Inflammatory Stress Exacerbates Ectopic Lipid Deposition In C57BL/6J Mice

Objective: Ectopic lipid deposition which is defined as excess lipids deposited in nonadipose tissues, mainly in liver and skeletal muscle, is rapidly becoming a world-wide public health problem because of the associated development of type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease.Chronic systemic inflammation and abnormal free fatty acid metabolism are closely related to ectopic lipid deposition. Sterol regulatory element binding protein 1 (SREBP-1) is a particularly important transcription factor which promotes the activation of genes encoding for key enzymes of fatty acid biosynthesis,such as fatty acid synthase (FAS) and acetyl-CoA carboxylase alpha (ACCα). In this study, we investigated whether inflammation tissue-specifically disrupted lipogenesis and lipolysis in nonadipose tissues and adipose tissue, resulting in ectopic lipid deposition in vitro and in vivo.Materials/Methods: We used tumor necrosis factor alpha (TNF-α) ,interleukin-6 (IL-6) and endotoxin (LPS) stimulation in human hepatoblastoma cell line (HepG2) cells and adipocytes in vitro.We used casein injection in C57BL/6J mice to induce a chronic systemic inflammatory stress in vivo. The effects of inflammatory stress on lipid accumulation were examined by histochemical staining, Oil red O staining and a quantitative intracellular lipid assay. The gene and protein expressions of molecules involved in adipogenisis and lipolysis were examined by real-time polymerase chain reaction (PCR) and western blot. Cytokine production in the plasma of C57BL/6J mice was measured by enzyme-linked immunosorbent assay. Insulin sensitivities were evaluated by glucose and insulin tolerance tests.Results: In vitro, TNF-αand IL-6 significantly increased triglyceride and free fatty acid accumulation in HepG2 cells in the presence of palmitate while decreased these lipid in adipocytes. Further analysis showed that inflammatory stress increased the expression of SREBP-1, FAS, and ACCαwhile decreased these molecules in adipocytes. Inflammatory cytokines also increased the activity of fatty acid synthase in HepG2 cells in the absence or presence of palmitate.In vivo,Casein injection elevated serum levels of IL-6, TNF-αand SAA in mice, which are associated with increased lipid accumulation in liver and muscle, suggesting that chronic systemic inflammation induces ectopic lipid deposition in nonadipose tissues. The inflammatory stress upregulated mRNA and protein expression of sterol regulatory element binding protein 1, fatty acid synthase, and acetyl CoA carboxylase alpha, while inhibited these molecules expression in adipose tissue. Interestingly, in the same experimental setting, inflammation increased adipose triglyceride lipase and hormone-sensitive lipase expression in white adipose tissue. Inflammation also induced insulin resistance and increased serum free fatty acid levels in C57BL/6J mice.Conclusions: In conclusion, inflammatory stress exacerbates hepatic lipid accumulation and decrease adipocytes lipid accumulation in vitro. Chronic systemic inflammation increased lipogenesis in liver and muscle, and lipolysis in white adipose tissue, resulting in ectopic lipid deposition in nonadipose tissues. This disturbed free fatty acid homeostasis and caused insulin resistance in C57BL/6J mice.