Changes in essential fatty acid patterns associated with normal liver regeneration and the progression of hepatocyte nodules in rat hepatocarcinogenesis

Abstract

Changes in lipid metabolism were monitored in rat hepatocyte nodules at certain time points over 9 months. Tissue obtained from partially hepatectomized rats, collected over a period of 7 days, were included as a control for normal hepatocyte cell proliferation. Two important features regarding the lipid profiles of hepatocyte nodules and normal regenerating liver were the increased concentrations of phosphatidylethanolamine (PE), resulting in a decreased phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio, and cholesterol. These changes coincided with increased membrane fluidity in the nodules and regenerating liver. With respect to the fatty acid (FA) profiles of the nodules, C18:1omega9 and C18:2omega6 increased in PE and PC whereas C20:4omega6 decreased in PC and increased in PE. C22:5omega6 and C22:6omega3, the end products of the omega6 and omega3 metabolic pathways, respectively, decreased in PC and remained unchanged in PE. The FA levels in PC reflected an impaired delta-6 desaturase enzyme, whereas this effect was masked in PE due to the increased concentration of this phospholipid fraction. In regenerating liver, the FA profiles of PC and PE showed the same pattern as described for the hepatocyte nodules, except for C18:1omega9 which decreased in PC and increased non-significantly in PE. The increased C18:1omega9 level, a FA with anti-oxidative properties, as well as the decreased levels of the long-chain polyunsaturated fatty acids (C20 and C22 carbon chains), have been associated with the decreased lipid peroxidation level in hepatocyte nodules. The resultant decrease in peroxidative metabolites, known to affect apoptosis, could be important in the progression of the nodules into neoplasia. The present results indicate that the altered lipid parameters associated with hepatocyte nodules closely mimics cellular proliferation in regenerating liver and could be responsible for the enhanced proliferation and/or altered growth pattern in these lesions. The altered FA profiles suggest various pathways in which FA could play a role in transmembrane signalling related to the altered cell proliferative and apoptotic pathways. The persistent changes in the hepatocyte nodules suggest that the lipid metabolism escapes the regulatory mechanisms required for normal cellular homeostasis at different levels.

Metabolomics Study of Stepwise Hepatocarcinogenesis From the Model Rats to Patients: Potential Biomarkers Effective for Small Hepatocellular Carcinoma Diagnosis

“…Poly unsaturated fatty acids (PUFA) such as clupanodonic acid and docosahexaenoic acid, could play important roles in the modulation of cell proliferation through cellular lipids peroxidation (38). The deregulation of PUFA has been considered as the early events in the liver carcinogenesis (39). L-carnitine acts as a protector from liver carcinogenesis by decreasing free fatty acid in blood and lower the oxidative damage from lipids peroxidation (40,41).…”

Oral administration of fumonisin B1and T-2 individually and in combination affects hepatic total and mitochondrial membrane lipid profile of rabbits

“…Although different cell organelles and lipid fractions react with FB 1 -induced stimuli divergently, Burger et al (6) reported supportive results in which FB 1 was liberated from the PC fraction, augmenting prostaglandin E2 series synthesis and inducing sustaining cell proliferation (2). The further fact to take into account is that impaired arachidonic acid metabolism, in particular its proportional decrease in the PC fraction has been implied as a growth stimulus for hepatocellular nodules (1). Docosapentaenoic acid (C22:5 n3) proportion was decreased significantly in both separate treatments compared to the combined group, but not differing from the control.…”

“…The homogenized fungal cultures contained FB 1 at a concentration of 3,440 mg/kg, while T-2 toxin concentration was 1,338 mg/kg (HT-2 toxin 285 mg/kg), respectively. These fungal cultures were mixed into the basal feed of the experimental animals, so as to provide contaminated feeds with 2 mg/kg feed T-2 toxin and/or 10 mg/kg feed FB 1 .…”

Imaging Lipid Synthesis in Hepatocellular Carcinoma with [Methyl-11C]Choline: Correlation with In Vivo Metabolic Studies

“…In an examination of endogenous lipid components in the HCC nodule, the phosphatidylcholine and phosphatidylethanolamine content in C18:1v9 (oleic acid) and C18:2v6 (linoleic acid) had increased, whereas the contents of phosphatidylcholine and phosphatidylethanolamine in C20:4v6 (arachidonic acid) had decreased and increased, respectively. Phosphatidylcholine and phosphatidylethanolamine contents were decreased in both C22:5v6 (docosapentaenoic acid) and C22:6v3 (decosahexaenoic acid) (31). This altered endogenous lipid profile in HCCs may create distinct microenvironments between HCCs and the surrounding hepatic tissues, resulting in the stimulation of CCT activity in HCCs (Supplemental Fig.…”