Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

Wu, Wei; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

doi:10.1016/j.bbrc.2013.11.057

Cited by 92 publications

(74 citation statements)

References 38 publications

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“…The regular Lieber-DeCarli ethanol liquid diet (ETOH group) or an isocaloric control diet (pair-fed group) were purchased from Trophic Animal Feed High-tech Co., Ltd. (Nantong, China), and were fed to the male mice ad libitum , as previously described (20). The percentages of caloric intake from ethanol (maltose dextrin), proteins, carbohydrates and fats were 35.5, 18, 11.5 and 35%, respectively.…”

Section: Methodsmentioning

confidence: 99%

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease

Wang

Zheng

et al. 2017

Molecular Medicine Reports

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Increased plasma levels of bilirubin have been reported in rat models and patients with alcoholic liver disease (ALD). The constitutive androstane receptor (CAR) is a known xenobiotic receptor, which induces the detoxification and transport of bilirubin. In the present study, the bilirubin transport regulatory mechanisms, and the role of CAR activation in hepatic and extrahepatic bilirubin clearance were investigated in a murine model of ALD. The mice were fed a Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks, followed by the administration of CAR agonists, 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB), and their vehicles to examine the effect of the pharmacological activation of CAR on serum levels of bilirubin and on the bilirubin clearance pathway in ALD by serological survey, western blotting and reverse transcription-quantitative polymerase chain reaction. The results showed that chronic ethanol ingestion impaired the nuclear translocation of CAR, which was accompanied by elevated serum levels of bilirubin, suppression of the expression of hepatic and renal organic anion transporting polypeptide (OATP) 1A1 and hepatic multidrug resistance-associated protein 2 (MRP2), and induction of the expression of UDP-glucuronosyltransferase (UGT) 1A1. The activation of CAR by TCPOBOP and PB resulted in downregulation of the serum levels of bilirubin followed by selective upregulation of the expression levels of OATP1A1, OATP1A4, UGT1A1 and MRP2 in ALD. These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.

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Section: Methodsmentioning

confidence: 99%

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease

Wang

Zheng

et al. 2017

Molecular Medicine Reports

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“…Interestingly, FXR was also found to play an important role in the pathogenesis and progression of alcoholinduced hepatic TG retention. The FXR activity was functionally impaired by chronic ethanol ingestion in a murine model of alcoholic liver disease [39] . In addition, the activation of FXR by its specific agonists, WAY-362450 or INT747, rescued the Acta Pharmacologica Sinica npg FXR activity, thereby attenuating the ethanol-induced hepatic liver injury, steatosis and cholestasis [39,40] .…”

Section: Fxr In Hepatic Triglyceride Metabolismmentioning

confidence: 99%

“…The FXR activity was functionally impaired by chronic ethanol ingestion in a murine model of alcoholic liver disease [39] . In addition, the activation of FXR by its specific agonists, WAY-362450 or INT747, rescued the Acta Pharmacologica Sinica npg FXR activity, thereby attenuating the ethanol-induced hepatic liver injury, steatosis and cholestasis [39,40] . In addition, the activation of FXR was shown to protect against fructose-induced liver steatosis [41] , suggesting several diverse roles for FXR in …”

Section: Fxr In Hepatic Triglyceride Metabolismmentioning

confidence: 99%

Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

Jiao¹,

Lu²,

Li³

2014

Acta Pharmacol Sin

155

127

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Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.

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“…FXR impairment is exhibited in the ethanol group. FXR agonist therapy is found to be hepatoprotective, likely from suppression of microsomal CYP2E1 enzyme upregulation[179]. FXR activation is shown in other studies to prevent and improve liver fibrosis in mice[180,181].…”

Section: New Therapeutic Optionsmentioning

confidence: 99%

Emerging concepts in alcoholic hepatitis

Fung¹,

Pyrsopoulos²

2017

WJH

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Severe alcoholic hepatitis is implicated as a costly, worldwide public health issue with high morbidity and mortality. The one-month survival for severe alcoholic hepatitis is low with mortality rates high as 30%-50%. Abstinence from alcohol is the recommended first-line treatment. Although corticosteroids remain as the current evidence based option for selected patients with discriminant function > 32, improvement of short-term survival rate may be the only benefit. Identification of individuals with risk factors for the development of severe alcoholic hepatitis may provide insight to the diverse clinical spectrum and prognosis of the disease. The understanding of the complex pathophysiologic processes of alcoholic hepatitis is the key to elucidating new therapeutic treatments. Newer research describes the use of gut microbiota modification, immune modulation, stimulation of liver regeneration, caspase inhibitors, farnesoid X receptors, and the extracorporeal liver assist device to aid in hepatocellular recovery. Liver transplantation can be considered as the last medical option for patients failing conventional medical interventions. Although the preliminary data is promising in patients with low risk of recividism, controversy remains due to organ scarcity. This review article comprehensively summarizes the epidemiology, pathophysiology, risk factors, and prognostic indicators of severe alcoholic hepatitis with a focus on the current and emerging therapeutics.

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Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

Cited by 92 publications

References 38 publications

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease

Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease

Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

Emerging concepts in alcoholic hepatitis

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