Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr -/- mice (Taconic) were fed a control diet and exposed to 3,3\',4,4\',5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr -/-. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr -/-. The liver proteome was impacted more so by Ahr -/- genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD). Previously, we demonstrated that the PCB mixture, Aroclor1260, exacerbated NAFLD, reflective of toxicant-associated steatohepatitis, in diet-induced obese mice, in part through pregnane-xenobiotic receptor (PXR) and constitutive androstane receptor (CAR) activation. Recent studies have also reported PCB-induced changes in the gut microbiome that consequently impact NAFLD. Therefore, the objective of this study is to examine PCB effects on the gut-liver axis and characterize the role of CAR and PXR in microbiome alterations. C57Bl/6 (wildtype, WT), CAR and PXR knockout mice were fed a high fat diet and exposed to Aroclor1260 (20 mg/kg, oral gavage, 12 weeks). Metagenomics analysis of cecal samples revealed that CAR and/or PXR ablation increased bacterial alpha diversity regardless of exposure status. CAR and PXR ablation also increased bacterial composition (beta diversity) versus WT; Aroclor1260 altered beta diversity only in WT and CAR knockouts. Distinct changes in bacterial abundance at different taxonomic levels were observed between WT and knockout groups; however Aroclor1260 had modest effects on bacterial abundance within each genotype. Notably, both knockout groups displayed increased Actinobacteria and Verrucomicrobia abundance. In spite of improved bacterial diversity, the knockout groups however failed to show protection from PCB-induced hepato- and intestinal- toxicity including decreased mRNA levels of ileal permeability markers (occludin, claudin3). In summary, CAR and PXR ablation significantly altered gut microbiome in diet-induced obesity while Aroclor1260 compromised intestinal integrity in knockout mice, implicating interactions between PCBs and CAR, PXR on the gut-liver axis.

Hepatic steatosis and steatohepatitis are common histologic findings that can be caused by multiple etiologies. The three most frequent causes for steatosis/steatohepatitis are alcohol (alcoholic steatohepatitis, ASH), obesity/metabolic syndrome (nonalcoholic steatohepatitis, NASH), and environmental toxicants (toxicant-associated steatohepatitis, TASH). Hepatic steatosis is an early occurrence in all three forms of liver disease, and they often share common pathways to disease progression/severity. Disease progression is a result of both direct effects on the liver as well as indirect alterations in other organs/tissues such as intestine, adipose tissue, and the immune system. Although the three liver diseases (ASH, NASH, and TASH) share many common pathogenic mechanisms, they also exhibit distinct differences. Both shared and divergent mechanisms can be potential therapeutic targets. This review provides an overview of selected important mechanistic similarities and differences in ASH, NASH, and TASH.