High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway

Abstract

Background: Hyperhomocysteinemia (HHcy) causes increased oxidative stress and is an independent risk factor for cardiovascular disease. Oxidative stress is now believed to be a major contributory factor in the development of non alcoholic fatty liver disease, the most common liver disorder worldwide. In this study, the changes which occur in homocysteine (Hcy) metabolism in high fat-diet induced non alcoholic fatty liver disease (NAFLD) in rats were investigated.

Methods and results: After feeding rats a standard low fat diet (control) or a high fat diet (57% metabolisable energy as fat) for 18 weeks, the concentration of homocysteine in the plasma was significantly raised while that of cysteine was lowered in the high fat as compared to the control diet fed animals. The hepatic activities of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS), the enzymes responsible for the breakdown of homocysteine to cysteine via the transsulphuration pathway in the liver, were also significantly reduced in the high fat-fed group.

Conclusions: These results indicate that high fat diet-induced NAFLD in rats is associated with increased plasma Hcy levels caused by down-regulation of hepatic CBS and CGL activity. Thus, HHcy occurs at an early stage in high fat diet-induced NAFLD and is likely to contribute to the increased risk of cardiovascular disease associated with the condition.

Figure 1

Effect of high fat diet feeding on plasma insulin and HOMA-IR. Rats were fed standard low fat diet (Control diet) or a high fat diet for 18 weeks. Blood samples were then collected and the concentration of insulin in plasma (A) were determined and the HOMA-IR (B) calculated. Data are the mean from 6 (Control diet) or 4 (High fat diet) animals and error bars show the SEM. **P < 0.01, ***P < 0.001 vs Control diet.

Figure 2

Effect of high fat diet feeding on plasma homocysteine and liver CBS and CGL activities. Rats were fed a standard low fat (Control diet) or a high fat diet for 18 weeks and blood samples and livers were then collected. A. Plasma Hcy; B. Plasma Cys; C. Liver CBS activity; D. Liver CGL activity. Data are the mean from 6 (Control diet) or 4 (High fat diet) animals. Error bars show the SEM. *P < 0.05, ***P < 0.001 vs Control diet.