Chronic Activation of LXRα Sensitizes Mice to Hepatocellular Carcinoma

Yang Xie, Runzi Sun, Li Gao, Jibin Guan, Jingyuan Wang, Aaron Bell, Junjie Zhu, Min Zhang, Meishu Xu, Peipei Lu, Xinran Cai, Songrong Ren, Pengfei Xu, Satdarshan P. Monga, Xiaochao Ma, Da Yang, Yulan Liu, Binfeng Lu, Wen Xie

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


The oxysterol receptor liver X receptor (LXR) is a nuclear receptor best known for its function in the regulation of lipid and cholesterol metabolism. LXRs, both the α and β isoforms, have been suggested as potential therapeutic targets for several cancer types. However, there was a lack of report on whether and how LXRα plays a role in the development of hepatocellular carcinoma (HCC). In the current study, we found that systemic activation of LXRα in the VP-LXRα knock-in (LXRαKI) mice or hepatocyte-specific activation of LXRα in the VP-LXRα transgenic mice sensitized mice to liver tumorigenesis induced by the combined treatment of diethylnitrosamine (DEN) and 3,3',5,5'-tetrachloro-1,4-bis (pyridyloxy) benzene (TCPOBOP). Mechanistically, the LXRα-responsive up-regulation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and the complement system, and down-regulation of bile acid metabolism, may have contributed to increased tumorigenesis. Accumulations of secondary bile acids and oxysterols were found in both the serum and liver tissue of LXRα activated mice. We also observed an induction of monocytic myeloid–derived suppressor cells accompanied by down-regulation of dendritic cells and cytotoxic T cells in DEN/TCPOBOP-induced liver tumors, indicating that chronic activation of LXRα may have led to the activation of innate immune suppression. The HCC sensitizing effect of LXRα activation was also observed in the c-MYC driven HCC model. Conclusion: Our results indicated that chronic activation of LXRα promotes HCC, at least in part, by promoting innate immune suppressor as a result of accumulation of oxysterols, as well as up-regulation of the IL-6/Janus kinase/STAT3 signaling and complement pathways.

Original languageEnglish (US)
Pages (from-to)1123-1139
Number of pages17
JournalHepatology Communications
Issue number5
StatePublished - May 2022
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the National Institutes of Health (DK117370 and ES030429 to W.X.).

Funding Information:
Wen Xie is supported in part by the Joseph Koslow Endowed Professorship provided by the University of Pittsburgh School of Pharmacy. The authors thank Laura Dubois for the sample preparation, data collection, data analysis, and report writing; J. Will Thompson and Matt Foster for the data analysis and report review; and Arthur Moseley for the scientific oversight, at the Duke University School of Medicine, for the use of the Proteomics and Metabolomics Shared Resource, which provided the service of oxysterol analysis.

Publisher Copyright:
© 2022 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.


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