Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis

Modica, Salvatore; Petruzzelli, Michele; Bellafante, Elena; Murzilli, Stefania; Salvatore, Lorena; Celli, Nicola; Tullio, Giuseppe Di; Palasciano, Giuseppe; Moustafa, Tarek; Halilbasic, Emina; Trauner, Michael; Moschetta, Antonio

doi:10.1053/j.gastro.2011.10.028

Cited by 237 publications

(179 citation statements)

References 33 publications

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“…Indeed, constitutive intestinal FXR activation has been reported to protect mice from cholestasis and to lower both biliary BA and cholesterol ( 132 ). These data seem to implicate a link between upregulation of intestinal FXR transcriptome and modulation of cell and tissue sterol content.…”

Section: Pparsmentioning

confidence: 85%

Intestinal nuclear receptors in HDL cholesterol metabolism

Degirolamo

Sabbá

Moschetta

2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org ( 2 ). At the cellular level, de novo cholesterol synthesis and uptake of lipoprotein cholesterol are modulated through a negative feedback loop responding to elevations in intracellular cholesterol and regulated by a family of membranebound transcription factors named sterol-regulatory element binding proteins (SREBPs) ( 3 ). Earlier studies by Dietschy, Spady, and colleagues ( 4-6 ) provided evidence that, although virtually every tissue can synthesize sterol from acetyl-CoA, cholesterol may also be absorbed into the body from dietary sources, thus supporting an intestinal route of sterol infl ux. The elucidation of the molecular mechanisms underlying cholesterol absorption and the identifi cation of pharmacological compounds able to interfere with the absorptive process have greatly endorsed the intestinal apical and basolateral proteins as promising targets to modulate cholesterol metabolism ( 7,8 ).The handling of cholesterol by the enterocyte controls the metabolic fate of dietary and biliary cholesterol. In the lumen of the small intestine, free cholesterol (FC) from dietary intake and biliary secretion is solubilized in mixed micelles containing BAs and phospholipids . The apical protein Niemann-Pick C1-like 1 (NPC1L1) is both the crucial and major determinant of the amount of cholesterol absorbed by the enterocytes, as both NPC1L1 defi ciency and treatment with the inhibitor ezetimibe result in a markedly reduced intestinal cholesterol absorption ( 9-13 ). Furthermore, BA presence in the intestinal lumen is an essential prerequisite for absorption to occur and, accordingly, cholesterol-7 ␣ -hydroxylase (CYP7A1)-defi cient mice, which are unable to synthesize BAs in the liver, display virtually zero cholesterol absorption ( 14 ). Abstract

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Section: Pparsmentioning

confidence: 85%

Intestinal nuclear receptors in HDL cholesterol metabolism

Degirolamo

Sabbá

Moschetta

2015

Journal of Lipid Research

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“…This hormone, when released from the gut, binds to the tyrosine kinase receptor FGF receptor 4/β-Klotho on hepatocytes, which activates the jun N-terminal kinase 1/2 signaling pathway [53]. Intestinal FXR activation [54] and the FGF19 mimetic M70 [55,56] dampen cholestatic liver injury by strongly reducing hepatic bile acid synthesis and the circulating bile acid pool. So, mouse studies clearly show hepatoprotection through (gut-specific) FGF15/19 signaling, primarily by reducing bile acid pools, sharing its mode of action with ASBT-inhibition.…”

Section: Inhibition Of Bile Acid Uptake To Ameliorate Cholestatic LIVmentioning

confidence: 99%

Bile Acid Uptake Transporters as Targets for Therapy

Slijepćević¹,

Graaf²

2017

Dig Dis

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Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

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“…Notably, activation of FXR in the intestine has been shown to control intestinal integrity, inflammation and microbiota [86,87] and to suppress intestinal tumorigenesis [88] .…”

Section: Novel Therapeutic Approaches To Psc -Therapy Tomorrowmentioning

confidence: 99%

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

Halilbasic

Fuchs

Hofer

et al. 2015

Dig Dis

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Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C₂₃ homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease.

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Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis

Cited by 237 publications

References 33 publications

Intestinal nuclear receptors in HDL cholesterol metabolism

Intestinal nuclear receptors in HDL cholesterol metabolism

Bile Acid Uptake Transporters as Targets for Therapy

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

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