Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice

Jiang, Jingyang; Ma, Yuandi; Liu, Yameng; Lu, Dasheng; Gao, Xiaoxia; Krausz, Kristopher W.; Desai, Dhimant; Amin, Shantu; Patterson, Andrew D.; Gonzalez, Frank J.; Xie, Cen

doi:10.1002/hep4.2099

Cited by 12 publications

(6 citation statements)

References 52 publications

(71 reference statements)

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“…Reduced lipid accumulation, inflammatory response (in injury markers, ALT and AST), and collagen deposition in NAFLD and NASH models. Lower liver endoplasmic reticulum stress and proinflammatory cytokine production (97).…”

Section: Fxr Agonistsmentioning

confidence: 99%

“…Improved MASLD was explained by a decreased de novo lipogenesis in treated mice ( 118 ). Glycine-β-muricholic acid (Gly-MCA) is an FXR agonist that suppresses ceramide synthesis-related genes, thus reducing ceramide levels in the livers of treated mice ( 97 ). A generally improved inflammatory response was seen in both MASLD and MASH mice models treated with this agonist, which showed fewer injury markers and lower levels of aspartate and alanine transaminases ( 97 ).…”

Section: Experimental/clinical Evidence Of Therapies Targeting Sphing...mentioning

confidence: 99%

“…Glycine-β-muricholic acid (Gly-MCA) is an FXR agonist that suppresses ceramide synthesis-related genes, thus reducing ceramide levels in the livers of treated mice ( 97 ). A generally improved inflammatory response was seen in both MASLD and MASH mice models treated with this agonist, which showed fewer injury markers and lower levels of aspartate and alanine transaminases ( 97 ). The reduction of ceramide levels was concomitant with a lower liver ER stress and reduced proinflammatory cytokine production, which accounted for the much lower degree of inflammation in the livers of treated mice ( 97 ).…”

Section: Experimental/clinical Evidence Of Therapies Targeting Sphing...mentioning

confidence: 99%

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Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

Ramos-Molina,

Rossell,

Pérez-Montes de Oca

et al. 2024

Front. Endocrinol.

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The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.

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Section: Fxr Agonistsmentioning

confidence: 99%

Section: Experimental/clinical Evidence Of Therapies Targeting Sphing...mentioning

confidence: 99%

Section: Experimental/clinical Evidence Of Therapies Targeting Sphing...mentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

Ramos-Molina,

Rossell,

Pérez-Montes de Oca

et al. 2024

Front. Endocrinol.

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“…We have summarized the hypoglycemic mechanisms and glucose outcomes of bile acid-related drugs, as shown in Table 1. In these studies, BAs (CDCA [42,43], TUDCA [31,44,45], HCA [46], GUDCA [47]), FXR inhibitors (HS218 [48], Gly-MCA [49,50]), FXR agonists (Fexaramine [51,52], GW4064 [53,54]), FXR/TGR5 agonists (INT-767 [55]), TGR5 agonists (INT-777 [52], RO5527239 [52]), and clinical drugs (Colesevelam [56], Metformin [37,57,58], Acarbose [41], Obeticholic acid (OCA) [59][60][61]) all demonstrated hypoglycemic effects by activating different mechanisms. However, one study found that blood glucose increased in mice treated with GW4064 [62].…”

Section: Bile Acids and Diabetes Drugs (Metformin And Acarbose)mentioning

confidence: 99%

Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus

Hou,

Zhai,

Wang

et al. 2023

Diabetol Metab Syndr

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Bile acids, which are steroid molecules originating from cholesterol and synthesized in the liver, play a pivotal role in regulating glucose metabolism and maintaining energy balance. Upon release into the intestine alongside bile, they activate various nuclear and membrane receptors, influencing crucial processes. These bile acids have emerged as significant contributors to managing type 2 diabetes mellitus, a complex clinical syndrome primarily driven by insulin resistance. Bile acids substantially lower blood glucose levels through multiple pathways: BA-FXR-SHP, BA-FXR-FGFR15/19, BA-TGR5-GLP-1, and BA-TGR5-cAMP. They also impact blood glucose regulation by influencing intestinal flora, endoplasmic reticulum stress, and bitter taste receptors. Collectively, these regulatory mechanisms enhance insulin sensitivity, stimulate insulin secretion, and boost energy expenditure. This review aims to comprehensively explore the interplay between bile acid metabolism and T2DM, focusing on primary regulatory pathways. By examining the latest advancements in our understanding of these interactions, we aim to illuminate potential therapeutic strategies and identify areas for future research. Additionally, this review critically assesses current research limitations to contribute to the effective management of T2DM.

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“…Bile acids can be agonists or antagonists of FXR in a structureand concentration-dependent manner [15][16][17][18]. For instance, the main species comprising 40% of the total bile acid pool in humans, chenodeoxycholic acid (DCA), is a FXR agonist, while the main family of bile acids in mice, muricholic acids (MCAs), are generally FXR antagonists [18,19]. The activation of FXR limits intracellular bile acid levels and overall results in bile acid elimination [20].…”

Section: Introductionmentioning

confidence: 99%

The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice

Yang,

Hsiao,

Liu

et al. 2023

Toxics

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Inorganic arsenic in drinking water is prioritized as a top environmental contaminant by the World Health Organization, with over 230 million people potentially being exposed. Arsenic toxicity has been well documented and is associated with a plethora of human diseases, including diabetes, as established in numerous animal and epidemiological studies. Our previous study revealed that arsenic exposure leads to the inhibition of nuclear receptors, including LXR/RXR. To this end, FXR is a nuclear receptor central to glucose and lipid metabolism. However, limited studies are available for understanding arsenic exposure-FXR interactions. Herein, we report that FXR knockout mice developed more profound glucose intolerance than wild-type mice upon arsenic exposure, supporting the regulatory role of FXR in arsenic-induced glucose intolerance. We further exposed mice to arsenic and tested if GW4064, a FXR agonist, could improve glucose intolerance and dysregulation of hepatic proteins and serum metabolites. Our data showed arsenic-induced glucose intolerance was remarkably diminished by GW4064, accompanied by a significant ratio of alleviation of dysregulation in hepatic proteins (83%) and annotated serum metabolites (58%). In particular, hepatic proteins “rescued” from arsenic toxicity by GW4064 featured members of glucose and lipid utilization. For instance, the expression of PCK1, a candidate gene for diabetes and obesity that facilitates gluconeogenesis, was repressed under arsenic exposure in the liver, but revived with the GW4064 supplement. Together, our comprehensive dataset indicates FXR plays a key role and may serve as a potential therapeutic for arsenic-induced metabolic disorders.

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Glycine‐β‐muricholic acid antagonizes the intestinal farnesoid X receptor–ceramide axis and ameliorates NASH in mice

Cited by 12 publications

References 52 publications

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis

Research progress on the relationship between bile acid metabolism and type 2 diabetes mellitus

The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice

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