A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development - 29/05/24
, Jian Li b, ⁎ , Yan You a, ⁎ Abstract |
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
The multifaceted regulatory role of FXR in NAFLD and potential agents targeting FXR for the treatment of NAFLD. The activation of FXR or antagonism of intestinal FXR exerts pleiotropic effects on NAFLD/NASH by regulating BA metabolism, lipid metabolism, and intestinal homeostasis. OCA, vonafexor, tropifexor, and HPG1860 are direct agonists of FXR, whereas HDCA, Gly-MCA, CAPE, F6, and V023–9340 exhibit inhibitory effects on intestinal FXR signaling. EMO, SS, and hyperoside have the ability to upregulate FXR expression. CSE/H2S can enhance FXR activity by facilitating FXR sulfhydration. DSF and HDCA can regulate gut microbiota to indirectly activate hepatic FXR.
The multifaceted regulatory role of FXR in NAFLD and potential agents targeting FXR for the treatment of NAFLD. The activation of FXR or antagonism of intestinal FXR exerts pleiotropic effects on NAFLD/NASH by regulating BA metabolism, lipid metabolism, and intestinal homeostasis. OCA, vonafexor, tropifexor, and HPG1860 are direct agonists of FXR, whereas HDCA, Gly-MCA, CAPE, F6, and V023–9340 exhibit inhibitory effects on intestinal FXR signaling. EMO, SS, and hyperoside have the ability to upregulate FXR expression. CSE/H2S can enhance FXR activity by facilitating FXR sulfhydration. DSF and HDCA can regulate gut microbiota to indirectly activate hepatic FXR.Le texte complet de cet article est disponible en PDF.
Highlights |
• | FXR is a crucial therapeutic target for the management of NAFLD. |
• | Dyslipidemia and pruritus remain major challenges in the development of FXR agonists. |
• | Intestinal FXR antagonists represent a promising strategy for NAFLD therapy. |
Keywords : NAFLD, Bile acid, FXR, Intestinal homeostasis, Metabolic imbalance
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Vol 175
Article 116658- juin 2024 Retour au numéro
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