Molecular mechanisms of liver carcinogenesis related to metabolic syndrome

Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.

Chlorothalonil induces metabolic syndrome in mice by regulating host gut microbiota and bile acids metabolism via FXR pathways

Background：The most commonly used organochlorine pesticide, chlorothalonil (CHI), is ubiquitous in a natural environment and poses many adverse effects to organisms. Unfortunately, the toxicity mechanisms of CHI have not been clarified yet.Results: This study found that the low-dose CHI based on acceptable daily intake (ADI) level could induce metabolic syndrome (MetS) in mice, including obesity, hepatic steatosis, dyslipidemia, and insulin resistance. In addition, exposure to low-dose CHI could induce an imbalance in the gut microbiota of mice, resulting in a significant increase in the ratio of Firmicutes to Bacteroidetes. Furthermore, the results of the antibiotic treatment and gut microbiota transplantation experiments showed that the low-dose CHI could induce MetS in mice in a gut microbiota-dependent manner. Based on the results of targeted metabolomics and gene expression analysis, the low-dose CHI could disturb the serum metabolism of bile acids (BAs) in mice, causing the inhibition of the signal response of BAs receptor farnesol X receptor (FXR) and leading to glycolipid metabolism disorders in liver tissue and epididymal white adipose tissue (epiWAT) of mice. The administration of FXR agonist GW4064 and CDCA could significantly improve the low-dose CHI-induced MetS in mice.Conclusions: In conclusion, the low-dose CHI was found to induce MetS in mice by regulating the gut microbiota and BAs metabolism via the FXR signaling pathway. This study provides evidence linking the gut microbiota and pesticides exposure with the progression of MetS, demonstrating the key role of gut microbiota in the toxic effects of pesticides.

Interactions of Blood Serum, Urine and Fecal Metabolites of Cats Fed by Different Dietary Protein and Carbohydrate Levels

Objectives Because dietary protein and carbohydrate levels impact the gastrointestinal (GI) microbiome and host metabolism, this study evaluated their effect on serum, urine and fecal metabolites. Methods Three complete and balanced isocaloric foods (mean 3940 kcals/kg) were used. Their protein (P) and carbohydrate (CHO) levels were: LP (P: 25.84%, CHO: 46.9%), MP (P: 32.0%, CHO: 39.9%) and HP (P: 50.67%, CHO: 21.2%). The study used 30 adult healthy cats and a balanced Latin-Square design. Food offering was adjusted to maintain weight; cats were fed for 80 days before receiving the next food. This study was reviewed and approved by IACUC and all cats included in this study were allowed routine social activities. Serum (S), urine (U) and fecal (F) samples were collected at the end of each treatment period and analyzed for non-targeted metabolomics by Metabolon Inc. (Morrisville, NC). Data analysis was performed by using JMP v14.0. Variables with significance at P < 0.05 are reported. Results PCA analysis of S, U and F metabolites together shows that the cats fed HP clustered separately from the cats fed LP and MP foods. Independent PCA analysis of S, U and F metabolites revealed that F metabolites show clear separation from the cats fed HP compared with LP and MP foods. However, S and U metabolites did not show this. Fecal samples showed that carbohydrates, acylglycerols, endocannabinoids and bile acids metabolism was significantly impacted by HP when compared with LP and MP foods. This resulted in elevations of a number of toxic metabolites (e.g., 3-indoxyl sulfate, p-cresol sulfate and trimethylamine N-oxide). The F concentration of these metabolites was positively correlated to that of S and U. This positive relationship in all three sample types was not observed for acylglycerols, endocannabinoids and sugars suggesting that those metabolites were not absorbed and excreted as were the mentioned toxins. Conclusions Dietary P and CHO levels influence cat's GI metabolism with impacting specific urine and serum metabolites. Cats fed HP food had F increases of toxic metabolites related to renal and cardiovascular disorders and these metabolites were positively associated with S and U concentrations. Dietary P and CHO levels may directly impact renal and cardiovascular disorders. Funding Sources Hill's Pet Nutrition, Inc.