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Alcohol consumption induces liver steatosis; therefore, this study investigated the possible role of adipose tissue dysfunction in the pathogenesis of alcoholic steatosis. Mice were pair-fed an alcohol or control liquid diet for 8 weeks to evaluate the alcohol effects on lipid metabolism at the adipose tissue-liver axis. Chronic alcohol exposure reduced adipose tissue mass and adipocyte size. Fatty acid release from adipose tissue explants was significantly increased in alcohol-fed mice in association with the activation of adipose triglyceride lipase and hormone-sensitive lipase. Alcohol exposure induced insulin intolerance and inactivated adipose protein phosphatase 1 in association with the up-regulation of phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling 3 (SOCS3). Alcohol exposure up-regulated fatty acid transport proteins and caused lipid accumulation in the liver. To define the mechanistic link between adipose triglyceride loss and hepatic triglyceride gain, mice were first administered heavy water for 5 weeks to label adipose triglycerides with deuterium, and then pair-fed alcohol or control diet for 2 weeks. Deposition of deuterium-labeled adipose triglycerides in the liver was analyzed using Fourier transform ion cyclotron mass spectrometry. Alcohol exposure increased more than a dozen deuterium-labeled triglyceride molecules in the liver by up to 6.3-fold. These data demonstrate for the first time that adipose triglycerides due to alcohol-induced hyperlipolysis are reverse transported and deposited in the liver.

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BackgroundPrimary or acquired resistance to cetuximab often occurs during targeted therapy in metastatic colorectal cancer (mCRC) patients. In many cancers, the key role of the long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in anticancer drug resistance has been confirmed. Emerging evidence has shown that specific exosomal lncRNAs may serve as meaningful biomarkers. In this study, we hypothesize that exosomal UCA1 might predict the response to cetuximab in CRC patients.MethodsFirst, acquired cetuximab-resistant cell lines were generated, and UCA1 expressions in these cells and their exosomes were compared. We also systematically evaluate the stability of exosomal UCA1. Thereafter, the predictive value of exosomal UCA1 in CRC patients treated with cetuximab was evaluated. Finally, through cell apoptosis assays and immunofluorescence staining, we analyzed the role of UCA1-containing exosomes in conferring cetuximab resistance.ResultsUCA1 expression was markedly higher in cetuximab-resistant cancer cells and their exosomes. Exosomal UCA1 was shown to be detectable and stable in serum from CRC patients. In addition, circulating UCA1-containing exosomes could predict the clinical outcome of cetuximab therapy in CRC patients, and UCA1 expression was considerably higher in the progressive disease/stable disease patients than in the partial response/complete response patients. Furthermore, exosomes derived from cetuximab-resistant cells could alter UCA1 expression and transmit cetuximab resistance to sensitive cells.ConclusionsWe discovered a novel role of UCA1-containing exosomes, showed their capability to transmit drug resistance and investigated their potential clinical use in predicting cetuximab resistance.

A method of employing high-resolution mass spectrometry in combination with in vivo metabolite deuterium labeling was developed in this study to investigate the effects of alcohol exposure on lipid homeostasis at the white adipose tissue (WAT)-liver axis in a mouse model of alcoholic fatty liver. In order to differentiate the liver lipids synthesized from the fatty acids that were transported back from adipose tissue and the lipids synthesized from other sources of fatty acids, a two-stage mouse feeding experiment was performed to incorporate deuterium into metabolites. Hepatic lipids extracted from mouse liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (sWAT) were analyzed. It was found that 13 and 10 triacylglycerols (TGs) incorporated with a certain number of deuterium were significantly increased in alcohol induced fatty liver at two and four weeks of alcohol feeding periods, respectively. The concentration changes of these TGs ranged from 1.7 to 6.3-fold increase. A total of 14 deuterated TGs were significantly decreased in both eWAT and sWAT at the two and four weeks and the fold-change ranged from 0.19 to 0.77. The increase of deuterium incorporated TGs in alcohol-induced fatty liver and their decrease in both eWAT and sWAT indicate that alcohol exposure induces hepatic influx of fatty acids which are released from WATs. The results of time course analysis further indicate a mechanistic link between adipose fat loss and hepatic fat gain in alcoholic fatty liver.

Altered expression of microRNA-590-5p (miR-590-5p) is involved in tumorigenesis, however, its role in colorectal cancer (CRC) remains to be determined. In this study, we focused on examining the effects of different expression levels of miR-590-5p in cancer cells and normal cells. Results showed that there are lower expression levels of miR-590-5p in human CRC cells and tissues than in normal control cells and tissues. Similarly, in our xenograft mouse model, knockdown of miR-590-5p promoted the progression of CRC. However, an overexpression of miR-590-5p in the mice inhibited angiogenesis, tumor growth, and lung metastasis. Nuclear factor 90 (NF90), a positive regulator of vascular endothelial growth factor (VEGF) mRNA stability and protein synthesis, was shown to be a direct target of miR-590-5p. The overexpression of NF90 restored VEGFA expression and rescued the loss of tumor angiogenesis caused by miR-590-5p. Conversely, the NF90-shRNA attenuated the increased tumor progression caused by the miR-590-5p inhibitor. Clinically, the levels of miR-590-5p were inversely correlated with those of NF90 and VEGFA in CRC tissues. Furthermore, knockdown of NF90 lead to a reduction of pri-miR-590 and an increase of mature miR-590-5p, suggesting a negative feedback loop between miR-590-5p and NF90. Collectively, these data establish miR-590-5p as an anti-onco-miR that inhibits CRC angiogenesis and metastasis through a new mechanism involving NF90/VEGFA signaling axis, highlighting the potential of miR-590-5p as a target for human CRC therapy.

The interactions among the gut, liver, and immune system play an important role in liver disease. Probiotics have been used for the treatment and prevention of many pathological conditions, including liver diseases. Comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOF MS) was used herein, in conjunction with chemometric data analysis, to identify metabolites significantly affected by probiotics in mice fed with or without alcohol. The metabolomics analysis indicates that the levels of fatty acids increased in mouse liver and decreased in mouse feces when mice were chronically exposed to alcohol. Supplementing the alcohol-fed mice with culture supernatant from Lactobacillus rhamnosus GG (LGGs) normalized these alcohol-induced abnormalities and prevented alcoholic liver disease (ALD). These results agree well with previous studies. In addition to diet-derived long chain fatty acids (LCFAs), LGGs may positively modify the gut's bacterial population to stimulate LCFA synthesis, which has been shown to enhance intestinal barrier function, reduce endotoxemia, and prevent ALD. We also found that several amino acids, including l-isoleucine, a branched chain amino acid, were downregulated in the liver and fecal samples from animals exposed to alcohol and that the levels of these amino acids were corrected by LGGs. These results demonstrate that LGGs alleviates alcohol-induced fatty liver by mechanisms involving increasing intestinal and decreasing hepatic fatty acids and increasing amino acid concentration.

Alcoholic liver disease (ALD) ranks among major causes of morbidity and mortality. Diet and crosstalk between the gut and liver are important determinants of ALD. We evaluated the effects of different types of dietary fat and ethanol on the gut microbiota composition and metabolic activity and the effect of these changes on liver injury in ALD. Compared with ethanol and a saturated fat diet (medium chain triglycerides enriched), an unsaturated fat diet (corn oil enriched) exacerbated ethanol-induced endotoxemia, liver steatosis, and injury. Major alterations in gut microbiota, including a reduction in Bacteroidetes and an increase in Proteobacteria and Actinobacteria, were seen in animals fed an unsaturated fat diet and ethanol but not a saturated fat diet and ethanol. Compared with a saturated fat diet and ethanol, an unsaturated fat diet and ethanol caused major fecal metabolomic changes. Moreover, a decrease in certain fecal amino acids was noted in both alcohol-fed groups. These data support an important role of dietary lipids in ALD pathogenesis and provide insight into mechanisms of ALD development. A diet enriched in unsaturated fats enhanced alcohol-induced liver injury and caused major fecal metagenomic and metabolomic changes that may play an etiologic role in observed liver injury. Dietary lipids can potentially serve as inexpensive interventions for the prevention and treatment of ALD.