Conditional loss of geranylgeranyl diphosphate synthase alleviates acute obstructive cholestatic liver injury by regulating hepatic bile acid metabolism

FEBS Journal ◽  
2020 ◽  
Vol 287 (15) ◽  
pp. 3328-3345
Author(s):  
Wen‐Jun Jia ◽  
Qiao‐Li Tang ◽  
Shan Jiang ◽  
Shi‐Quan Sun ◽  
Bin Xue ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Hepatic Bile ◽  
Cholestatic Liver Injury

scholarly journals Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

2013 ◽  
Vol 272 (3) ◽  
pp. 816-824 ◽  
Author(s):  
Jie Liu ◽  
Yuan-Fu Lu ◽  
Youcai Zhang ◽  
Kai Connie Wu ◽  
Fang Fan ◽  
...  
Keyword(s):  
Bile Acid ◽  
Liver Injury ◽  
Oleanolic Acid ◽  
Acid Metabolism ◽  
Bile Acid Metabolism ◽  
Cholestatic Liver Injury

Allopurinol Protects Against Cholestatic Liver Injury in Mice Not Through Depletion of Uric Acid

2021 ◽  
Author(s):  
Jing Liu ◽  
Yang Fan ◽  
Hang Yu ◽  
Tong Xu ◽  
Chunze Zhang ◽  
...  
Keyword(s):  
Uric Acid ◽  
Bile Acid ◽  
Liver Injury ◽  
Liver Diseases ◽  
Acid Metabolism ◽  
Glutathione Depletion ◽  
Bile Acid Metabolism ◽  
New Perspective ◽  
Cholestatic Liver Injury

Abstract Cholestasis is one of the most severe manifestations of liver injury and has limited therapeutic options. Allopurinol (AP), an inhibitor of uric acid (UA) synthesis, was reported to prevent liver damage in several liver diseases. However, whether AP protects against intrahepatic cholestatic liver injury and what is the role of UA in the pathogenesis of cholestasis remain unknown. In this study, we reported that AP attenuated liver injury in a mouse model of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). AP showed no significant effect on glutathione depletion, inflammation, or bile acid metabolism in livers of ANIT-treated mice. Instead, AP significantly improved fatty acid β-oxidation in livers of ANIT-treated mice, which was associated with activation of PPARα. The protective effect of AP on cholestatic liver injury was not attributable to the depletion of UA, because both exogenous and endogenous UA prevented liver injury in ANIT-treated mice via inhibition of NF-kB-mediated inflammation. In conclusion, the present study provides a new perspective for the therapeutic use of AP and the role of UA in cholestatic liver injury.

scholarly journals Sortilin 1 Loss-of-Function Protects Against Cholestatic Liver Injury by Attenuating Hepatic Bile Acid Accumulation in Bile Duct Ligated Mice

2017 ◽  
Vol 161 (1) ◽  
pp. 34-47 ◽  
Author(s):  
Jibiao Li ◽  
Benjamin L Woolbright ◽  
Wen Zhao ◽  
Yifeng Wang ◽  
David Matye ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Liver Injury ◽  
Loss Of Function ◽  
Hepatic Bile ◽  
Acid Accumulation ◽  
Cholestatic Liver Injury

scholarly journals Inulin Supplementation Disturbs Hepatic Cholesterol and Bile Acid Metabolism Independent from Housing Temperature

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3200
Author(s):  
Mira J. Pauly ◽  
Julia K. Rohde ◽  
Clara John ◽  
Ioannis Evangelakos ◽  
Anja Christina Koop ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Metabolism ◽  
Plasma Cholesterol ◽  
Cold Treatment ◽  
Short Chain Fatty Acids ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism ◽  
Short Term ◽  
Hepatic Bile ◽  
Brown Adipose

Dietary fibers are fermented by gut bacteria into the major short chain fatty acids (SCFAs) acetate, propionate, and butyrate. Generally, fiber-rich diets are believed to improve metabolic health. However, recent studies suggest that long-term supplementation with fibers causes changes in hepatic bile acid metabolism, hepatocyte damage, and hepatocellular cancer in dysbiotic mice. Alterations in hepatic bile acid metabolism have also been reported after cold-induced activation of brown adipose tissue. Here, we aim to investigate the effects of short-term dietary inulin supplementation on liver cholesterol and bile acid metabolism in control and cold housed specific pathogen free wild type (WT) mice. We found that short-term inulin feeding lowered plasma cholesterol levels and provoked cholestasis and mild liver damage in WT mice. Of note, inulin feeding caused marked perturbations in bile acid metabolism, which were aggravated by cold treatment. Our studies indicate that even relatively short periods of inulin consumption in mice with an intact gut microbiome have detrimental effects on liver metabolism and function.

scholarly journals Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

2021 ◽  
Vol 22 (15) ◽  
pp. 7898
Author(s):  
Grigorios Christidis ◽  
Ersin Karatayli ◽  
Rabea A. Hall ◽  
Susanne N. Weber ◽  
Matthias C. Reichert ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Liver Injury ◽  
Fibroblast Growth Factor ◽  
Acid Metabolism ◽  
Regulatory Mechanism ◽  
Chronic Liver ◽  
Bile Acid Metabolism ◽  
Fibroblast Growth ◽  
Chronic Liver Injury

Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4−/− (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.

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