Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

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...

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Vydáno v:	Journal of hepatology Ročník 76; číslo 2; s. 283 - 293
Hlavní autoři:	Sen, Partho, Qadri, Sami, Luukkonen, Panu K., Ragnarsdottir, Oddny, McGlinchey, Aidan, Jäntti, Sirkku, Juuti, Anne, Arola, Johanna, Schlezinger, Jennifer J., Webster, Thomas F., Orešič, Matej, Yki-Järvinen, Hannele, Hyötyläinen, Tuulia
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Netherlands Elsevier B.V 01.02.2022 Elsevier Science Ltd
Témata:	Adult Amino Acids - analysis Amino Acids - blood Animal models Animals Bile bile acid Bile acids Biopsy chemical exposure Cohort Studies Contaminants Disease Models, Animal Environmental Exposure - adverse effects Environmental Exposure - statistics & numerical data Epidemiology exposome Fatty Acids, Nonesterified - analysis Fatty Acids, Nonesterified - blood Fatty liver Female Females fibrosis Glucose metabolism Humans Lipid metabolism Lipid Metabolism - immunology Lipid Metabolism - physiology lipidome Lipids Liver diseases Male Mass spectroscopy metabolic pathway Metabolic pathways Metabolism metabolome Mice Middle Aged non- alcoholic steatohepatitis Non-alcoholic Fatty Liver Disease - complications Non-alcoholic Fatty Liver Disease - metabolism perfluorinated alkyl substance Sex differences metabolic pathway exposome bile acid perfluorinated alkyl substance fibrosis lipidome chemical exposure metabolome non-alcoholic steatohepatitis
ISSN:	0168-8278, 1600-0641, 1600-0641
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Shrnutí:	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. 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. 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. 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. 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. [Display omitted] •Environmental contaminants may contribute to the initiation and development of NAFLD.•Exposure to PFAS is associated with the alteration of bile acid profiles and NAFLD-related pathways in the human liver.•Other lipid-related changes may be secondary to the interplay between PFAS and bile acid metabolism.•Females may be more sensitive to the harmful impacts of PFAS than males.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0168-8278 1600-0641 1600-0641
DOI:	10.1016/j.jhep.2021.09.039