injury (alanine aminotransferase [ALT]) steatosis...

Cellular homeostais, that is normally maintained through autophagy, disrupted in alcoholic liver disease (ALD). Because autophagy and exosome biogenesis share common elements, we hypothesized increased production ALD may be linked to disruption of autophagic function. We found impaired both hepatitis (AH) mouse models human livers with as indicated by hepatic p62 LC3‐II levels. Alcohol reduced flux vivo chloroquine‐treated mice well vitro hepatocytes macrophages treated bafilomycin A. Our...

We and others have previously shown that even acute ethanol exposure has the capacity to modulate immune functions, particularly monocyte functions. Herein, we tested hypothesis treatment inhibits inflammatory, while increasing inhibitory cytokine production in human blood monocytes that, tum, could contribute overall abnormalities seen after alcohol use. Our data show vitro of with a physiologically relevant dose (W mM) results significantly decreased induction tumor necrosis factor‐α...

Toll-like receptor 4 (TLR4) and its coreceptor, myeloid differentiation factor-2 (MD-2), are key in recognition of lipopolysaccharide (LPS) activation proinflammatory pathways. Here we tested the hypothesis that TLR4 coreceptor MD-2 play a central role nonalcoholic steatohepatitis (NASH) liver fibrosis fatty disease. Mice control genotypes those deficient or [knockout (KO)] received methionine choline-deficient (MCD) choline-supplemented (MCS) diet. In mice genotypes, MCD diet resulted NASH,...

Impaired host defense after alcohol use is linked to altered cytokine production, however, acute and chronic differently modulate monocyte/macrophage activation. We hypothesized that in human monocytes, induces hyporesponsiveness LPS, resulting decreased TNF-alpha, whereas increases TNF-alpha by sensitization LPS. found increased IL-1R-associated kinase-monocyte (IRAK-M), a negative regulator of IRAK-1, monocytes. This was associated with IkappaB alpha kinase activity, NFkappaB DNA binding,...

Alcoholic and nonalcoholic steatohepatitis are leading causes of liver diseases worldwide. While different etiology, these share common pathophysiological mechanisms feature abnormal fat metabolism, inflammation fibrosis. MicroRNAs (miRNA) highly conserved noncoding RNAs that control gene expression at the post-transcriptional level either via degradation target mRNAs or inhibition translation. Each miRNA controls multiple targets; miRNAs have been linked to regulation lipid metabolism...

Abstract Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-α, (HIF-1α) may regulate liporegulatory genes, but the relationship of HIF-1 to remains unknown. We investigated HIF-1α in alcohol-induced lipid accumulation. Alcohol administration resulted steatosis, increased triglyceride levels, serum alanine aminotransferase (ALT) suggesting injury wild-type (WT) mice. There was messenger RNA (mRNA), protein, DNA-binding activity alcohol-fed...

Background: In contrast to the deleterious effects of chronic excessive alcohol consumption on liver and cardiovascular system, modest intake, such as 1 2 drinks per day, has benefits mortality. Little is known about length time or amounts consumed that may cause alterations in inflammatory cells monocytes are crucial atherosclerotic vascular disease. Here, we determine vivo acute cytokine production nuclear regulatory factor κ B (NF‐ B) binding human monocytes. Methods: Human blood were...

Abstract Background Hepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by inflammation in the liver peripheral immune cells. Chronic progressive damage. MicroRNAs (miRNA) regulate (miR-155, -146a -125b) as well hepatocyte function (miR-122). Methods Here we hypothesized that microRNAs are dysregulated HCV infection. We examined miRNAs circulation monocytes patients with evaluate if specific miRNA expression...

Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for development fibrosis. Interferon regulatory factor 3 (IRF3) regulates apoptosis and production type I IFNs. In liver, IRF3 activated via Toll-like receptor 4 (TLR4) signaling or endoplasmic reticulum (ER) adapter, stimulator interferon genes (STING). We...

Abstract Circulating miRNAs can be found in extracellular vesicles (EV) and could involved intercellular communication. Here, we report the biodistribution of EV associated miR-155 using KO mouse model. Administration exosomes loaded with synthetic mimic into mice resulted a rapid accumulation clearance plasma subsequent distribution liver, adipose tissue, lung, muscle kidney (highest to lowest, respectively). expression was detected isolated hepatocytes liver mononuclear cells recipient...

miR-122 is the most abundant miRNA in liver particularly hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty disease, regulated by hypoxia-inducible factor-1α (HIF-1α). Here, we hypothesized that reduced has pathogenic role steatohepatitis.miR-122 and its target genes were evaluated mouse livers and/or isolated after methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet.Liver hepatocyte expression was significantly...

A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment inflammatory monocytes macrophages (MØs). These key cellular events ALD pathogenesis may be mediated by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins microRNAs, have recently emerged as important effectors intercellular communication. We hypothesized that circulating from mice with a protein cargo characteristic the mediate biological effects activating immune...

Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes enteric microbiome composition a model early steatohepatitis dissect pathogenic role microbes alcohol-induced pathology.Wild type mice received 10-day diet that was either 5% alcohol-containing or an isocaloric control plus single binge. 16S rDNA sequencing defined bacterial communities cecum alcohol- pair-fed animals....