Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease

Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.

Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver

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(Cyp1 a1 and Cyp1 a2)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 ligandactivation,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.