Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Effect of Statin Use on Cancer-related Mortality in Nonalcoholic Fatty Liver Disease: A Prospective United States Cohort Study.

BACKGROUND: Indications for use of statins are common among patients with nonalcoholic fatty liver disease (NAFLD). Epidemiologic studies have suggested a possible association between statins and decreased risk of malignancies. We hypothesized that statin use has a protective effect on cancer mortality in patients with NAFLD. METHODS: Participants with NAFLD in 8 rounds of National Health and Nutrition Examination Survey (NHANES) were included in this study. Mortality data were obtained by linking the NHANES data to National Death Index. NAFLD was defined using the previously validated Hepatic Steatosis Index model. RESULTS: A total of 10,821 participants with NAFLD were included and 23% were statin users (n=2523). Statin use was associated with a 43% lower risk of cancer mortality [hazard ratio (HR)=0.57, 95% confidence interval (CI): 0.43-0.75, P<0.001] in multivariable analysis. Statin use under 1 year did not show a significant effect on cancer mortality (HR=0.72, 95% CI: 0.46-1.12), while statin use for 1 to 5 years decreased cancer mortality by 35% (HR=0.65, 95% CI: 0.42-0.99, P=0.46), and statin use >5 years decreased cancer mortality by 56% (HR=0.44, 95% CI: 0.29-0.66, P<0.001). Statin use was associated with a significant decrease in the risk of cancer mortality in NAFLD patients with both low and high risk of liver fibrosis (HR=0.55, 95% CI: 0.38-0.81; and HR=0.53, 95% CI: 0.31-0.89, respectively). CONCLUSION: Using a large US prospective cohort, we showed statin use is associated with a considerable decrease in cancer-related mortality among patients with NAFLD. These results are important for clinical decision making, as statin indications are prevalent among NAFLD patients, but many do not receive benefit in the event that the statin is discontinued due to liver test abnormalities.

Monoalkylglycerol ether lipids promote adipogenesis.

The molecular mechanisms that lead to the generation of adipose tissue (adipogenesis) are of basic and biomedical interest. Cellular models of adipogenesis have proven extremely valuable in defining biomolecules-primarily genes and proteins-that regulate adipogenesis. Here, the analysis of differentiating adipocytes using an untargeted metabolomics approach led to the discovery of the monoalkylglycerol ethers as a natural class of adipocyte differentiation factors.