Inhibition of JNK signalling mediates PPARα‐dependent protection against intrahepatic cholestasis by fenofibrate

Dai, Manyun; Yang, Jinjin; Xie, Minzhu; Lin, Jian‐Li; Luo, Moulun; Hu, Hua; Xu, Gezhi; Lin, Hante; Song, Danjun; Cheng, Yuqing; Guo, Bin; Zhao, Jinshun; Gonzalez, Frank J.; Liu, Aiming

doi:10.1111/bph.13928

Cited by 44 publications

(40 citation statements)

References 72 publications

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“…Some pilot studies demonstrated the efficacy of fenofibrate and ursodeoxycholic acid combination in patients with primary biliary cirrhosis (Ghonem & Boyer, ; Zhang et al, ). Furthermore, fenofibrate could protect ethinylestradiol and chlorpromazine‐, bile duct‐ligated‐, α‐naphthylisothiocyanate‐, and lithocholic acid‐induced cholestasis (Cindoruk et al, ; Dai et al, ; El‐Sisi, Hegazy, & El‐Khateeb, ; Zhao, Yang, Liu, et al, ). In the present study, fenofibrate protected against sunitinib‐induced liver injury.…”

Section: Discussionmentioning

confidence: 99%

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Zhao

Zhang

Xiao

et al. 2019

British J Pharmacology

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Background and Purpose Sunitinib is a small‐molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. Experimental Approach In the present study, mice were treated with 60, 150, and 450 mg·kg−1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra‐performance LC electrospray ionization quadrupole time‐of‐flight MS‐based metabolomics. Key Results Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib‐induced hepatotoxicity. Using a non‐targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid β‐oxidation (β‐FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. Conclusions and Implications These studies identified significant alterations in mitochondrial β‐FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

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Section: Discussionmentioning

confidence: 99%

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Zhao

Zhang

Xiao

et al. 2019

British J Pharmacology

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“…In this study, gemfibrozil (0.375%) and fenofibrate (0.075%) were found to be effective against MS development. This dose was only 1/3–1/2 of the clinical dose level by comparing the trough concentration between mouse model and the clinical data . Risk of adverse reactions would be considerably decreased if this low dose is proven to be effective as well in the clinic.…”

Section: Discussionmentioning

confidence: 99%

“…This dose was only 1/3-1/2 of the clinical dose level by comparing the trough concentration between mouse model and the clinical data. [38] Risk of adverse reactions would be considerably decreased if this low dose is proven to be effective as well in the clinic. So the dose-effect relationship found in this study was quite clinical relevant.…”

Section: Discussionmentioning

confidence: 99%

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

Yang

Lin

et al. 2018

Journal of Pharmacy and Pharmacology

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Objectives Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high-density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established. Methods In this study, wild-type and Ppara-null mice fed a medium fat diet (MFD) were administered gemfibrozil and fenofibrate for three months, to explore the effect and action mechanism. Key findings In Ppara-null mice, MFD treatment increased body weight, adipose tissue, serum TG, and impared glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild-type group. In 3T3-L1 adipogenic stem cells treated with high-glucose, STAT3 knockdown greatly decreased the number of lipid droplets. Conclusions Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signaling inhibition in adipose tissue, and to a lesser extent in hepatic tissues.

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“…ANIT-induced intrahepatic cholestasis was established according to previous reports (Dai et al, 2017). Briefly, mice were randomized into two groups based on body weight.…”

Section: Identification Of Differential Paracrine Fgfs Between Anit-imentioning

confidence: 99%

Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid

et al. 2019

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Endocrine fibroblast growth factor (FGF) 19 has been shown to be capable of maintaining bile acid (BA) homeostasis and thus hold promise to be a potential therapeutic agent for cholestasis liver disease. However, whether paracrine FGFs possess this BA regulatory activity remains to be determined. In our study, we identified that paracrine fibroblast growth factor 1 (FGF1) was selectively downregulated in the liver of alpha naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis mice, suggesting a pathological relevance of this paracrine FGF with abnormal BA metabolism. Therefore, we evaluated the effects of engineered FGF1 mutant-FGF1 DHBS on the metabolism of hepatic BA and found that this protein showed a more potent inhibitory effect of BA biosynthesis than FGF19 without any hepatic mitogenic activity. Moreover, the chronic administration of FGF1 DHBS protected liver against ANIT-induced injury by reducing hepatic BA accumulation. Taken together, these data suggest that FGF1 DHBS may function as a potent therapeutic agent for intrahepatic cholestasis liver disease.

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Inhibition of JNK signalling mediates PPARα‐dependent protection against intrahepatic cholestasis by fenofibrate

Cited by 44 publications

References 72 publications

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

PPARα-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling

Paracrine Fibroblast Growth Factor 1 Functions as Potent Therapeutic Agent for Intrahepatic Cholestasis by Downregulating Synthesis of Bile Acid

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