Hepatocellular carcinoma in a mouse model fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet

Abstract

SummaryHepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). However, details of the liver‐specific molecular mechanisms responsible for the NAFLD–NASH–HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis‐associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis.

Reduced Serum Cholesterol and Triglyceride Levels in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet (CDAHFD)-Induced Mouse Model of Non-alcoholic Steatohepatitis (NASH)

“…Hepatic Lipid Contents as Well as Serum Lipid Concentrations Histological analyses showed remarkable accumulation of lipid droplets and leukocytes, as well as fibrosis in livers of mice fed CDAHFD, but not SD, as previously described (data not shown). 8) Liver TG contents were significantly higher in mice fed CDAHFD (205.2 ± 9.2 mg/g) than those in mice fed SD (32.8 ± 24.3 mg/g, Fig. 2A).…”

“…7) More recently, a choline-deficient L-amino acid-defined high fat diet (CDAHFD) model has been developed in mice, in order to improve above points. Mice fed CDAHFD showed hepatic fibrosis much earlier than CDAA 8) and finally HCC. 9) However, relevance of this CDAHFD model with human NASH disease phenotypes has not yet been fully elucidated.…”

Towards a definite mouse model of NAFLD

“…Indeed, some mitigation of HFD-induced obesity and metabolic syndrome features has also been reported to occur with other protocols that induce progressive NASH in mice, based on studies of mice that develop fibrosing NASH when fed an HFD that is deficient in choline and restricted in methionine (CDAA-HFD diet model). 11,12 Importantly however, in all the aforementioned NASH models, mice do not lose sufficient weight to fall below the weight of chowfed controls or become hypoglycemic, as occurs when mice are fed strict methionine/choline-deficient diets for 6-8 weeks to rapidly induce pathology that resembles fibrosing NASH in humans. Further, all of the more metabolically-temperate models that gradually induce fibrosing NASH in mice activate hepatic stellate cells, evoke a ductular reaction, and eventually promote adenomatous hyperplasia and HCC development.…”

“…Interestingly, 100% of mice fed CDAA-HFD for 36 weeks were reported to have NASH, advanced fibrosis, and hepatic adenomas without overt HCCs and despite switching back to a standard diet at 37 weeks, many of these mice exhibited fibrosis progression, and 67% had demonstrable HCCs at 48 weeks. 11,12 Hence, some NASH protocols seem to evoke pathology that persists/progresses after NASH-inducing insults are withdrawn and thus, may model the subgroup of patients with NAFLD and inherently progressive liver damage.…”

18f-FDG Pet/Ct as an Assessment Tool of Hepatocellular Carcinoma Secondary to Non-Alcoholic Fatty Liver Disease Development in Experimental Model

“…Two models were developed with C57BL/6J rats, genetically predisposed, after high-fat diet consume. The study DIAMOND used high-fat diet in association to ad libitum consume of glucose and fructose (7) , in the meantime the other study used choline-deficient, L-aminoacid-defined, highfat diet (CDAHFD) (22) . In the DIAMOND model, the HCC was developed in 89% of the studied rats between 32 and 52 weeks of experimentation.…”