Kieu Pham

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer.¹ High alcohol intake has been linked to alcoholic liver disease (ALD), cirrhosis, and HCC.² Because HCC usually occurs in patients suffering from known liver diseases like ALD, diagnosing HCC typically occurs through surveillance.² Mechanistically, alcohol induces the translocation of liposaccharide from the gut to the liver, which increases its interaction with TLR4.¹ Such interaction leads to the production of pro-inflammatory cytokines like IL-17, which has been proposed to have a role in alcohol-induced HCC tumorigenesis.^1,3 Methods: HCC was induced in mice using DEN.³ Some DEN-challenged mice were given a high EtOH diet and later experienced IL-17 signaling knock down.³ Flow cytometry experiments and subsequent mi-RNA sequencing were performed to compare the amount of circulating extracellular vesicles (EVs) and their contents between alcoholic hepatitis (AH) and control mice.⁴  Localization of EVs was determined through immunofluorescence.⁴  Current literature indicates camel milk may be a potential therapy for ALD based on its nutritional components.⁵  Triglyceride content and total cholesterol in EtOH-treated mice were measured for control mice and camel milk-treated mice.⁵ Histology of mice livers and mRNA-seq were also performed.⁵ Results: DEN-challenged EtOH-fed mice displayed increased HCC tumorigenesis compared to DEN-challenged mice with normal diet.³ However, when IL-17 signaling was knocked down in EtOH-fed DEN-challenged mice, tumorigenesis was significantly reduced compared to EtOH-fed DEN-challenged WT mice.³ The IL-17RA-deficient group showed reduced inflammation, decreased cholesterol and fatty acid levels, and reduced expression of HCC markers.³ AH mice had more circulating EVs compared to control mice.⁴ miRNAs associated with fibrosis, a progenitor to cancer, were upregulated in AH-EVs.⁴ EVs were localized to hepatic stellate cells based on fluorescence.⁴ Triglyceride and total cholesterol content in EtOH-treated mice were significantly higher compared to control mice, but this finding was reversed in EtOH+CM-fed mice.⁵ Histology showed EtOH hepatocytes had a disordered arrangement, enlargement, steatosis, and infiltration of inflammatory cells.⁵ ET+CM group hepatocytes had reduced edema, steatosis, and inflammatory cell infiltration compared to the ET group.⁵ mRNA-seq indicate multiple genes were differentially expressed in IL-17 and TNF-α signaling pathways between EtOH+CM-fed mice and EtOH mice.⁵ Conclusions: Future therapies for alcohol-related liver disease, including hepatocellular carcinoma, may aim to downregulate IL-17 signaling.³ Important next steps may include identifying the exact components of camel milk that may protect against liver disease.⁵

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