Liver X Receptor (LXR) activation leads to liver steatosis

Of the originating work: Brigitte Landesmann, Marina Goumenou, Sharon Munn and Maurice Whelan, Joint Research Centre, European Commission, Ispra, Italy

Of the content populated in the AOP-Wiki:  John R. Frisch and Travis Karschnik, General Dynamics Information Technology, Duluth, Minnesota; Daniel L. Villeneuve, US Environmental Protection Agency, Great Lakes Toxicology and Ecology Division, Duluth, MN

Liver X receptor (LXR) belongs to a class of nuclear receptors [Arhyl hydrocarbon receptor (AHR), Constitutive androstane receptor (CAR), Oestrogen receptor (ER), Farnesoid X receptor (FXR), Glucocorticoid receptor (GR), Peroxisome proliferator-activated receptor (PPAR), Pregnane X receptor (PXR), Retinoic acid receptor (RAR)] that are needed for normal liver function, but for which increased activaton (i.e. activation by binding by chemical stressors) can lead to liver injury, including steatosis (Mellor et al. 1996).  An increasing number of chemical stressors have been shown to increase LXR activation (Moya et al. 2020).  Activation of LXR has been linked to increased expression of a group of genes (ChREBP, SREBP-1c, FAS and SCD1) involved in increasing de novo fatty acid synthesis (Mellor et al. 1996, Schultz et al. 2000, Postic and Girard 2008).  Increases in de novo fatty acid synthesis is one of the main pathways for increases in triglycerides in livers (Angrish et al. 2016).  Increases in triglycerides can result in histological changes to cell structure and disruption of normal biochemical function, ultimately resulting in steatosis as a primary adverse outcome (Angrish et al. 2016; Mellor et al. 1996).

This Adverse Outcome Pathway (AOP) was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki.  The originating work for this AOP was: Landesmann, B., Goumenou, M., Munn, S., and Whelan, M.  2012.  Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity.  European Commission Report EUR 25631, 49 pages.  https://op.europa.eu/en/publication-detail/-/publication/d2b09726-8267-42de-8093-8c8981201d65/language-en This publication, and the work cited within, were used create and support this AOP and its respective KE and KER pages.

Flame retardants are of environmental and human health concern because of increased use and ability to leach into the environment.  Exposure concerns include effects on reproduction, development, neurology, and endocrine pathways (Negi et al. 2021).   This AOP focuses on a subset of endocrine disruption related to loss of lipid homeostasis, specifically the pathway in which activation of Liver X Receptor (LXR) leads to liver steatosis through increased de novo fatty acid synthesis.  Environmental stressors result in activation of nuclear receptors linked to increases in triglyceride accumulation through several pathways.  One of the primary pathways linked to triglyceride accumulation, and focus of this AOP, is through activation of the LXR gene and coordinated molecular responses leading to increased de novo fatty acid synthesis.  This pathway has been particularly well studied in mammals (humans, lab mice, lab rats).

The focus of the originating work was to use an AOP framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD).  Landesmann et al. (2012) provided initial network analysis based on literature review of empirical studies with focus on pathways leading to liver steatosis.  The authors then used the AOP framework to identify a pathway: 1. originating with LXR activation; 2. intermediate steps increased gene expression of ChREBP, SREBP-1c, FAS, and SCD1; 3. increased de novo fatty acid synthesis; 4. liver triglyceride accumulation; 5. organelle, cellular, and tissue steps leading to steatosis.  

The originating authors conducted a literature search to develop a database of publications categorized by discipline or field of study: toxicology, epidemiology, exposure, and gene-environment interaction. The literature search relied on standard search engines such as Web of Science and Google Scholar, and the search strategy focused on toxicants known to disrupt lipid pathways in organisms, and diet studies with elevated levels of lipids. The originating authors reviewed references from individual citations to identify additional studies not captured through the literature search itself. They then included all relevant publications through 2023. Only studies focused primarily on developmental or neurotoxic endpoints were included; those focused on carcinogenesis or other systemic effects were not included unless there was a particular relevance to a neurotoxic or developmental outcome.

The scope of the aforementioned EPA project was limited to re-representing the AOP(s) as presented in the originating publication. The literature used to support this AOP and its constituent pages began with the originating publication and followed to the primary, secondary, and tertiary works cited therein. KE and KER page creation and re-use was determined using Handbook principles where page re-use was preferred.  

The authors of AOP 518 also referred to AOP 34: LXR activation leading to hepatic steatosis by Marina Goumenou, coauthor of Landesmann et al. (2012).  In contrast to AOP 34, we have condensed the number of key events leading to de novo fatty acid synthesis.  We recognize that there is a complex interaction of genes within organisms, and focus attention on the role of upregulation of genes linked to increased LXR expression, leading to increased de novo fatty acid synthesis.

Angrish, M.M., Kaiser, J.P., McQueen, C.A., and Chorley, B.N.  2016. Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis.  Toxicological Sciences 150(2): 261-268.

Landesmann, B., Goumenou, M., Munn, S., and Whelan, M.  2012.  Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity.  European Commission Report EUR 25631, 49 pages.  https://op.europa.eu/en/publication-detail/-/publication/d2b09726-8267-42de-8093-8c8981201d65/language-en

Mellor, C.L., Steinmetz, F.P., and Cronin, T.D.  2016.  The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways.  Critical Reviews in Toxicology, 46(2): 138-152.

Moya, M., Gomez-Lechon, M.J., Castell, J.V., and Jovera, R.  2010.  Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile.  Chemico-Biological Interactions 184: 376–387.

Negi, C.K., Bajard, L., Kohoutek, J., and Blaha, L.  2021.  An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis.  Environmental Pollution 289: 117855.

Postic, C. and Girard, J.  2008.  Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.  The Journal of Clinical Investigation 118(3): 829-838.

Schultz, J.R., Tu, H., Luk, A., Repa, J.J., Media, J.C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D.J., Lustig, K.D., and Shan, B.  2000.  Role of LXRs in control of lipogenesis.  Genes and Development 14:2831–2838.