Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling

Marchianò, Silvia; Biagioli, Michele; Roselli, Rosalinda; Zampella, Angela; Giorgio, Cristina Di; Bordoni, Martina; Bellini, Rachele; Urbani, Ginevra; Morretta, Elva; Monti, Maria Chiara; Distrutti, Eleonora; Fiorucci, Stefano

doi:10.1016/j.bbalip.2022.159218

Cited by 11 publications

(17 citation statements)

References 65 publications

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“…However, when directly investigated, norUDCA did not activate mouse PXR or the bile acid sensing nuclear receptors, FXR, or VDR as measured using nuclear receptor-luciferase reporter assays in transfected human hepatoma Huh7 cells. These findings are in agreement with recent results showing that norUDCA did not activate or inhibit FXR in HepG2 cells transfected with a FXR reporter plasmid ( 53 ) and are consistent with previous data ( 6 ). Other hepatic gene expression pathways that were significantly induced by administration of norUDCA included those regulated by the nuclear receptor constitutive androstane receptor (CAR; NR1L3 ).…”

Section: Discussionsupporting

confidence: 94%

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Truong¹,

Li²,

Qin³

et al. 2023

JCI Insight

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Section: Discussionsupporting

confidence: 94%

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Truong¹,

Li²,

Qin³

et al. 2023

JCI Insight

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“…UDCA has been shown effective in slowing disease progression in PBC patients, thus reducing the need for liver transplantation and increasing survival rate and quality of life 62 . In contrast, several clinical trials have reported that UDCA is only partially effective in reversing histopathology and biochemical features of NASH 38 , 39 , 63 , 64 . Furthermore, while using doses higher than 15 mg/kg (recommended for PBC) seems to expand the clinical efficacy of UDCA 39 , 64 the lack of a formal trial prevents its use in the treatment of NASH.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, while using doses higher than 15 mg/kg (recommended for PBC) seems to expand the clinical efficacy of UDCA 39 , 64 the lack of a formal trial prevents its use in the treatment of NASH. We have recently shown that UDCA is a weak GPBAR1 ligand 61 and clinical studies have confirmed that UDCA increases GLP1 release form the intestine 63 and there is evidence that UDCA ameliorates insulin sensitivity in NAFLD patients. We have confirmed these findings and demonstrated that UDCA exerts some beneficial effects in our model of NASH, but it failed to improve liver histopathology 63 and did not reduced the neither hepatocytes ballooning or liver fibrosis.…”

Section: Discussionmentioning

confidence: 94%

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Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH

Marchianò

Biagioli

Morretta

et al. 2023

Sci Rep

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Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids are signaling molecules acting on two main receptors the Farnesoid-x-receptor (FXR) and G protein coupled receptor GPB AR1. Clinical trials have shown that FXR agonism might result in side effects along with lack of efficacy in restoring liver histopathology. For these reasons a multi-targets therapy combined FXR agonists with agent targeting additional molecular mechanisms might have improved efficacy over selective FXR agonists. In the present study we have compared the effects of BAR502, a dual FXR/GPBAR1 ligand) alone or in combination with ursodeoxycholic acid (UDCA) in a model of NAFLD/NASH induced by feeding mice with a Western diet for 10 weeks. The results demonstrated that while BAR502 and UDCA partially protected against liver damage caused by Western diet, the combination of the two, reversed the pro-atherogenic lipid profile and completely reversed the histopathology damage, attenuating liver steatosis, ballooning, inflammation and fibrosis. Additionally, while both agents increased insulin sensitivity and bile acid signaling, the combination of the two, modulated up top 85 genes in comparison of mice feed a Western diet, strongly reducing expression of inflammatory markers such as chemokines and cytokines. Additionally, the combination of the two agents redirected the bile acid metabolism toward bile acid species that are GPBAR1 agonist while reduced liver bile acid content and increased fecal excretion. Together, these data, highlight the potential role for a combinatorial therapy based on BAR502 and UDCA in treating of NAFLD.

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“…UDCA is a classical drug with immunomodulatory, anti-oxidant and anti-apoptotic effects. However, its effect on NAFLD/NASH has not been confirmed in clinical trials ( Marchianò et al., 2022 ). However, some derivatives of UDCA have shown good therapeutic effects in mouse NASH models, such as norUDCA, which is currently in phase II clinical trials.…”

Section: Novel Strategy For Nafld Treatment Based On Gut Microbiotamentioning

confidence: 99%

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

Fang

Yu²,

Li³

et al. 2022

Front. Cell. Infect. Microbiol.

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The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing recently and has become one of the most common clinical liver diseases. Since the pathogenesis of NAFLD has not been completely elucidated, few effective therapeutic drugs are available. As the “second genome” of human body, gut microbiota plays an important role in the digestion, absorption and metabolism of food and drugs. Gut microbiota can act as an important driver to advance the occurrence and development of NAFLD, and to accelerate its progression to cirrhosis and hepatocellular carcinoma. Growing evidence has demonstrated that gut microbiota and its metabolites directly affect intestinal morphology and immune response, resulting in the abnormal activation of inflammation and intestinal endotoxemia; gut dysbiosis also causes dysfunction of gut-liver axis via alteration of bile acid metabolism pathway. Because of its composition diversity and disease-specific expression characteristics, gut microbiota holds strong promise as novel biomarkers and therapeutic targets for NAFLD. Intervening intestinal microbiota, such as antibiotic/probiotic treatment and fecal transplantation, has been a novel strategy for preventing and treating NAFLD. In this article, we have reviewed the emerging functions and association of gut bacterial components in different stages of NAFLD progression and discussed its potential implications in NAFLD diagnosis and therapy.

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Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling

Cited by 11 publications

References 65 publications

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice

Combinatorial therapy with BAR502 and UDCA resets FXR and GPBAR1 signaling and reverses liver histopathology in a model of NASH

Gut dysbiosis in nonalcoholic fatty liver disease: pathogenesis, diagnosis, and therapeutic implications

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