Molecular mechanism of non-alcoholic fatty liver disease induced and aggravated by chronic stress through HSL/ATGL-FFA which promotes fat mobilization

Abstract

Objective: To study the effects of social stress (CS) and social stress combined with high-fat diet on fat mobilization as a candidate mechanism for the induction or aggravation of non-alcoholic fatty liver disease (NAFLD). Methods: Thirty-two male Wistar rats (250 ± 10 g) were randomly allocated to a blank control group (BC), a high-fat diet group (HFD), a CS group, and a combined CS and high-fat diet group (CS + HFD). Rats were sacrificed and tissues were collected after 8 weeks. Liver and body mass were measured and used to calculate the liver index. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and free fatty acids (FFAs) were measured. Liver sections were examined microscopically after oil red O and hematoxylin and eosin staining. The relative mRNA expression of acetyl-CoA carboxylase (ACCase), hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in liver, and hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) in subcutaneous adipose tissue, were measured by real-time PCR. The liver concentrations of triglyceride, reactive oxygen species, and ACCase were measured by ELISA and HSL activity was determined using turbidimetry. Results: NAFLD developed in the CS, HFD, and CS + HFD groups, with the most severe NAFLD being in the CS + HFD group. Serum AST, ALT, and FFA, liver index, and hepatic triglyceride, FFA, and tumor necrosis factor-α were significantly higher in both the CS and CS + HFD groups. However, food intake and ACCase mRNA expression were lower. The mRNA expression of HSL and ATGL in adipose tissue was much higher, and HSL activity was higher in the CS group than in the BC group, and in the CS + HFD group than in the HFD group. Conclusion: We have successfully established two models of stress-induced NAFLD, suggesting stress can induce and aggravate NAFLD by promoting fat mobilization through upregulation of HSL and ATGL. Keywords: Non-alcoholic fatty liver disease, Chronic stress, Fat mobilization, Free fatty acid