Journal
TOXICOLOGY
Volume 458, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2021.152831
Keywords
Aryl hydrocarbon receptor (AHR); Lipogenesis; Ceramide; Sptlc2
Categories
Funding
- National Institute of Environmental Health Sciences [ES004869, ES019964, ES028244, ES028288, ES026684, ES022186, S10 OD021750-01A1]
- National Natural Science Foundation of China [21577169, 21635006]
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Activation of Aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzofuran (TCDF) leads to hepatic ceramide accumulation, increased expression of ceramide biosynthetic genes, and elevated activity of their respective enzymes. AHR activation directly upregulates Sptlc2, resulting in ceramide accumulation, which promotes lipogenesis and hepatic lipid accumulation.
Aryl hydrocarbon receptor (AHR) activation via 2,3,7,8-tetrachlorodibenzofuran (TCDF) induces the accumulation of hepatic lipids. Here we report that AHR activation by TCDF (24 mu g/kg body weight given orally for five days) induced significant elevation of hepatic lipids including ceramides in mice, was associated with increased expression of key ceramide biosynthetic genes, and increased activity of their respective enzymes. Results from chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and cell-based reporter luciferase assays indicated that AHR directly activated the serine palmitoyltransferase long chain base subunit 2 (Sptlc2, encodes serine palmitoyltransferase 2 (SPT2)) gene whose product catalyzes the initial rate-limiting step in de novo sphingolipid biosynthesis. Hepatic ceramide accumulation was further confirmed by mass spectrometry-based lipidomics. Taken together, our results revealed that AHR activation results in the upregulation of Sptlc2, leading to ceramide accumulation, thus promoting lipogenesis, which can induce hepatic lipid accumulation.
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