Activating FXR & LXR for fun and health
Linking water homeostasis with detoxification
Definition of a transcription factor and “classic” roles of FXR and LXR
In molecular biology, a transcription factor is a protein that allows detecting the presence of a molecule such as an hormone (e.g. vitamin D or bile acids) or a physico-chemical property (e.g. osmotic stress) and that acts so that certain genes/proteins are produced.
Like NFAT5/TonEBP already mentioned in other posts, FXR (Farnesoid X Receptor) and LXR (Liver X Receptor) are such transcription factors. Given what has been found regarding their classic roles, they are called the “yin and yang” of cholesterol and fat metabolism, as they typically have a reciprocal relation:
The elegant, dual interplay between these two receptor systems suggests that they coevolved to constitute a highly sensitive and efficient system for the maintenance of total body fat and cholesterol homeostasis. Emerging evidence suggests that the tissue-specific action of these receptors is also crucial for the proper function of the cardiovascular, immune, reproductive, endocrine pancreas, renal, and central nervous systems. Together, LXRs and FXR represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases.
LXRS AND FXR: The Yin and Yang of Cholesterol and Fat Metabolism
Other functions of LXR and FXR: water homeostasis and detoxification
LXR and FXR are involved in water homeostasis and seem to be tied to detoxification processes too. For example, in this mouse model, FXR was found to be involved in controlling some of the genes related to detoxification:
In this study, we found that FXR protein levels are elevated in the livers of Little mice of different ages. We identified novel FXREs in three xenobiotic detoxification genes belonging to different phases, Fmo3 (phase 1), Gsta2 (phase 2), and Abcb1a (phase 3), and revealed that FXR activates these genes via direct binding to these regulatory elements as a heterodimer with RXRα.
The word xenobiotic refers to something that is coming from outside the body (xeno meaning foreign) and that is generally considered toxic. These kind of substances need to be detoxified through different phases of detoxification that happen in the body, typically in the liver or the kidneys. It means that the body needs different steps to make the toxic substance more water soluble, bind it to a carrier (a step called “conjugation”) and then proceed to its excretion. This publication shows that FXR, in this species of mouse, activates important genes involved in detoxification.
The following paper also assigns a role to LXR and FXR regarding detoxification processes of mammals, while a parallel with different organisms is drawn and how their genes controlling detoxification are evolutionary related to those of mammals, proving the importance of FXR and LXR in the detoxification processes:
Up-regulation of xenobiotic detoxification genes is a transcriptomic signature shared by long-lived nematodes, flies and mice, suggesting that protection of cells from toxicity of xenobiotics may contribute to longevity. Expression of genes involved in xenobiotic detoxification is controlled by evolutionarily conserved transcriptional regulators. Three closely related subgroups of nuclear hormone receptors (NHRs) have a major role, and these include DAF-12 and NHR-8 in C. elegans, DHR96 in Drosophila and FXR, LXRs, PXR, CAR and VDR in mammals.
What is interesting is that FXR and LXR are thought to be involved in water homeostasis too:
Recently, a large body of evidence demonstrates that nuclear receptors especially PPARγ, LXRβ, FXR, GR, MR and ERα play an important role in regulating AQP2 abundance and membrane translocation (Figure 3). Dysregulated nuclear receptors may therefore contribute to the development of disorders of water balance including body fluid retention and diabetes insipidus.
According to this publication, FXR and LXR (which also belongs to what is called the nuclear receptors family) seem to have inverse actions, promoting either water retention or excretion.
Indeed, as quickly tackled at the end of my post on the link between thyroid and water homeostasis in section “Bile acids and water homeostasis”, FXR which is known to be a sensor of bile acids1, is actively involved in water reabsorption in the kidney:
FXR plays crucial roles in regulating bile acid metabolism, cholesterol homeostasis, glucose and lipid metabolism. Emerging evidence demonstrates that FXR agonists are functional for metabolic syndrome and are considered potential therapeutic agents. FXR is widely expressed in the kidneys. Under physiological conditions, it plays important roles in urine concentration by promoting water reabsorption and cell survival under hyperosmotic stress.
Role of FXR in Renal Physiology and Kidney Diseases
It is even suggested in the following publication that FXR could be a sensor of hypertonicity/hyperosmolarity itself like NFAT5 (also called TonEBP in the scientific literature) is, in the kidneys:
Similar to TonEBP, FXR may also represent a hypertonicity-responsive gene. Twenty-four-hour water restriction selectively up-regulated FXR expression in renal medulla at both mRNA and protein levels. Similarly, hypertonic stress significantly induced FXR mRNA and protein levels and its transcriptional activity in cultured MCDs. These findings demonstrate that FXR gene is transcriptionally regulated in response to hypertonicity. However, it is currently unclear whether there is a hypertonicity-responsive element in the promoter region of FXR gene. It is also uncertain whether FXR is under the transcriptional regulation of TonEBP. Addressing these important issues may significantly advance our knowledge in understanding the mechanism by which FXR is regulated and the importance of FXR in renal physiology.
Data linking water restriction/dehydration with detoxification
In nematodes, a species able to survive harsh dehydration states (with help of mechanisms involving for example osmolytes), dehydration has been found to activate genes that are related to detoxification:
Desiccated nematodes undergo extended life span, and it is critical to maintain health during such process. Our data have shown that genes that are key to xenobiotic detoxification network were activated in desiccated nematodes, suggesting the connection between desiccation and healthy aging via detoxification.
The broad induction of detoxification-related genes was the single most striking pattern to emerge from the desiccation-related transcriptome. This result is intriguing, as it parallels the broad induction of detoxification-related gene expression that has been reported in C. elegans’ stress-tolerant, growth-arrested dauer larvae and in the long-lived C. elegans daf-2 mutant (Gems and McElwee, 2005; Erkut et al., 2013). Both dauers and long-lived mutants upregulate CYPs, SDRs, UGTs and GSTs (McElwee et al., 2004). Evidence suggests that induction of the detoxification program may occur broadly in response to dehydration: several previous studies of anhydrobiotic organisms have noted upregulation of detoxification-related genes.
This data suggests that it seems like it’s not a coincidence if FXR is linked both to water homeostasis and detoxification: it even appears like detoxification is needed for their survival under these severe dehydration conditions.
In the mouse, it was found that water restriction induced an important enzyme of the first phase of detoxification called CYP3A4:
Effects of tonicity changes on in vivo CYP3A expression and function were examined in a humanized CYP3A transgenic mouse with similar tissue expression in humans. More specifically, intervention with prolonged dehydration involving alternating between 24-hour cycles of water-deprivation and water ad lib for 1 week (cyclic water-deprivation; four 24-hour water-deprivation and three 24-hour water ad lib periods), […]. Most importantly, CYP3A4 mRNA levels were noted to be elevated in the liver and kidney (11.8 ± 4.8-fold over water ad lib, n = 14, p = 0.04 and 2.2 ± 0.4-fold, n = 9, p = 0.02, respectively), with concurrent CYP3A protein and activity increase.
Hypertonicity Regulation of Cytochrome P450 CYP3A
Final nugget and conclusion
Interestingly, LXR seems to help with the production of cerebrospinal fluid:
The data show that LXR is a regulator of cerebrospinal fluid (CSF) both at the choroid plexus and at the astrocytic end feet and defects in the synthesis of cerebrospinal fluid may be targeted by LXR agonists to facilitate CSF production, turnover and clearance in CNS diseases.
Liver X receptors regulate cerebrospinal fluid production
This suggests that LXR could be linked to the glymphatic system somehow, as NFAT5 could be through the aquaporin AQP4.
Finally, we can conclude that LXR and FXR seem to be part of a regulatory system which influences, among other things, detoxification and water homeostasis. Some data suggests that water restriction could induce the detoxification machinery. How to use this knowledge in practice is another question: applying dehydration and rehydration cycles seems a good idea if someone wants to activate both LXR and FXR, provided the yin and yang relation indeed holds true for these functions.
Note: another receptor called TGR5 is also linked to both bile acids and water reabsorption in the kidneys.