Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH

Welch, Ryan D.; Billon, Cyrielle; Losby, McKenna; Bedia-Diaz, Gonzalo; Yuan, Fang; Avdagic, Amer; Elgendy, Bahaa; Burris, Thomas P.; Griffett, Kristine

doi:10.3390/metabo12030238

Cited by 15 publications

(5 citation statements)

References 193 publications

(273 reference statements)

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“…Studies comparing dual TGR5 and FXR agonists (e.g., INT-767 [21,[42][43][44], BAR502 [45]) to single TGR5 or FXR agonists support this view; this is in accordance with the fact that natural bile acids activate both TGR5 and FXR, even if with different affinities. Next to bile acid receptors, the joint activation of TGR5 and other nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) or liver X receptors (LXRs) would be of interest for the treatment of NASH [46].…”

Section: Discussionmentioning

confidence: 99%

Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism

et al. 2022

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Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. Molecules developed to activate the bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5 ligands or administered pharmacological TGR5 agonists, INT-777 and RO5527239, to study the effect of TGR5 activation on liver and metabolic diseases in high-fat diet-fed foz/foz mice. Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. INT-777 and RO5527239 directly activated TGR5. INT-777 only increased the TGR5 activation capacity of the portal blood; RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved glucose tolerance. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD.

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Section: Discussionmentioning

confidence: 99%

Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism

et al. 2022

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“…Regarding hyperlipidemia, FXR overexpression suppresses mRNA levels of SREBP-1c, PEPCK, and G6Pase in the liver to reduce plasma free fatty acid levels to subsequently improve insulin resistance in db / db mice [ 105 ]. FXR is thus considered the pharmaceutical target for developing drugs for non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), and synthetic agonists, such as obeticholic acid, tropifexor, cilofexor, EDP-305, and MET-409 have been developed and used in clinical practice or under clinical trials [ 106 , 107 , 108 ].…”

Section: Fxrmentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

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Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

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“…have therapeutic potential for the treatment of NASH with fibrosis (51). PPAR agonists (PPARα and PPARγ) have been clinically used for many years as treatments for diabetes and dyslipidemia while mixed (PPARα/δ/γ) agonists have been evaluated for efficacy against NASH (52)(53)(54)(55). Here, we will focus on the LXRs, as they are master regulators of hepatic lipogenesis and are intricately involved in a variety of processes that lead to the development of MAFLD.…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

Griffett

Burris

2023

Front. Med.

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Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia.

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Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH

Cited by 15 publications

References 193 publications

Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism

Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

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