Dynamic expression of carnitine palmitoyltransferase II in the mitochondrial inner membrane during hepatocyte malignant transformation induced by lipid accumulation

Abstract

Objective: To investigate the dynamic expression of hepatic carnitine palmitoyltransferase-II (CPT-II) in the mitochondrial inner membrane during hepatocyte malignant transformation induced by lipid accumulation. Methods: Male Sprague-Dawley rats were divided randomly into control, fatty liver, and induced cancer groups, which were fed with normal, high-fat (HF), and HF containing 2-fluorenylacetamide (0.05%, 2-FAA) diets, respectively, for 14 weeks. One rat from each group was sacrificed every two weeks and the blood and liver samples were collected. Liver morphological changes were evaluated with hematoxylin and eosin staining, and the liver tissue samples were divided into control, fatty liver, degeneration, precancerous, and cancerous groups accordingly. Hepatic lipids were dyed by the oil red O method. The CPT-II expression was measured by immunohistochemistry and compared with the specific CPT-II concentration (ng/mg liver protein, ng/mg P) among different groups. Serum levels of circulating total cholesterol (Tch), triglyceride (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were quantitatively analyzed. Results: Massive lipid accumulation hepatocytes was seen in rats on HF and HF containing 2-FAA diets. The lipid levels in the control group were significantly lower than those in the fatty liver (t = -11.556, P < 0.001), degeneration (t = -4.847, P = 0.04), precancerous (t = -13.652, P = 0.005), and cancerous groups (t = -10.896, P = 0.008). The serum TG and Tch levels in the degeneration, precancerous, and cancerous groups were 2-3 times higher than those in the control group (P < 0.05). After 2-FAA treatment, the morphological changes of rat hepatocytes showed the progression from degeneration and precancerosis to cancerosis, with hepatocyte injury. The serum AST and ALT levels in the degeneration, precancerous, and cancerous groups were significantly higher (4-8 times) than those in the control group (P < 0.05). The specific concentration of liver CPT-II expression was significantly reduced during hepatocyte malignant transformation, as confirmed by immunohistochemistry, with the CPT-II levels significantly lower in the cancerous group than in any of other groups (P < 0.05). Conclusion: Low hepatic CPT-II expression might lead to abnormal lipid accumulation in hepatocytes, which should promote the malignant transformation of hepatocytes.