Journal of Hepatology, Volume 76, February 2022,
Background & aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. Methods: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. Results: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. Conclusions: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. Lay summary: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.
4,4' Isopropylidenediphenol; Adult; Adverse Event; Alanine Aminotransferase; Alanine Aminotransferase Blood Level; Alkaline Phosphatase; Alkaline Phosphatase Blood Level; Amino Acid; Amino Acids; Animal; Animal Experiment; Animal Model; Animals; Article; Aspartate Aminotransferase; Aspartate Aminotransferase Blood Level; Basal Metabolic Rate; Bile Acid; Bile Acid Blood Level; Bile Acid Metabolism; Biological Variation; Blood; Ceramide; Chemical Exposure; Cholesterol; Cholesterol Synthesis; Cholic Acid; Cohort Analysis; Cohort Studies; Complication; Controlled Study; Deoxycholic Acid; Diabetes Mellitus; Diacylglycerol; Disease Model; Disease Models, Animal; Environmental Exposure; Exposome; Fat Content; Fatty Acid; Fatty Acids, Nonesterified; Female; Fibrosis; Fluorination; Gamma Glutamyl Transferase Blood Level; Gamma Glutamyltransferase; Glucose; Glucose Blood Level; Glucose Metabolism; Glycochenodeoxycholic Acid; Glycocholic Acid; Glycohyocholic Acid; HOMA Index; Homeostasis Model Assessment; Human; Human Tissue; Humans; Immunology; Insulin; Insulin Blood Level; Lathosterol; Lipid; Lipid Liver Level; Lipid Metabolism; Lipidome; Liver Biopsy; Liver Metabolism; Macrosteatosis; Major Clinical Study; Male; Mass Spectrometry; Metabolic Pathway; Metabolic Regulation; Metabolism; Metabolome; Metabolomics; Mice; Middle Aged; Mouse; Non-alcoholic Fatty Liver Disease; Non-alcoholic Steatohepatitis; Nonalcoholic Fatty Liver; Nonalcoholic Steatohepatitis; Nonhuman; Perfluorinated Alkyl Substance; Perfluoro Compound; Perfluorononanoic Acid; Perfluorooctanesulfonic Acid; Perfluorooctanoic Acid; Peroxisome Proliferator Activated Receptor Alpha; Phosphatidylcholine; Phosphatidylethanolamine; Physiology; Sex Difference; Sphingomyelin; Tauro Beta Muricholic Acid; Taurochenodeoxycholic Acid; Taurocholic Acid; Triacylglycerol; Unclassified Drug; Upregulation; Global