Modulation of transport and metabolism of bile acids and bilirubin by chlorogenic acid against hepatotoxicity and cholestasis in bile duct ligation rats: involvement of SIRT1-mediated deacetylation of FXR and PGC-1α

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated.

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Bile acids elicited endothelium-dependent vasoconstrictor hypo-activity through TRPV4 channels in the thoracic aorta of bile duct ligation rats

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.10.151 ◽

2019 ◽

Vol 109 ◽

pp. 511-518

Author(s):

Hong-Qian Wang ◽

Xiao-Yan Meng ◽

Mo Chen ◽

Sai-hong Xu ◽

Mei Zhu ◽

...

Keyword(s):

Bile Duct ◽

Bile Acids ◽

Thoracic Aorta ◽

Bile Duct Ligation ◽

Duct Ligation

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Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00097.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. G319-G333 ◽

Cited By ~ 6

Author(s):

Nadine Gehrke ◽

Michael Nagel ◽

Beate K. Straub ◽

Marcus A. Wörns ◽

Marcus Schuchmann ◽

...

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Bile Acids ◽

Bile Duct Ligation ◽

Ex Vivo ◽

Mapk Signaling ◽

Caspase 8 ◽

Duct Ligation ◽

Cholestatic Liver Injury

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

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The effect of hydrophobic bile acids on gallbadder (GB) musscle function after common bile duct ligation in guinea pigs

Gastroenterology ◽

10.1016/s0016-5085(01)80068-8 ◽

2001 ◽

Vol 120 (5) ◽

pp. A14-A14

Author(s):

Z XIAO ◽

P BIANCANI ◽

J BEHAR

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Bile Acids ◽

Guinea Pigs ◽

Bile Duct Ligation ◽

Common Bile Duct Ligation ◽

Duct Ligation

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Intrinsic factor receptor activity and cobalamin transport in bile duct-ligated rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1992.262.2.g210 ◽

1992 ◽

Vol 262 (2) ◽

pp. G210-G215 ◽

Cited By ~ 1

Author(s):

S. Seetharam ◽

K. S. Ramanujam ◽

B. Seetharam

Keyword(s):

Bile Duct ◽

Bile Acids ◽

Brush Border Membrane ◽

Bile Duct Ligation ◽

Intrinsic Factor ◽

Membrane Receptor ◽

Receptor Activity ◽

Jejunal Mucosa ◽

Duct Ligation ◽

Cytosolic Factor

The intrinsic factor (IF)-cobalamin (Cbl) receptor activity in the mucosal homogenates progressively decreased after bile duct ligation in the rat, and 80% of the receptor activity was decreased in 96 h after ligation. The activity was restored to normal values of 5.5-6 pmol of IF-[57Co]Cbl bound/g mucosa when the assays were performed with both conjugated and unconjugated bile acids. When [57Co]Cbl bound to intrinsic factor was orally administered, the tissue levels of [57Co]Cbl were decreased by 75-80% in bile duct-ligated rats. The apical membrane receptor activity was also decreased after bile duct ligation; however, the activity was stimulated twofold by the addition of ileal cytosol and threefold with the addition of both ileal cytosol and taurocholate (1 mM). Enhanced binding of IF-[57Co]Cbl to the apical ileal brush-border membrane occurred with the use of dialyzed ileal cytosol but not with cytosol isolated from duodenal or proximal jejunal mucosa. The enhanced binding obtained with ileal cytosol was abolished after its treatment with trypsin. These results suggest that luminal bile acids optimize the binding of IF-Cbl by the ileal membrane receptor via interactions with a cytosolic factor and thus influence the gastrointestinal absorption of cobalamin.

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The effect of hydrophobic bile acids on gallbadder (GB) musscle function after common bile duct ligation in guinea pigs

Gastroenterology ◽

10.1016/s0016-5085(08)80068-6 ◽

2001 ◽

Vol 120 (5) ◽

pp. A14

Author(s):

Zuo-Liang Xiao ◽

Piero Biancani ◽

Jose Behar

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Bile Acids ◽

Guinea Pigs ◽

Bile Duct Ligation ◽

Common Bile Duct Ligation ◽

Duct Ligation

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Effect of cholestasis on regulation of cAMP synthesis by glucagon and bile acids in isolated hepatocytes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.1.g164 ◽

1997 ◽

Vol 273 (1) ◽

pp. G164-G174 ◽

Cited By ~ 4

Author(s):

Y. Matsuzaki ◽

B. Bouscarel ◽

M. Le ◽

S. Ceryak ◽

T. W. Gettys ◽

...

Keyword(s):

Bile Duct ◽

Bile Acids ◽

Prolonged Exposure ◽

Bile Duct Ligation ◽

Isolated Hepatocytes ◽

Bile Acid Concentration ◽

Camp Synthesis ◽

Duct Ligation ◽

Pkc Alpha ◽

Camp Formation

Previously, we have reported that bile acids can directly inhibit hormone-induced adenosine 3',5'-cyclic monophosphate (cAMP) formation through a protein kinase C (PKC)-dependent mechanism [Bouscarel, B., T.W. Gettys, H. Fromm, and H. Dubner. Am. J. Physiol. 268 (Gastrointest. Liver Physiol. 31): G300-G310, 1995]. Therefore, the regulation of cAMP synthesis by glucagon and bile acids was investigated in hepatocytes isolated after 2-day ligation of the common bile duct in Golden Syrian hamsters. The bile acid concentration was increased 30-fold in the serum, whereas it was not significantly different in the bile of duct-ligated vs. sham-operated hamsters. The glycine/taurine and cholate/chenodeoxycholate ratios were significantly increased fourfold and sevenfold, respectively, only in the serum of bile duct-ligated hamsters. Ligation of the bile duct decreased the efficacy of glucagon-stimulated cAMP synthesis by 40-50% without changing its potency. This attenuation of cAMP synthesis, which was also observed with forskolin, remained in the absence of any detectable amount of bile acids in the hepatocytes. The decrease in glucagon-stimulated cAMP production was also not attributable to changes in either the affinity or the number of receptors for this hormone. The potency and efficacy of the bile acids to inhibit glucagon-induced cAMP formation was also reduced in bile duct-ligated hamsters. The inhibitory regulation of cAMP synthesis through angiotensin II was similarly diminished after bile duct ligation. Although the total expression of PKC-alpha was not affected, an increased translocation by 60% from the cytosol to the membrane fraction was observed in hepatocytes isolated after bile duct ligation. Therefore, during cholestasis and prolonged exposure of the liver to bile acids, both the stimulatory and inhibitory regulatory, mechanisms of cAMP synthesis are compromised in an irreversible manner because the effects persist even after isolation of the hepatocytes. This decreased regulation of cAMP synthesis is possibly mediated through PKC-alpha activation.

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