Liver Lipids of Patients with Hepatitis B and C and Associated Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.

Accumulation of cholesterol, triglycerides and ceramides in hepatocellular carcinomas of diethylnitrosamine injected mice

“…The decline of SMs in the murine tumors reveals an involvement of sphingomyelinases [ 5 , 84 ]. In strong contrast to the murine situation, in most human HCC tissues ceramide levels are low while SM concentrations increase [ 5 , 26 , 85 ]. Thus the animal model described herein may be used to study the molecular adaption of liver tumor cells, which succeed to survive and proliferate despite high endogenous ceramide levels.…”

“…HCCs are heterogeneous tumors and disease etiology may affect tumor-associated lipid composition [ 85 ]. DEN-injected C3H/HeNRj mice fed a low methionine, choline-deficient diet were used to study HCC development in non-alcoholic steatohepatitis.…”

Lipid alterations in chronic liver disease and liver cancer

“…Hepatic steatosis is often associated with both HBV and HCV infections, 51 , 52 , 61 as well as being observed in HBx (HBx protein is crucial in HBV tumorigenesis) transgenic 62 , 63 and HCV transgenic mouse models. 64 Hence, viral hepatitis leads to prominent changes in both the serum 61 and hepatic (tumour and tumour-adjacent compartments) 65 lipidomes ( Table 1 ). Indeed, the blood FA composition is significantly altered in HBV- and HCV-infected patients.…”

Hepatocyte expressed chemerin-156 does not protect from experimental non-alcoholic steatohepatitis

“…Cholesterol concentrations of the two human hepatocyte cell lines were rather similar. In the murine and human liver triglyceride levels are about 10 nmol/mg, cholesteryl ester about 1 nmol/ml and free cholesterol about 7 nmol/mg [ 35 , 36 , 52 ]. Thus, triglycerides of Hepa1-6 cells are about threefold lower, of Huh7 cells are about ninefold and of HepG2 cells about fourfold higher compared to the liver.…”