Bile acid feeding induces cholangiocyte proliferation and secretion: Evidence for bile acid–regulated ductal secretion

Alpini, Gianfranco; Glaser, Shannon; Ueno, Yoshiyuki; Rodgers, Rebecca; Phinizy, Jo Lynne; Francis, Heather; Baiocchi, Leonardo; Holcomb, Leigh A.; Caligiuri, Alessandra; LeSage, Gene

doi:10.1016/s0016-5085(99)70242-8

Cited by 158 publications

(218 citation statements)

References 25 publications

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“…It should be noted that the dosage used by us 8 and by others 9 to prove the stimulatory effect of bile salts is far from that used for therapeutic purposes in humans. However, our previous findings showing that long-term administration of tauroursodeoxycholate was able to increase PCNA-LI in patients with chronic liver disease should be taken into account as well.…”

Section: Discussionmentioning

confidence: 94%

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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Hepatitis B virus (HBV) transgenic mice (official designation, Tg [Alb-1 HBV] Bri 44) invariably develop macroscopically evident tumors within the 20th month of life. Sustained proliferative activity seems to play an important role in the development of these lesions. We previously showed that ursodeoxycholate (UDC) stimulates hepatocyte proliferation in various experimental settings. Herein, we tested the assumption that biological factors able to further increase liver cell proliferation, such as UDC, could accelerate tumor development in this animal model. For this study, 22 eight-week-old male transgenic mice were divided into 2 groups; 11 animals received a standard diet, and 11 received a UDC-enriched diet. The 2 groups were further divided into 2 subgroups of 5 and 6 animals each and were sacrificed at 3 and 15 months of age, respectively. These different times were chosen to exclude diet-related toxicity (in 3-month-old mice) and evaluate tumor growth (in 15-month-old mice). In addition, hepatocyte proliferation was assessed in all animals. In 3-month-old mice receiving UDC, cholestatic and cytolytic indices as well as liver histology were comparable to those in controls. At 15 months, all UDC-treated mice showed large multinodular tumors whereas only 33% of controls developed smaller uninodular neoplasms. Hepatocyte proliferation was increased in all animals receiving UDC compared with controls. In conclusion, the increase in serum UDC (undetectable in mice fed a standard diet), in the absence of any toxic effect on the liver, suggests the involvement of this bile salt in the stimulation of hepatocyte proliferation and tumor growth. (HEPATOLOGY 2003;37:880-886.) T ransgenic mice with hepatitis B virus (HBV) sequences encoding for viral proteins pre-S, S, and X (official designation, Tg [Alb-1 HBV] Bri 44) develop progressive hepatocyte damage due to intracellular accumulation of these proteins. 1-5 During the first months of life, the hepatic damage consists of degenerative alterations. 2 Later, an active inflammatory response commences that induces a marked damage-related compensatory proliferative reaction. 3,5 Such a condition should be considered precancerous because it is constantly followed after the 8th to 9th month of life by the development of dysplastic hepatic lesions 3,4 that progress to overt liver cancer after the 12th month of life. 3 The progressive growth of these neoplastic lesions leads to macroscopic nodules that are invariably observed in all transgenic mice within the 20th month of life. 4 Interestingly, these transgenic mice, harboring hepatocellular carcinomas, do not manifest any specific alteration of known oncogenes or tumor suppressor genes at any stage of neoplastic transformation. 6 It has therefore been suggested that the damage-related sustained proliferative activity observed in the liver of these animals could play an important role in tumor development. 5 We have already shown that bile salts can stimulate proliferation in cultured hepatocytes and augment the regene...

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Section: Discussionmentioning

confidence: 94%

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Barone¹,

Maiorano

Ladisa³

et al. 2003

Hepatology

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“…Our studies were performed in normal rats fed for 1 week 1% TC or 1% TLC in AIN 76, which represent approximate doses of 275 and 260 mol/day, respectively. 12 Control rats were fed the control diet, AIN 76. In vitro studies were performed in small and large cholangiocytes from normal rats.…”

Section: Methodsmentioning

confidence: 99%

“…15 In vivo studies have also shown that a 2-to 3-fold increased biliary BA concentration (resulting from chronic feeding of TC and TLC) increases proliferative activity of the intrahepatic biliary epithelium. 12 On the basis of these findings, we proposed 12 that accumulation of BA in human cholestatic liver diseases promotes the bile duct proliferation characteristic of cholestatic liver diseases.…”

mentioning

confidence: 99%

“…In animal models, cholangiocytes markedly proliferate in response to a number of pathological maneuvers including bile duct ligation (BDL), [2][3][4][5][6] partial hepatectomy, 7,8 or feeding of carbon tetrachloride (CCl 4 ), 6,9 ␣-naphthylisothiocyanate (ANIT), 10,11 or specific bile salts. 12 In the intrahepatic biliary tree, there are different proliferative compartments that differentially respond to the aforementioned liver injury/toxins. 3,6,8,9,11 Consistent with this novel concept, in rats with BDL only large cholangiocytes undergo replication with enhanced DNA replication and increased number of large bile ducts.…”

mentioning

confidence: 99%

“…12,15 Specifically, in vitro studies have shown that both TC and TLC (at 20 mol/L) increase proliferative capacity of large (but not small) cholangiocytes from normal rats. 15 In vivo studies have also shown that a 2-to 3-fold increased biliary BA concentration (resulting from chronic feeding of TC and TLC) increases proliferative activity of the intrahepatic biliary epithelium.…”

mentioning

confidence: 99%

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Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

2001

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Vanishing Bile Duct Syndrome

Grünhage¹,

Sauerbruch²

2007

Textbook of Hepatology

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Bile acid feeding induces cholangiocyte proliferation and secretion: Evidence for bile acid–regulated ductal secretion

Abstract: These data indicate that elevated BA levels stimulate ductal secretion and cholangiocyte proliferation.

Cited by 158 publications

References 25 publications

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Influence of ursodeoxycholate-enriched diet on liver tumor growth in HBV transgenic mice

Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

Vanishing Bile Duct Syndrome

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