Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

Ho, Peggy P.; Steinman, Lawrence

doi:10.1073/pnas.1524890113

Cited by 65 publications

(61 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The anti-inflammatory phenotype induced by GW4064-mediated activation of FXR in peripheral myeloid cells, such as BMMs, is well documented [15, 25]. However, expression of FXR is not limited to myeloid cells, but is also present in microglia as well as astrocytes [25].…”

Section: Discussionmentioning

confidence: 99%

“…In accordance with its expression pattern, FXR activation has been shown to confer protection in several animal models of innate intestinal and hepatic inflammation [11]. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), pharmacological activation of FXR significantly ameliorated the disease course by induction of anti-inflammatory macrophages [15, 25]. Interestingly, FXR agonists are currently tested in clinical trials for treatment of alcoholic hepatitis, type 2 diabetes mellitus and primary biliary cirrhosis, demonstrating that FXR already represents an attractive pharmacological target in human metabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of FXR pathway does not alter glial cell function

Albrecht

Fleck

Kirchberg

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundThe nuclear receptor farnesoid-X-receptor (FXR; NR1H4) is expressed not only in the liver, gut, kidney and adipose tissue but also in the immune cells. FXR has been shown to confer protection in several animal models of inflammation, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). FXR agonists are currently tested in clinical trials for treatment of human metabolic diseases. The beneficial effect of FXR agonists in EAE suggests that FXR might represent a potential target in inflammatory-demyelinating CNS diseases, such as MS. In MS, oligodendrocytes not only undergo cell death but also contribute to remyelination. This repair mechanism is impaired due to a differentiation block of oligodendroglial progenitor cells. Activation of other nuclear receptors that heterodimerize with FXR promote oligodendroglial differentiation. Therefore, we wanted to address the functional relevance of FXR for glial cells, especially for oligodendroglial differentiation.MethodsWe isolated primary murine oligodendrocytes from FXR-deficient (FXR Ko) and wild-type (WT) mice and determined the effect of FXR deficiency and activation on oligodendroglial differentiation by analysing markers of oligodendroglial progenitor cells (OPCs) and mature oligodendrocytes (OLs) using qRT-PCR and immunocytochemistry. Additionally, we determined whether FXR activation modulates the pro-inflammatory profile of astrocytes or microglia and whether this may subsequently modulate oligodendroglial differentiation. These in vitro studies were complemented by histological analyses of oligodendrocytes in FXR Ko mice.ResultsFXR is expressed by OPCs and mature oligodendrocytes. However, lack of FXR did not affect oligodendroglial differentiation in vitro or in vivo. Furthermore, activation of FXR using the synthetic agonist GW4064 did not affect oligodendroglial differentiation, remyelination in an ex vivo model or the expression of pro-inflammatory molecules in astrocytes or microglia. Concordantly, no effects of supernatants from macrophages cultured in the presence of GW4064 were observed regarding a possible indirect impact on oligodendroglial differentiation.ConclusionsOur data suggest that FXR is dispensable for oligodendroglial differentiation and that FXR agonists, such as GW4064, represent a potential therapeutic approach for MS which specifically targets peripheral immune cells including macrophages but not brain-resident cells, such as oligodendrocytes, astrocytes or microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0833-6) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of FXR pathway does not alter glial cell function

Albrecht

Fleck

Kirchberg

et al. 2017

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…In a recent study involving the ovalbumin-induced acute murine asthma model, CDCA administration lead to reduced infiltration of cells into the airspace and peribronchial areas, goblet cell hyperplasia, mucus secretion and serum immunoglobulin E levels, as well as reduced T helper type 2 cytokines such as IL-4, IL-5 and IL-13, and TNF-α, suggesting FXR agonists may have therapeutic potential in allergic asthma [45]. In the EAE mouse model, FXR-/-mice exhibited increased disease severity compared to wild type mice, while FXR agonist administration resulted in reduced lymphocyte activation and cytokine production, suggesting FXR agonists may also have therapeutic potential in multiple sclerosis [12].…”

Section: ) Fxrmentioning

confidence: 99%

“…Recently, bile acids were found to regulate inflammation and mediate immune homeostasis [9][10][11][12][13][14][15][16]. Moreover, natural, semi-synthetic, and fully synthetic drugs that target these receptors were developed and are currently being studied for use in various inflammatory disorders such as alcoholic hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis [17,18].…”

Section: Introductionmentioning

confidence: 99%

The Role of Bile Acid Receptors in Chronic Inflammatory Diseases

Park

2017

J Rheum Dis

View full text Add to dashboard Cite

With recent developments, biologic therapies has shown superior efficacy for rheumatic diseases compared with preexisting pharmacologic therapies, which are associated with high costs, non-response in certain patient groups, and severe adverse effects such as infections limiting their wide-spread use and revealing a need for the development of novel treatments. Since discovering the role of bile acid receptors in regulating inflammation, clinical trials evaluating the use of bile acid receptor agonists as a means to potentially treat various inflammatory disorders, such as alcoholic hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis have been ongoing. This review summarizes the results of studies on the anti-inflammatory effects and mechanisms of bile acid receptors and the results of previous to date looking at the use of bile acid receptor agonists in animal models of inflammatory disorders and clinical trials. Furthermore, we present the potentials of the bile acid receptor agonists in the treatment of inflammatory rheumatic diseases, including rheumatoid arthritis. (J Rheum Dis 2017;24:253-260)

show abstract

“…The farnesoid X receptor (FXR) is a target for bile acids. Recent extensive study of FXR has shown its ability to down‐regulate inflammation in multiple target organs including the liver, intestine and brain . Activation of FXR reduces bile acid synthesis through inhibition of cholesterol 7‐alpha‐hydroxylase (CYP7A1), known to be the rate limiting step of bile acid synthesis .…”

Section: Currently Approved Treatments For Pbcmentioning

confidence: 99%

Old and new treatments for primary biliary cholangitis

Chascsa

Carey

Lindor

2017

Liver International

View full text Add to dashboard Cite

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.

show abstract

Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

Cited by 65 publications

References 57 publications

Activation of FXR pathway does not alter glial cell function

Activation of FXR pathway does not alter glial cell function

The Role of Bile Acid Receptors in Chronic Inflammatory Diseases

Old and new treatments for primary biliary cholangitis

Contact Info

Product

Resources

About