Cardiac Changes in An Animal Model of Liver Disease Using Bile Duct Ligation

1. Several growth factors important in liver regeneration and fibrosis stimulate phospholipase D in plasma membranes via a receptor/G-protein-coupled mechanism resulting in hydrolysis of phosphatidylcholine to phosphatidate. Phosphatidate can be further hydrolysed to diacylglycerol by phosphatidate phosphohydrolase. Phosphatidate and diacylglycerol can act as ‘second-messengers’ and regulation of phosphatidate phosphohydrolase activity could control the balance between them. 2. A form of phosphatidate phosphohydrolase, located in the plasma membrane and insensitive to inhibition by N-ethylmaleimide, has recently been identified that is distinct from the ‘metabolic’ form, which is present in the cytosol and microsomes and is sensitive to N-ethylmaleimide. 3. We have investigated the hypothesis that the balance between regeneration and fibrosis is, in part, determined by the activity of plasma membrane phosphatidate phosphohydrolase through its effect on the phosphatidate/diacylglycerol ratio. N-Ethylmaleimide-insensitive and -sensitive phosphatidate phosphohydrolase activities were measured in three hepatic conditions characterized by regeneration and/or fibrosis: alcoholic liver disease in humans (regeneration and fibrosis) and rat livers after either acute CCl-4-induced injury (regeneration) or common bile duct ligation (fibrosis). 4. In patients with alcoholic liver disease, N-ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was higher in cirrhotic biopsies (5.82±0.3 nmol of Pi min−1 mg−1 of protein, n = 19) than in non-cirrhotic biopsies (2.17 ±0.2, n = 23) or in wedge biopsies from healthy subjects undergoing routine cholecystectomy (2.16 ±0.5, n = 6). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was unchanged in the 10 days after CCl4 treatment but increased progressively in common bile duct-ligated rats (e.g. day 28: ‘sham’ operation, 1.97 ±0.3, chronic bile duct ligation, 6.91 ±1.24 nmol of Pi min−1 mg−1 of protein). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity correlated closely with the degree of fibrosis in humans and rats. N-Ethylmaleimide-sensitive phosphatidate phosphohydrolase activity was unchanged after CCI4 treatment or common bile duct ligation and was not increased in cirrhotic livers. 5. Plasma membrane N-ethylmaleimide-insensitive phosphatidate phosphohydrolase increases in liver fibrosis but not regeneration. Stimulation of phosphatidate phosphohydrolase activity with its effect on the diacylglycerol/phosphatidate ratio may play a role in transduction of the fibrosis signal.

Download Full-text

Differential effects of malnutrition, bile duct ligation and galactosamine injection in young rats on serum levels and gene expression of IGF-binding proteins

Journal of Endocrinology ◽

10.1677/joe.0.1490465 ◽

1996 ◽

Vol 149 (3) ◽

pp. 465-472 ◽

Cited By ~ 5

Author(s):

R I G Holt ◽

A J Baker ◽

J S Jones ◽

P A Crossey ◽

N M Stone ◽

...

Keyword(s):

Gene Expression ◽

Liver Disease ◽

Bile Duct ◽

Binding Proteins ◽

Bile Duct Ligation ◽

Igf Binding Proteins ◽

Duct Ligation ◽

Igf Binding ◽

Group 2 ◽

Igfbp 3

Abstract Hepatic gene expression and circulating levels of IGF-binding proteins (IGFBP)-1 to -4 were examined in two rat models of liver disease employing acute hepatitis or chronic structural damage. The study comprised four groups: group 1 (n=6) was injected intraperitoneally with saline and food was available ad libitum (AL), group 2 (n=6) underwent bile duct ligation (BDL), group 3 (n=6) was injected with 400 mg galactosamine (GAL), group 4 (n=6) was sham-operated and pair-fed to group 2 (PF). All were killed by decapitation at day 7. Serum IGF-I, by RIA, was significantly (P<0·05) lower in the BDL group (458 ± 37 μg/l) and PF group (451 ±51 μg/l) compared with the AL group (643 ± 77 μg/l) and GAL group (720 ± 67 μg/l). Immunoblotting showed raised IGFBP-2 levels in all groups compared with AL (BDL, 167 ± 14% of AL; GAL, 173 ± 13%; PF, 149 ± 9%). IGFBP-3 was decreased in the GAL (56 ± 11%) and PF groups (66 ± 5%) but increased in the BDL group (154 ± 29%). IGFBP-4 was decreased in the GAL (76 ± 11%) and PF groups (47 ± 5%) but unchanged in the BDL group (90 ± 10%). By Northern analysis, IGFBP-1 mRNA expression was increased in the GAL (321 ± 51%) and PF groups (263 ± 12%) but reduced in the BDL group (68 ± 8%). IGFBP-2 expression increased in all groups (PF, 836 ± 19%; BDL, 683 ± 121%; GAL, 372 ± 68%) and was highest in the BDL and PF groups. IGFBP-3 expression was reduced in all groups (BDL, 57 ± 16%; GAL, 52 ± 12% PF, 51 ± 13%). IGFBP-4 expression was reduced in the GAL (30 ± 4%) and PF (28 ± 5%) groups but unchanged in the BDL group (76 ± 9%). Marked changes in gene expression of IGFBPs occurred in both models of liver disease, together with serum changes, which were different from each other and from malnutrition alone. Journal of Endocrinology (1996) 149, 465–472

Download Full-text

Activation of the Glutathione Peroxidase by Metformin in the Bile-duct Ligation induced Liver Injury: In vivo Combined with Molecular Docking Studies

Current Pharmaceutical Design ◽

10.2174/1381612824666181003114108 ◽

2018 ◽

Vol 24 (27) ◽

pp. 3256-3263 ◽

Cited By ~ 7

Author(s):

Mahboubeh Mansourian ◽

Hossein Sadeghi ◽

Amir Hossein Doustimotlagh

Keyword(s):

Antioxidant Enzymes ◽

Molecular Docking ◽

Liver Disease ◽

Bile Duct ◽

Liver Injury ◽

Glutathione Peroxidase ◽

Bile Duct Ligation ◽

Cholestatic Liver Disease ◽

Hydroxyproline Content ◽

Duct Ligation

Background: Inhibition of hepatic fibrosis is an attainable objective in managing the chronic liver disease. The present study aimed to investigate possible defensive effects of metformin on the activities of antioxidant enzymes, hydroxyproline content, and biochemical factors in bile duct ligation (BDL)-induced cholestatic rats. The interactive behavior of metformin with glutathione peroxidase (GPx) enzyme was also explained by molecular docking and conformation characterization. Methods: The present study was conducted on 28-adult male Wistar rats classified into four 7-animal groups: sham-control, mere BDL, and BDL+ metformin that received daily metformin as gavage in two doses of 250 and 500 mg/kg bw for 10 days. Biochemical analysis, hydroxyproline content, and antioxidant enzymes activity were also determined. Results: The hydroxyproline content significantly increased, but the GPx enzyme activity significantly decreased in the hepatic tissue following BDL, indicating that an oxidative stress-related model in rats was successfully constituted. Administration of metformin at two doses attenuated hydroxyproline content in the cholestatic liver and ameliorated the depletion of GPx enzyme activities compared to the non-treated BDL group (P-value ≤ 0.05). Molecular docking study provides the evidence for metformin ability to regulate enzymatic activity of GPx. Conclusion: The research data indicated that due to novel hepatoprotective effects of metformin in an animal model with BDL-induced liver injury, it was a potential beneficial therapeutic agent for treating the cholestatic liver disease. The main mechanism might contribute to antioxidant actions, particularly via GPx enzyme.

Download Full-text

Body distribution of stable copper isotopes during the progression of cholestatic liver disease induced by common bile duct ligation in mice

Metallomics ◽

10.1039/c8mt00362a ◽

2019 ◽

Vol 11 (6) ◽

pp. 1093-1103 ◽

Cited By ~ 8

Author(s):

Marta Costas-Rodríguez ◽

Sanne Van Campenhout ◽

Agustina A. M. B. Hastuti ◽

Lindsey Devisscher ◽

Hans Van Vlierberghe ◽

...

Keyword(s):

Liver Disease ◽

Bile Duct ◽

Common Bile Duct ◽

Bile Duct Ligation ◽

The Body ◽

Cholestatic Liver Disease ◽

Common Bile Duct Ligation ◽

Body Distribution ◽

Duct Ligation ◽

Severity Of The Disease

The effect of cholestatic liver disease on the body Cu isotopic distribution was investigated in a common bile duct ligation mouse model. The isotopic composition of Cu in serum and organs becomes gradually lighter with increasing severity of the disease.

Download Full-text

Experimental cholestatic liver disease through bile-duct ligation in rats results in skeletal fragility and impaired osteoblastogenesis

Journal of Hepatology ◽

10.1016/j.jhep.2003.11.032 ◽

2004 ◽

Vol 40 (3) ◽

pp. 385-390 ◽

Cited By ~ 18

Author(s):

Miron Weinreb ◽

Rivka Dresner Pollak ◽

Zvi Ackerman

Keyword(s):

Liver Disease ◽

Bile Duct ◽

Bile Duct Ligation ◽

Cholestatic Liver Disease ◽

Skeletal Fragility ◽

Duct Ligation

Download Full-text

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Cellular Physiology and Biochemistry ◽

10.1159/000475566 ◽

2017 ◽

Vol 41 (6) ◽

pp. 2133-2149 ◽

Cited By ~ 4

Author(s):

Nina Sarah Gowert ◽

Meike Klier ◽

Maria Reich ◽

Friedrich Reusswig ◽

Lili Donner ◽

...

Keyword(s):

Liver Disease ◽

Bile Duct ◽

Platelet Activation ◽

Bile Duct Ligation ◽

Thrombus Formation ◽

Bleeding Complications ◽

Cholestatic Liver Disease ◽

Triggered Release ◽

Platelet Surface ◽

Duct Ligation

Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin αIIbβ3 on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

Download Full-text