Lipid and Cholesterol Homeostasis after Arsenic Exposure and Antibiotic Treatment in Mice: Potential Role of the Microbiota

Arsenic-induced liver X receptor/retinoid X receptor (LXR/RXR) signaling inhibition is a potential mechanism underlying the cardiovascular effects caused by arsenic. The gut microbiota can influence arsenic toxic effects. We aimed to explore whether gut microbiota play a role in arsenic-induced LXR/RXR signaling inhibition and the subsequent lipid and cholesterol dysbiosis. Conventional and antibiotic-treated mice (AB-treated mice) were exposed to and arsenic for 2 wk. Hepatic mRNAs were extracted and sequenced. The expression levels of genes associated with LXR/RXR signaling were quantified by quantitative real-time polymerase chain reaction (qPCR), and serum and hepatic cholesterol levels were measured. Liquid chromatography-mass spectrometry (LC-MS)-based lipidomics were used to examine serum and hepatic lipids. Pathway analysis indicated that arsenic exposure differentially influenced the hepatic signaling pathways in conventional and AB-treated mice. The expression of sterol regulatory element-binding protein 1 ( ), 3-hydroxy-3-methylglutaryl-CoA reductase ( ), and cytochrome P450 family 7 subfamily A member 1 ( ), as well as cholesterol efflux genes, including ATP binding cassette subfamily G member 5/8 ( ) and cluster of differentiation 36 ( ), was lower in arsenic-exposed conventional mice but not in AB-treated mice. Similarly, under arsenic exposure, the hepatic expression of scavenger receptor class B member 1 ( ), which is involved in reverse cholesterol transport (RCT), was lower in conventional mice, but was higher in AB-treated animals compared with controls. Correspondingly, arsenic exposure exerted opposite effects on the serum cholesterol levels in conventional and AB-treated mice, i.e., higher serum cholesterol levels in conventional mice but lower levels in AB-treated mice than in respective controls. Serum lipid levels, especially triglyceride (TG) levels, were higher in conventional mice exposed to arsenic, while arsenic exposure did not significantly affect the serum lipids in AB-treated mice. Liver lipid patterns were also differentially perturbed in a microbiota-dependent manner. Our results suggest that in mice, the gut microbiota may be a critical factor regulating arsenic-induced LXR/RXR signaling perturbation, suggesting that modulation of the gut microbiota might be an intervention strategy to reduce the toxic effects of arsenic on lipid and cholesterol homeostasis. https://doi.org/10.1289/EHP4415.