FXR: structures, biology, and drug development for NASH and fibrosis diseases

Tian, Siyu; Chen, Shuming; Pan, Chengxi; Li, Yong

doi:10.1038/s41401-021-00849-4

Cited by 32 publications

(11 citation statements)

References 91 publications

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“…As mentioned earlier, a possible mechanism by which Salubrinal attenuates hepatic steatosis and fat deposition is by inhibiting ER stress and alerting autophagy via eIF2α signaling ( 25 ). The bile acid receptor farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily that is highly expressed in the liver ( 116 ). FXR ligands have many beneficial effects treating NAFLD and/or NASH by decreasing hepatic lipogenesis, steatosis, and insulin resistance while also inhibiting inflammatory and fibrogenic responses in NASH patients ( 125 – 127 ).…”

Section: Treatmentmentioning

confidence: 99%

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Zhou

Shen²,

Li³

et al. 2022

Front. Immunol.

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Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.

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Section: Treatmentmentioning

confidence: 99%

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Zhou

Shen²,

Li³

et al. 2022

Front. Immunol.

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“…FXR agonist, notably OCA, has been proved to ameliorate key components of NASH activity including impaired glucose and lipid homeostasis as well as inflammasome activation [ [25] , [26] , [27] ]. However, there are lack of systematic studies to conclude specific impacts of OCA on NASH profiles.…”

Section: Resultsmentioning

confidence: 99%

Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice

Zhuge¹,

Li²,

Yuan³

et al. 2023

Redox Biology

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“…However, this hypothesis is in contrast with the assumption of FXR activation being beneficial during NAFLD [ 69 ]. Thus, intestinal FXR antagonists are considered for the treatment of metabolic diseases: the glycine-beta-muricholic acid (namely, a tauro-beta-muricholic acid derivative) is used in experimental models of NAFLD, producing a reduction in obesity, insulin resistance, and liver fibrosis/inflammation grading [ 70 , 71 , 72 ].…”

Section: Resultsmentioning

confidence: 99%

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

et al. 2022

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Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new “actor” that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut–liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM.

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FXR: structures, biology, and drug development for NASH and fibrosis diseases

Cited by 32 publications

References 91 publications

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease

Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

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