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Camel milk ameliorates inflammatory mechanisms in an alcohol-induced liver injury mouse model.

ABSTRACT: Camel milk (CM) is considered to protect the liver in the practice of traditional medicine in nomadic areas. The purpose of the present study was to investigate the effects of CM on the hepatic biochemical and multiple omics alterations induced by chronic alcoholic liver disease (ALD). An intragastric gavage mice Lieber DeCarli + Gao binge model (NIAAA model) was employed to investigate the inflammatory mechanism of camel milk on the liver tissue of mice. A gut microbiota of the feces of mice and transcriptomic and proteomic analyses of the liver of mice were performed. Analysis of serum and liver biochemical indexes revealed that camel milk not only prevents alcohol-induced colonic dysfunction and lipid accumulation, but also regulates oxidative stress and inflammatory cytokine production to protect against chronic ALD in mouse. The gut microbial community of mice treated with camel milk was more similar to the untreated control group than to the model group, indicating that the intake of camel milk pre- and post-alcohol gavage effectively prevents and alleviates the intestinal microbial disorder caused by chronic alcoholism in mice. Furthermore, the results of the transcriptomic and proteomic analyses of the liver tissue showed that camel milk can improve alcoholic liver injury in mice by regulating inflammatory factors and immune system disruptions. This study provides insights into the molecular mechanism by which camel milk can be developed as a potential functional food with no side effects and against liver injury.

SUBMITTER: Ming L

PROVIDER: S-EPMC8613211 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI2) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H2 (PGH2) to PGI2. PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.

Project description:BackgroundAlcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent liver diseases that may coexist and contribute significantly to liver disease-related mortality. Obesity is a common underlying risk factor for both disorders. There has been little research investigating the combined effects of high fat diet (HFD) and alcohol. Current mouse models of alcohol- or fat-rich diet alone do not lead to severe liver injury. There is a need to develop animal models recapitulating human settings of drinking and diet to study the mechanisms of liver injury progression.MethodsC57BL6 male mice were fed either chow or HFD ad libitum for 12 weeks. A sub-set of mice from each group were also given alcohol (2?g?kg(-)(1) body weight) twice a week via intra-gastric lavage. Animals were monitored progressively for weight gain and blood and livers were harvested at termination. The extent of liver injury was examined by histopathology as well as by liver and serum biochemistry. The expression of lipid metabolism, inflammation and fibrogenesis-related molecules was examined by quantitative reverse transcription PCR (Q-PCR) and immunofluorescence staining.ResultsHFD significantly increased total body weight, triglyceride and cholesterol, whereas alcohol increased liver weight. Alcohol+HFD in combination produced maximum hepatic steatosis, increased micro- and macro-vesicular lipid droplets, increased de novo lipogenesis (steroid response-element binding protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1)) and proliferation peroxisome activated receptor alpha (PPAR?), and decreased fatty acid ?-oxidation (Acyl-CoA oxidase 1 (ACOX1)). Alcohol+HFD treatment also increased the inflammation (CD45+, CD68+, F4/80+ cells; tumour necrosis factor-alpha (TNF-?), F4/80 mRNAs) and fibrogenesis (vimentin+ activated stellate cells, collagen 1 (Col1) production, transforming growth factor-beta (TGF-?) and Col-1 mRNAs) in mice livers.ConclusionsWe report a novel mouse model with more severe liver injury than either alcohol or HFD alone recapitulating the human setting of intermittent alcohol drinking and HFD.

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Camel milk ameliorates inflammatory mechanisms in an alcohol-induced liver injury mouse model.

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