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

Abstract

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...

FXR: a metabolic regulator and cell protector

“…BAs have been implicated in the induction of liver apoptosis and injury [76]. BAs can promote liver tumors in a HBV transgenic mouse model and are thought to induce inflammation and liver tumorigenesis in mdr-2 knockout mice [77][78][79]. This is now further confirmed in our study as feeding of a cholic-aciddiet promoted chemical-induced hepatocarcinogenesis [14].…”

Deciphering the nuclear bile acid receptor FXR paradigm

“…A BA-supplied diet in a Hepatitis B Virus (HBV) transgenic mouse model was able to promote hepatic tumors, an effect also observed in Mdr2 knock-out mice [Barone et al, 2003; Katzenellenbogen et al, 2006; Mauad et al, 1994]. Moreover, a CA diet has been shown to promote chemical-induced hepatocarcinogenesis [Yang et al, 2007].…”

Ursodeoxycholic acid — adverse effects and drug interactions

“…It is unclear so far whether treatment of primary sclerosing cholangitis with UDCA may lower the risk of development of cholangiocarcinoma by lowering the degree of inflammation around the bile ductules and ducts 78 . However, a UDCA‐enriched diet stimulated hepatocyte proliferation and tumour growth in hepatitis B virus transgenic mice 79 …”