A conexão entre ácidos biliares e diabetes mellitus tipo 2 - Uma revisão / The connection between bile acids and type 2 diabetes mellitus - a review

ABSTRACT Background: Bile acids (BAs) are steroid molecules synthesized exclusively in the liver, being end products of cholesterol catabolism. BAs are known to be involved in several metabolic alterations, including metabolic syndrome and type 2 diabetes mellitus (DM2). DM2 is a chronic degenerative disease characterized by insulin resistance, insulin deficiency due to insufficient production of pancreatic ß-cells, and elevated serum glucose levels leading to multiple complications. Objective: The objective of this study is to investigate the role of BAs in the pathophysiology of DM2, highlighting the possibilities in the development of therapeutic procedures targeting BAs as an optional pathway in the treatment of DM2. Methods: The research was carried out through narrative review and publications on the relationship between BAs and DM2. The databases used for the search include PubMed, Scopus, and Web of Science. The keywords used for the search include bile acids, type 2 diabetes mellitus, metabolic syndrome, and metabolic disorders. Results: The studies have reported the involvement of BAs in the pathophysiology of DM2. BAs act as a ligand for the nuclear farnesoid X receptor, regulating glucose metabolism, lipid metabolism, and cellular energy production. Additionally, BAs modulate the production, elimination, and mobilization of BAs through the farnesoid X receptor. BAs also act as a signaling pathway through Takeda G protein-coupled receptor 5, further contributing to metabolic regulation. These findings suggest that targeting BAs may offer a novel therapeutic approach in the treatment of DM2. Conclusion: This study highlights the important role of BAs in DM2, specifically through their interactions with key metabolic pathways. Targeting BAs may represent an innovative and effective approach to the treatment of DM2.

RESUMO Contexto: Os ácidos biliares (ABs) são moléculas esteróides sintetizadas exclusivamente no fígado, sendo produtos finais do catabolismo do colesterol. Os ABs são conhecidos por estarem envolvidos em várias alterações metabólicas, incluindo a síndrome metabólica e o diabetes mellitus tipo 2 (DM2). A DM2 é uma doença crônica degenerativa caracterizada pela resistência insulínica, deficiência de insulina devido à produção insuficiente de células ß pancreáticas e hiperglicemia levando a múltiplas complicações. Objetivo: O objetivo deste estudo é investigar o papel dos ABs na fisiopatologia da DM2, destacando as possibilidades no desenvolvimento de procedimentos terapêuticos visando os ABs como uma via opcional no tratamento da DM2. Métodos: A pesquisa foi realizada por meio de revisão narrativa e publicações sobre a relação entre ABs e DM2. As bases de dados usadas para a pesquisa incluem PubMed, Scopus e Web of Science. As palavras-chave usadas para a pesquisa incluíram: ácidos biliares, diabetes mellitus tipo 2, síndrome metabólica e distúrbios metabólicos. Resultados: Os estudos relataram o envolvimento dos ABs na fisiopatologia da DM2. Os ABs atuam como ligantes para o receptor nuclear farnesoide X, regulando o metabolismo da glicose, metabolismo lipídico e produção de energia celular. Além disso, os ABs regulam a produção, eliminação e mobilização de ABs através do receptor farnesoide X. Os ABs também atuam como uma via de sinalização através do receptor acoplado à proteína G Takeda 5, contribuindo ainda mais para a regulação metabólica. Esses achados sugerem que o ABs pode oferecer uma nova abordagem terapêutica no tratamento da DM2. Conclusão: Este estudo destaca o papel importante do ABs na DM2, especificamente por meio de suas interações com vias metabólicas-chave. O redirecionamento ao ABs pode representar uma abordagem inovadora e eficaz para o tratamento da DM2.

Fexaramine improves non-alcoholic fatty liver disease in mice by stimulating intestinal FXR / 药学学报

Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of metabolic syndrome and has become one of the chronic diseases that endanger health around the world. There is still a lack of effective therapeutic drugs in clinical practice. Farnesoid X receptor (FXR) has been a popular target for NAFLD research in recent years. Fexaramine (Fex) is a potent and selective agonist of FXR, and its mechanism of action to improve NAFLD is unclear. Therefore, in this study, a mouse model of NAFLD was constructed using a high-fat, high-cholesterol diet and treated with Fex orally for 6 weeks. We evaluated the ameliorative effect of Fex on disorders of glucolipid metabolism in NAFLD mice, and preliminarily explored its potential mechanism of action. The animal experiments were approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval number: PZSHUTCM210913011). In this study, it was found that 100 mg·kg-1 Fex significantly inhibited body weight gain, alleviated insulin resistance, improved liver injury and lipid accumulation in NAFLD mice. The effect of Fex on the expression of hepatic intestinal FXR and its target genes in NAFLD mice was further examined. Analysis of serum and hepatic bile acid profiles and expression related to hepatic lipid metabolism. It was found that Fex could stimulate intestinal FXR, promote fibroblast growth factor 15 (FGF15) secretion, inhibit the expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, regulate bile acid synthesis by negative feedback, and improve the disorder of bile acid metabolism. At the same time, Fex reduces liver lipid synthesis and absorption, increases fatty acid oxidation, thus improving liver lipid metabolism. This study shows that Fex can improve NAFLD by activating intestinal FXR-FGF15 signal pathway and regulating liver lipid metabolism.

Effects and mechanism of Hugan buzure formula on intrahepatic cholestatic liver injury in rats / 中国药房

OBJECTIVE To study the effects of Hugan buzure formula （HBF） on intrahepatic cholestatic liver injury in rats and its potential mechanism. METHODS Rats were randomly divided into control group， model group， ursodeoxycholic acid （UDCA） group （positive control， 60 mg/kg ） and HBF low-dose， middle-dose and high-dose groups （HBF-L， HBF-M， HBF-H groups， 0.4， 0.8， 1.6 g/kg ）， with 6 rats in each group. The rats in each drug group were given the corresponding drug solution intragastrically， once a day， for 7 consecutive days. The rats in the control group and the model group were given equal volumes of water intragastrically. On the 5th day， except for the control group， the rats in other groups were single intragastrically administered with alpha-naphthyl isothiocyanate olive oil solution （100 mg/kg） to establish the model. After 48 h of modeling， the contents of liver function indexes （aspartate aminotransferase， alanine aminotransferase， alkaline phosphatase， total bile acid， total bilirubin， direct bilirubin） and oxidative stress indexes [malondialdehyde （MDA）， glutathione （GSH）， superoxide dismutase] in serum of rats were detected； the pathological changes of liver tissue were observed. The mRNA expressions of inflammation-related factors [tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）] and farnesoid X receptor （FXR） signaling pathway-related factors [FXR， small heterodimer partner （SHP）， multidrug resistance protein 2 （MRP2）， bile salt export pump （BSEP）， Na+-taurocholate cotransporting polypeptide （NTCP）， organic anion-transporting polypeptide 2 （OATP2） and cholesterol 7α-hydroxylase （CYP7A1）]， the expressions of FXR signaling pathway-related proteins （FXR， MRP2， BSEP， NTCP） and nuclear factor- κB p65 （NF- κB p65） in liver tissue were detected.RESULTS Compared with the model group， the contents of liver function indexes and the level of MDA in serum， the mRNA expressions of the above inflammation-related factors and CYP7A1， and the relative expression of NF-κB p65 in liver tissue were significantly decreased； the levels of GSH in serum， the mRNA expressions of FXR， SHP， MRP2， BSEP， NTCP and OATP2， and the relative expressions of FXR， MRP2， BSEP and NTCP in liver tissue were significantly increased （P＜0.05 or P＜0.01）； the pathological changes of liver tissue were significantly improved. Only some indexes in HBF-L group， HBF-M group and UDCA group were significantly reversed （P＜0.05 or P＜0.01）. CONCLUSIONS HBF can prevent intrahepatic cholestatic liver injury in rats， and the effects may be related to the activation of FXR signaling pathway and the reduction of inflammation and oxidative stress.

Association between bile acids and nonalcoholic fatty liver disease / 临床肝胆病杂志

With the rapid increase in the prevalence rate of nonalcoholic fatty liver disease (NAFLD), new treatment methods are needed to prevent disease progression to liver fibrosis, liver cirrhosis, and liver cancer. Although great efforts have been made to clarify the pathological mechanisms of NAFLD disease progression, there are still no effective treatment methods at present. Bile acids (BAs) regulate systemic metabolism by activating nuclear receptors and G protein-coupled receptors and have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis is associated with the severity of NAFLD. This article summarizes the important ligands in BA metabolism and their role in the progression of NAFLD, in order to provide a basis for the treatment of NAFLD by targeting BA messengers.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Effect of Modified Gegen Qinliantang on FXR/SHP/PPARα Signaling Pathway in Type 2 Diabetic db/db Mice / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Gegen Qinliantang on the expression levels of proteins related to the farnesoid X receptor/small heterodimer partner/peroxisome proliferator-activated receptor α （FXR/SHP/PPARα） signaling pathway in the liver tissue of db/db model mice with type 2 diabetes mellitus （T2DM） and explore the underlying mechanism of action of modified Gegen Qinliantang. MethodThirty db/db mice were randomly divided into model group， metformin group （0.2 g·kg-1）， and high-， medium-， and low-dose modified Gegen Qinliantang groups （31.9， 19.1， 6.4 g·kg-1）， with 6 mice in each group. An additional six m/m mice were assigned to the blank group. Respective drugs were administered via oral gavage for 12 weeks. Mouse body weight， fasting blood glucose （FBG）， total cholesterol （TC）， triglyceride （TG）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） levels were measured. Oil red O staining was used to observe hepatic lipid accumulation and periodic acid-schiff （PAS） staining was used to assess hepatic glycogen deposition. Ammonium ferric sulfate staining was used to observe cholesterol deposition in intestinal tissues. Western blot was employed to detect the expression of FXR， cholesterol 7α-hydroxylase （CYP7A1）， SHP， and PPARα proteins in liver tissues， and enzyme-linked immunosorbent assay （ELISA） was used to measure serum free fatty acid （FFA） levels. ResultAt the end of the treatment， compared with the blank group， the model group exhibited significant increases in mouse body weight， FBG， FFA， TC， TG， and LDL-C levels （P<0.01）， along with significant hepatic lipid droplets， reduced hepatic glycogen， noticeable cholesterol accumulation in intestinal tissues， significantly decreased expression of FXR， SHP， PPARα proteins， and significantly increased expression of CYP7A1 protein in liver tissues （P<0.01）. Compared with the model group， the metformin group and the high- and medium-dose modified Gegen Qinliantang groups demonstrated significant reductions in mouse body weight， FBG， FFA， TC， TG， LDL-C levels （P<0.05， P<0.01）， significant increases in HDL-C levels （P<0.05， P<0.01）， decreased hepatic lipid accumulation， increased hepatic glycogen， reduced intestinal cholesterol accumulation， significantly increased expression of FXR， SHP， PPARα proteins， and significantly decreased expression of CYP7A1 protein in liver tissues （P<0.01）. ConclusionModified Gegen Qinliantang may regulate the FXR/SHP/PPARα signaling pathway to suppress FFA levels and improve lipid metabolism in T2DM mice.

Effect of Modified Da Chaihutang on FXR/FGF15/FGFR4 Signaling Pathway in Mice with Cholesterol Gallstone Differentiated into Damp-Heat Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Da Chaihutang on cholesterol gallstone （CS） in mice due to damp-heat based on the farnesoid X receptor （FXR）/fibroblast growth factor 15 （FGF15）/fibroblast growth factor receptor 4 （FGFR4） pathway and explore the molecular biological mechanisms of CS differentiated into damp-heat syndrome from the perspective of correspondence between prescription and syndrome. MethodForty-eight six-week-old mice were randomly divided into the blank group， model group， modified Da Chaihutang （23.4 g·kg-1） group， and ursodeoxycholic acid （0.12 g·kg-1） group， with 12 mice in each group. The ones in the latter three groups were exposed to "internal dampness + external dampness + high-cholesterol diet" for 12 weeks for inducing CS due to damp-heat. Mice in the modified Da Chaihutang group and ursodeoxycholic acid group were gavaged with the corresponding drugs， while those in the model and blank groups with the same amount of normal saline for a total of four weeks. Before and after modeling， mice in each group were subjected to open field tests for determining their activities and mental states. Such general conditions as body mass， food intake， fur， and urine and stool of mice in each group were observed and recorded weekly for judging the damp-heat syndrome. After the intervention， the sampled liver and gallbladder tissues of mice in each group were stained with hematoxylin-eosin （HE） staining， and the serum γ-glutamyltransferase （GGT）， alkaline phosphatase （ALP）， and total bilirubin （TBIL） were determined. The total cholesterol （TC） and total bile acid （TBA） contents in bile were measured by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of FXR， FGF15， FGFR4， and cholesterol 7α-hydroxylase gene （CYP7A1） were assayed by real-time fluorescence quantitative polynucleotide chain reaction （Real-time PCR） and Western blot. ResultCompared with the blank group， the model group exhibited enlarged gallbladder， brown turbid bile with flocculent precipitation visible to the naked eye， obvious damp-heat syndrome， lipoid degeneration in the liver tissue， rough and thickened gallbladder wall， elevated ALP， GGT， and TBIL in serum （P<0.01） and TC in bile （P<0.01）， reduced TBA （P<0.01）， up-regulated FXR， FGF15， and FGFR4 mRNA and protein expression in ileum （P<0.05， P<0.01）， and down-regulated CYP7A1 mRNA and protein expression （P<0.01）. Compared with the model group， the two medication groups displayed improved bile turbidity， and the bile in the modified Da Chaihutang group became clearer. After intervention， the damp-heat syndrome of mice in the modified Da Chaihutang group was significantly alleviated. The liver and gallbladder lesions of mice in the two medication groups were significantly relieved， manifested as reduced serum ALP， GGT， and TBIL （P<0.01）. The reduction in ALP and TBIL of the modified Da Chaihutang group was more significant （P<0.01）. The TC contents in the bile of mice from the two medication groups were significantly lowered， whereas the TBA contents were elevated （P<0.01）， with more significant changes present in the modified Da Chaihutang group （P<0.01）. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the modified Da Chaihutang group were down-regulated （P<0.05， P<0.01）， while the mRNA and protein expression levels of CYP7A1 rose （P<0.05）， except that the elevation in FGF15 and FGFR4 protein expression and reduction in CYP7A1 protein expression were not significant. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the ursodeoxycholic acid group all decreased， among which the reduction in FXR was remarkable （P<0.05）， and the mRNA and protein expression levels of CYP7A1 were significantly up-regulated （P<0.05）. ConclusionModified Da Chaihutang significantly improves the stone， liver function， bile composition， abnormal cholesterol-bile acid metabolism， and damp-heat syndrome in the model mice of CS differentiated into damp-heat syndrome， which may be related to its regulation of key factors FXR， FGF15， FGFR4， and CYP7A1 mRNA and protein expression in the cholesterol-bile acid metabolism pathway.

Knockout of farnesoid X receptor gene aggravates cisplatin-induced kidney injury / 中南大学学报(医学版)

OBJECTIVES@#Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand activated transcription factors and belongs to bile acid receptor. Studies have shown that the expression of FXR in renal tissue can reduce renal injury via regulation of glucose and lipid metabolism, inhibition of inflammatory response, reduction of oxidative stress and renal fibrosis. However, it is unclear whether FXR is involved in autophagy in renal diseases. This study aims to investigate the role of FXR in cisplatin-induced acute renal injury and whether its mechanism is related to autophagy regulation.@*METHODS@#Twelve male WT or FXR-KO mice at 12 weeks were randomly divided into a WT group, a WT+cisplatin group, a FXR-KO group, and a FXR-KO+cisplatin group, with 6 mice in each group. The WT+cisplatin group and the FXR-KO+cisplatin group were intraperitoneally injected with cisplatin (20 mg/kg), and the WT group and the FXR-KO group were intraperitoneally injected with equal volume of cisplatin solvent. Seventy-two hours later, the mice were killed and blood and renal tissue samples were collected. The levels of SCr and BUN were detected by immunoturbidimetry. After the staining, the pathological changes of renal tissue were observed under optical microscope. The protein levels of LC3 and p62 were detected by Western blotting and immunohistochemistry. The clearance of damaged mitochondria and the accumulation of lysosomal substrate were observed under electron microscope. The apoptosis of renal tubular epithelial cells was detected by TUNEL.@*RESULTS@#Compared with the WT group or the FXR-KO group, both SCr and BUN levels in the WT+cisplatin group or the FXR-KO+cisplatin group were significantly increased (P<0.01 or P<0.001), and SCr and BUN levels in the FXR-KO+cisplatin group were significantly higher than those in the WT+cisplatin group (both P<0.05). Under the light microscope, there were no obvious pathological changes in the renal tissue of mice in the WT group and the FXR-KO group. Both the WT+cisplatin group and the FXR-KO+cisplatin group had vacuolar or granular degeneration of renal tubular epithelial cells, flat cells, lumen expansion, brush edge falling off, and even exposed basement membrane and tubular formation. The scores of renal tubular injury in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the score in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05). Under the transmission electron microscope, the mitochondria of mouse tubular epithelial cell in the WT+cisplatin group and the FXR-KO+cisplatin group was swollen, round, vacuolated, cristae broken or disappeared; the lysosome was uneven and high-density clumps, and the change was more obvious in the FXR-KO+cisplatin group. Western blotting showed that the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased in the WT+cisplatin group compared with the WT group and the FXR-KO+cisplatin group compared with FXR-KO group (P<0.05 or P<0.01); compared with the FXR-KO group, the ratio of LC3-II to LC3-I was decreased and the expression of p62 was increased significantly in the FXR-KO+cisplatin group (both P<0.05). Immunohistochemistry results showed that the expression of total LC3 and p62 in renal cortex of the WT+cisplatin group and the FXR-KO+cisplatin group was increased significantly, especially in the FXR-KO+cisplatin group. TUNEL results showed that the mice in the WT group and the FXR-KO group had negative staining or only a few apoptotic tubular epithelial cells, and the number of apoptotic cells in the WT+cisplatin group and the FXR-KO+cisplatin group were increased. The apoptosis rates of renal tubular epithelial cells in the WT+cisplatin group and the FXR-KO+cisplatin group were significantly higher than those in the WT group and the FXR-KO group, respectively (both P<0.001), and the apoptosis rate in the FXR-KO+cisplatin group was significantly higher than that in the WT+cisplatin group (P<0.05).@*CONCLUSIONS@#Knockout of FXR gene aggravates cisplatin induced acute renal injury, and its mechanism may be related to inhibiting autophagy and promoting apoptosis.

Non-alcoholic fatty liver disease: Epidemiology, pathophysiology and an update on the therapeutic approaches

Non-alcoholic fatty liver disease (NAFLD) denotes a spectrum of fatty liver disease in individuals without significant alcohol consumption. NAFLD is set to be the most common etiology of serious liver diseases in numerous nations when accompanied by obesity and type 2 diabetes. It is further histologically categorized into the non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and non-alcoholic steatohepatitis (NASH) which is characterized by the coexistence of hepatic steatosis and inflammation and is accompanied by hepatocyte injury (ballooning), either with or without fibrosis. NAFL is considered the benign and reversible stage arising from the excessive accumulation of triglycerides in hepatocytes. However, NASH is a more progressive stage of NAFLD, due to the increased risks of evolving more serious diseases such as cirrhosis, hepatocellular carcinoma. This concept, however, has been lately challenged by a hypothesis of multiple parallel hits of NAFLD, in which steatosis and NASH are separate entities rather than two points of the NAFLD spectrum, not only from a set of histological patterns but also from a pathophysiological perspective. The current review highlights the epidemiology and pathophysiology of NAFLD, and its progression towards steatohepatitis, with special focus on the novel imminent therapeutic approaches targeting the molecular aspects and the pathogenic pathways involved in the development, and progression of NAFLD.

Application of farnesoid X receptor agonists in treatment of nonalcoholic steatohepatitis / 临床肝胆病杂志

Nonalcoholic steatohepatitis (NASH) is a liver disease with a relatively high prevalence worldwide and greatly threatens human health. In recent years, farnesoid X receptor-related drugs have played an important role in regulating the metabolism of bile acid, glucose, and lipids and inhibiting inflammation. This article summarizes the application of farnesoid X receptor agonists in the treatment of NASH, so as to provide a basis for the prevention and treatment of NASH.

Expression of farnesoid X receptor in colorectal cancer and its clinical significance / 肿瘤研究与临床

Objective:To investigate the expression changes of farnesoid X receptor (FXR) in the evolution of normal intestinal mucosa, colorectal adenoma (CRA) and colorectal cancer (CRC), and the correlation of FXR expression with clinicopathological features and prognosis of patients with colorectal tumors.Methods:The UALCAN website tool was used to analyze the expression level of FXR gene transcripts of CRC and normal colorectal tissues in The Cancer Genome Atlas (TCGA) database. The patients undergoing colonoscopy and treatment in the Aerospace Center Hospital from January 2019 to September 2020 were selected, and the immunohistochemistry was used to detect the expression of FXR protein in 100 CRA tissues, 47 CRC tissues and 11 normal colonic mucosal tissues from healthy people (healthy control). Combining with clinical data, the relationship between FXR protein expression and clinicopathological characteristics of patients with colorectal tumors was analyzed. According to the Kaplan-Meier Plotter online database, the median expression level of FXR gene transcripts in CRC patients was analyzed, and the patients were divided into FXR low-expression group and high-expression group, the relationship between the expression of FXR gene and prognosis of CRC patients was investigated.Results:The analysis of data from TCGA database showed that the expression level of FXR gene transcripts in CRC tissues was lower than that in normal colorectal tissues ( P < 0.01). Immunohistochemical examination of the collected tissues showed that the positive rate of FXR protein gradually decreased from the cecum to the rectum. The positive rates of FXR protein in healthy control, CRA patients and CRC patients were 90.9% (10/11), 24.0% (24/100), 6.3% (3/47), and the difference was statistically significant ( χ2 = 35.56, P < 0.01); the positive rate of FXR protein in cancer tissues from CRC patients was lower than that in normal tissues adjacent to cancer [6.3% (3/47) vs. 65.2% (15/23)], and the difference was statistically significant ( χ2 = 27.98, P < 0.01). There was no statistical difference in the positive rate of FXR among CRA patients with different gender, age, maximum diameter of adenoma, and aggression (all P > 0.05). There was also no statistical difference in the positive rate of FXR among CRC patients with different gender, age, tumor site, maximum diameter of tumor, degree of differentiation, TNM staging, and vascular tumor thrombus (all P > 0.05). According to the survival analysis of Kaplan-Meier Plotter online database, the recurrence-free survival of CRC patients with high expression of FXR was better than that of patients with low expression of FXR ( P = 0.003). Conclusions:The expression level of FXR gradually decreases in the intestinal tissues of healthy people, CRA patients and CRC patients. The prognosis of CRC patients with low FXR expression is poor.

Research progress on the role of bile acids in regulating glycolipid metabolism / 药学学报

Bile acids (BAs) are increasingly being appreciated as signaling molecules. Studies have shown that BAs regulate glucose and lipid metabolism mainly through the intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5). FXR and TGR5 are highly expressed in the intestine. This article summarizes the synthesis, circulation, and regulation of BAs, as well as the effects of BAs on glycolipid metabolism through activation of liver FXR and inhibition or activation of intestinal FXR and TGR5. Furthermore, we illustrate the molecular mechanism of BAs on glycolipid metabolism by the relevant signaling pathways, including small heterodimer partner (SHP), fibroblast growth factor 15/19 (FGF15/19), ceramide and glucagon like peptide-1 (GLP-1). This review may serve as a reference for basic and clinical studies.

Research on Therapeutic Mechanism of Canhuang Tablets on Jaundiced Rats Induced by ANIT / 中国实验方剂学杂志

Objective:To explore the therapeutic mechanism of Canhuang tablets on the mRNA and protein expression of farnesoid X receptor (FXR), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and multidrug resistance associated protein 2 (MRP2) in the liver of jaundiced rats induced by α-naphthalene isothiocyanate (ANIT). Method:The rats were divided into normal group, model group, Canhuang tablets (CHP) group and ursodeoxycholic acid tablets (UDCA) group. The jaundice model was reproduced by ANIT. After the intervention of the corresponding drugs, the contents of total bilirubin (TBIL), total bile acid (TBA), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum and the liver histopathology were examined to evaluate the therapeutic effect of CHP. The relative mRNA and protein expressions of FXR, UGT1A1 and MRP2 in rat liver tissues were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Result:CHP can significantly reduce the increase of TBIL, TBA, ALT, AST and ALP caused by ANIT in rat serum, and inhibit the liver pathological changes, which showed that the removing jaundice effect of CHP was better than UDCA. Compared with the normal group, ANIT significantly inhibited the mRNA levels of FXR, UGT1A1 and MRP2 in rat liver tissues after modeling (P<0.01). Compared with the model group, CHP and UDCA significantly increased the mRNA levels of target genes of each protein after intervention (P<0.01), and CHP was superior to UDCA in improving the mRNA level of bilirubin metabolizing enzyme UGT1A1 (P<0.01). In the aspect of affecting protein expression, compared with the normal group, ANIT modeling significantly increased the expression of FXR in rats (P<0.05). CHP intervention showed a tendency to promote the expression of FXR, while UDCA did not, but there was no significant difference between them. In the aspects of promoting bilirubin metabolism and bile excretion, the expressions of UGT1A1 and MRP2 were significantly decreased by ANIT modeling (P<0.01), while the expressions of UGT1A1 and MRP2 proteins were significantly increased after treatment of CHP (P<0.01). CHP was superior to UDCA in increasing the expression of bilirubin and bile acid efflux protein MRP2 (P<0.01). Conclusion:The jaundice abating mechanism of CHP is related to activating FXR mRNA expression in liver, promoting the mRNA and protein expression of bilirubin metabolizing enzyme UGT1A1 and bile acid transporter MRP2, improving liver metabolism of free bilirubin and promoting bile acid excretion from the liver, and alleviating cholestatic liver injury.

Advances in farnesoid X receptor antagonists and their pharmacological activities / 中国临床药理学与治疗学

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily. It has extensive physiological functions in maintaining homeostasis of bile acids, lipids, and glucose. It also participates in the development of various tumors. Therefore, regulation of its transcriptional activity is accepted as an important strategy for treatment of many diseases, and various FXR agonists have been developed. In recent years, it has been found that inhibition of FXR transcriptional activity also shows beneficial effects on various diseases, therefore several FXR antagonists have been developed and their pharmacological activities have been tested in preclinical animal models. This article provides an update review on FXR antagonists and their pharmacological activities.

Alterations in bile acid levels in metabolic diseases and related treatment strategies / 上海交通大学学报（医学版）

Bile acid as a signaling molecule can specifically bind to bile acid receptors (such as farnesoid X receptor and G-protein-coupled bile acid receptor) to mediate a series of biological regulation reactions. In recent years, it has been found that bile acids are widely involved in glucose metabolism, lipid metabolism and energy metabolism. The development of metabolic diseases is usually accompanied by the changes of bile acid profiles and receptors, and thus bile acids may be applied as potential biomarkers for clinical diagnosis, prediction, and evaluation of therapeutic effects. This article reviews the relationship between bile acids and metabolic diseases, and the treatment of metabolic diseases based on the regulation of bile acid metabolism.

Activation of farnesoid X receptor by GW4064 inhibits invasive growth of colon cancer cells and expression of stromal cell-derived factor 1 / 第二军医大学学报

Objective To explore the mechanism by which specific agonist of farnesoid X receptor (FXR) GW4064 inhibits the growth and invasion of colon cancer cells. Methods Human colon cancer cell lines HT-29 were in vitro cultured. After treatment with GW4064 of 0, 0.1, 1, 3, 5, 7 and 10 μmol/L for 72 h, cell viability was measured by MTT assay. After treatment with GW4064 of 0, 1 and 5 μmol/L for 24 h, the cell morphology was observed under phase contrast microscope, and the mRNA expression levels of FXR and stromal cell-derived factor 1 (SDF-1) were detected by PCR. After treatment with GW4064 of 0 and 1 μmol/L for 24 h, the cell invasive ability was detected by cell scratch test. After treatment with GW4064 of 0, 1, 5 and 7 μmol/L for 24 h, the SDF-1 expression in the culture medium was detected by ELISA. Nude mouse. tumorigenesis model was established by subcutaneous inoculation of HT-29 cells. After intragastric administration with GW4064 or DMSO for 16 d, the tumor growth and the mRNA expression of FXR and SDF-1 in the tumors were determined. ResultsGW4064 inhibited the growth of HT-29 cells in a dose-dependent manner, and there was significant difference in the cell viability of HT-29 cells between the GW4064 groups (1, 3, 5, 7 and 10 μmol/L) and the control group (0 μmol/L, all P<0.05). After treatment with GW4064, phase contrast microscopy showed contracted and rounded colon cancer cells and slender cells transforming into epidermoid cells. The cell scratch test showed that the invasion ability of the colon cancer cells was significantly reduced after treatment with GW4064 compared with the control group (0 μmol/L, P<0.05). PCR results showed that the mRNA expression level of FXR was increased in a dose-dependent manner after GW4064 treatment, while the expression of SDF-1 mRNA changed in the opposite way. ELISA results showed that the SDF-1 expression in the cell culture supernant was decreased with the increase of GW4064 concentrations, and there were significant differences between the GW4064 (1, 5 and 7 μmol/L) groups and the control group (0 μmol/L, P<0.05). GW4064 significantly reduced tumor size compared with the control group (DMSO, P<0.05). In addition, the mRNA expression of FXR in the tumors was increased, and the mRNA expression of SDF-1 was decreased. ConclusionThe activation of FXR can inhibit the invasive growth of colon cancer cells and the expression of SDF-1.

The mechanism and research progress of obeticholic acid in the intervention of non-alcoholic fatty liver disease / 国际药学研究杂志

Non-alcoholic fatty liver disease(NAFLD)is a relatively common chronic liver disease with imbal- anced lipid metabolism, and its incidence is increasing year by year. NAFLD is closely related to bile acid excretion, ab- normal bile acid synthesis and liver fibrosis. Farnesolid X receptor(FXR)regulates bile acid transport, inhibits bile acid synthesis and resists liver fibrosis. Obeticholic acid is a targeted drug for the treatment of NAFLD targeting the farnesol X receptor, which can effectively regulate fat metabolism and blood sugar balance. This review summarizes the mechanism and research progress of obeticholic acid intervention in NAFLD, and provides a theoretical basis for its foundamental re- search and clinical application.

Bile-ology: from bench to bedside / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Bile acids (BAs) are originally known as detergents essential for the digestion and absorption of lipids. In recent years, extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes, including glucose and lipid metabolism, energy expenditure, inflammation, tumorigenesis, cardiovascular disease, and even the central nervous system in addition to cholesterol homeostasis, enterohepatic protection and liver regeneration. BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs. The signaling actions of BAs can also be mediated through specific nuclear receptors and membrane-bound G protein-coupled receptors. Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling. In this mini-review, we summarize recent advances in bile-ology, focusing on its translational studies.

Regulation of bile acid metabolism-related signaling pathways by gut microbiota in diseases / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. Bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial–host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.