Abstract WP534: Cyanidin 3-glucoside and its Metabolites Protect Against Nonalcoholic Fatty Liver Disease: Crosstalk Between Serum Lipids, Inflammatory Cytokines and MAPK/ERK Pathway

Abstract

Background: Serum lipids and inflammatory cytokines are considered as potential therapeutic targets for nonalcoholic fatty liver disease, which has become the most common chronic liver disease in adolescents. Cyanidin 3-glucoside (C3G) is a natural anthocyanin occurs widely in plants, and has shown potential inhibitory effect on inflammatory cytokines in our previous studies. Methods: First, serum levels of inflammatory cytokines including TNF-α and MCP-1 were measured in 80 adolescents (9-15 years old) selected based on their body mass index and serum levels of lipids. Second, the protective effects of C3G and its metabolites including protocatechuic acid (PCA), phloroglucinaldehyde (PGA), ferulic acid, and vanillic acid on nonalcoholic fatty liver disease were measured in a mouse model in which C57BL/6N mice (n=4 for each group) were fed a normal diet, high fat diet only, or high fat diet containing 0.4% of C3G or the four metabolites for 3 months. Finally, the regulatory effects of C3G and its metabolites on inflammatory pathways were clarified in mouse macrophages. Results: Compared with serum levels of MCP-1 (273.13±16.89 pg/ml, n=16) and TNF-α (26.07±1.36 pg/ml) in normal adolescents, those who were obese with abnormal high serum LDL-c/HDL-c ratio (2.88±0.11) had higher MCP-1 (345.19±11.82 pg/ml, P <0.05) and TNF-α (35.70±1.90 pg/ml, P <0.05) levels. However, no significant change was observed in MCP-1 or TNF-α levels in adolescents who had a lower LDL-c/HDL-c ratio, even though their serum levels of total cholesterol and triacylglycerol were significantly higher ( P <0.05) than normal level. Mice experiments revealed that supplement with C3G, PCA or PGA, but not ferulic acid or vanillic acid, prevented high fat diet-induced obesity and fatty liver with lower serum LDL-c/HDL-c ratio and levels of MCP-1 and TNF-α. Cell signaling analysis indicated that C3G, PCA and PGA suppressed the activation of MAPK pathway, especially, C3G and PGA could directly bind to ERK1/2. Conclusion: The serum LDL-c/HDL-c ratio is closely associated with the inflammatory status in nonalcoholic fatty liver disease, and C3G can suppress the inflammation via MAPK/ERK pathway potentially through its metabolites PCA and PGA.