Dietary fatty acids and bioactive fatty acid metabolites in alcoholic liver disease

Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.

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.