Polyunsaturated Fatty Acids Are FXR Ligands and Differentially Regulate Expression of FXR Targets

Zhao, Annie; Yu, Jinghua; Lew, Jane-L.; Huang, Li; Wright, Samuel D.; Cui, Jisong

doi:10.1089/1044549041562267

Cited by 111 publications

(65 citation statements)

References 46 publications

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“…Thus, distinct from rosiglitazone and pioglitazone, troglitazone acted as a dual ligand for both PPAR␥ and FXR. Similar overlapping ligand specificity phenomenon has also been reported for a class of polyunsaturated fatty acids, including arachidonic acid, docosahexaenoic acid, and linolenic acid (Zhao et al, 2004). Those polyunsaturated fatty acids are endogenous agonists of PPAR, antagonists of nuclear receptor liver X receptor, and ligands of FXR differentially modulating FXR target gene expression.…”

Section: Discussionsupporting

confidence: 71%

Differential Modulation of Farnesoid X Receptor Signaling Pathway by the Thiazolidinediones

Kaimal¹,

Song²,

Yan³

et al. 2009

J Pharmacol Exp Ther

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Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are agonists of peroxisome proliferator-activated receptor (PPAR)-␥ and belong to a class of insulin-sensitizing drugs for type 2 diabetes mellitus. However, memberspecific, PPAR␥-independent activities and toxicity have been reported, especially for troglitazone. Currently, the underlying mechanisms are not fully understood. In this study, we demonstrated that troglitazone but not rosiglitazone or pioglitazone modulated expression of farnesoid X receptor (FXR) target genes bile salt export pump (BSEP) and small heterodimer partner (SHP) in Huh-7 cells. More specifically, troglitazone acted as a partial agonist of FXR to weakly increase BSEP and SHP expression but functioned as a potent antagonist to significantly suppress bile acid-induced expression. Consistent with the finding, troglitazone partially induced but markedly antagonized bile acid-mediated BSEP promoter transactivation. However, such modulating effects were not detected with rosiglitazone or pioglitazone. Using the crystal structure of ligand-bound FXR ligand binding domain (LBD), molecular docking predicted that troglitazone, but not rosiglitazone or pioglitazone, could form a stable complex with FXR LBD. The specific ␣-tocopherol side chain of troglitazone significantly contributed to the formation of such a stable complex through extensive interactions with FXR LBD. The docking model was further validated by functional analyses of a series of dockingguided FXR mutants. In summary, the data demonstrated that troglitazone, but not rosiglitazone or pioglitazone, was an FXR modulator and potently antagonized bile acid-induced expression of FXR target genes. Such differential modulation of FXR signaling pathway by TZDs may represent one of the mechanisms for member-specific, PPAR␥-independent activities and toxicity.Thiazolidinediones (TZD), including troglitazone, rosiglitazone, and pioglitazone, are a class of insulin-sensitizing drugs to treat type 2 diabetes mellitus. Such therapeutic effect of TZDs is achieved through activating nuclear receptor peroxisome proliferator-activated receptor (PPAR)-␥, which is directly involved in the regulation of genes controlling glucose homeostasis and lipid metabolism. Studies also show that TZDs exhibit other important activities, such as cardiovascular, hypertension, and anticancer effects in a PPAR␥-dependent or -independent manner (Blanquicett et al., 2008;Rizos et al., 2008).

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Section: Discussionsupporting

confidence: 71%

Differential Modulation of Farnesoid X Receptor Signaling Pathway by the Thiazolidinediones

Kaimal¹,

Song²,

Yan³

et al. 2009

J Pharmacol Exp Ther

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“…Studies have demonstrated that the FXR can also be activated via triterpenoids (e.g. forskolin) (Zhao et al, 2004) and polyunsaturated fatty acids (e.g. arachidonic acid) (Iser et al, 1975).…”

Section: Farnesoid X Receptor (Fxr)mentioning

confidence: 99%

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

Mellor

Steinmetz

Cronin

2015

Critical Reviews in Toxicology

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The development of Adverse Outcome Pathways (AOPs) is becoming a key component of 21 st century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organised toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This paper reviews and summarises the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor, and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.

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“…It has been previously reported that polyunsaturated fatty acids, specifically arachidonic acid and docosahexaenoic acid (DHA) are ligands for hFXR␣, and modulate BSEP expression (33). Because skate hepatocytes contain a high content of lipids, including DHA (24), we tested whether polyunsaturated fatty acids could activate sFxr.…”

Section: Skate Fxr Identification and Tissue Distributionmentioning

confidence: 99%

The farnesoid X receptor FXRα/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution

Cai¹,

Xiong²,

Wray³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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There is an extra sequence in the middle of the sFxr ligand binding domain (LBD) compared with the LBD of FXR␣. Luciferase reporter assays demonstrated that sFxr responds weakly to scymnol sulfate, bile salts, and synthetic FXR␣ ligands, in striking difference from human FXR␣ (hFXR␣). Interestingly, all-trans retinoic acid was capable of transactivating both hFXR␣ and sFxr. When the extra amino acids in the sFxr LBD were deleted and replaced with the corresponding sequence from hFXR␣, the mutant sFxr gained responsiveness to ursodeoxycholic acid, GW4064, and fexaramine. Surprisingly, chenodeoxycholic acid antagonized this activation. Together, these results indicate that FXR is an ancient nuclear receptor and suggest that FXR␣ may have acquired ligand specificity for bile acids later in evolution by deletion of a sequence from its LBD. Acquisition of this property may be an example of molecular exploitation, where an older molecule is recruited for a new functional role. nuclear receptor; structure/function relationship NUCLEAR RECEPTORS PLAY CRITICAL roles in development and physiology by sensing cellular levels of steroid hormones and dietary metabolites, although the true ligands for many of these receptors have not yet been identified or may even not exist. It has been demonstrated that nuclear receptors have shifted or gained their ligand specificity during evolution (4, 10); however, it remains to be determined how most nuclear receptors have acquired their ligand specificity and when this occurred in the course of evolution.FXR␣ (NR1H4) and FXR␤ (NR1H5) represent two forms of the farnesoid X receptor (FXR) in mammals, although FXR␤ is a pseudogene in humans and other primates (23). FXR␣ and FXR␤ are members of the class I nuclear receptors, which heterodimerize with the retinoid X receptors (RXR, NR2B) and regulate gene expression. FXRs share the typical structure of other members in this family, including an activation function domain 1 (AF1) at the N-terminus, followed by a conserved DNA binding domain (DBD), a ligand binding domain (LBD) that also contains an activation function domain 2 (AF2) at the C-terminus, as well as a hinge region that links the DBD and LBD (11). FXR␣ and FXR␤ share ϳ50% amino acid identity, but their ligand specificity does not overlap (23).

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Polyunsaturated Fatty Acids Are FXR Ligands and Differentially Regulate Expression of FXR Targets

Cited by 111 publications

References 46 publications

Differential Modulation of Farnesoid X Receptor Signaling Pathway by the Thiazolidinediones

Differential Modulation of Farnesoid X Receptor Signaling Pathway by the Thiazolidinediones

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

The farnesoid X receptor FXRα/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution

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