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Title: Isocaloric pair-fed high-carbohydrate diet induced more hepatic steatosis and inflammation than high-fat diet mediated by miR- 34a/SIRT1 axis in mice

Author
item LI, XINLI - Medical College Of Soochow University
item LIAN, FUZHI - Tufts University
item LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HU, KANG QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/7/2015
Publication Date: 11/26/2015
Citation: Li, X., Lian, F., Liu, C., Hu, K., Wang, X. 2015. Isocaloric pair-fed high-carbohydrate diet induced more hepatic steatosis and inflammation than high-fat diet mediated by miR- 34a/SIRT1 axis in mice. Scientific Reports. 5:16774. doi: 10.1038/srep16774.

Interpretive Summary: The present study demonstrated that, under the same calorie intake (isocaloric), feeding high carbohydrate diet induced greater severity in hepatic fatty liver (steatosis) and inflammatory response than feeding a high fat diet. These changes were associated with higher expression of a key regulator (microRNA-34a for protein levels), which down regulated both protein level and activity of several key enzymes (SIRT1, NAMPT, SIRT1 and AMPK), then increased the expression of genes related to liver inflammatory response, and cholesterol deposition, decreased the expression of genes involved in fatty acid oxidation in the livers, thus, the enhanced hepatic inflammation, fatty liver and cholesterol deposition synergistically resulted in the liver injury. These findings indicate that regulating miR-34a/SIRT1/AMPK axis might be an effective strategy to alleviate the deleterious effects of high carbohydrate diet on liver.

Technical Abstract: To investigate the different effects of isocaloric high-fat diet (HFD) and high-carbohydrate diet (HCD) on hepatic steatosis and the underlying mechanisms, especially the role of microRNA- 34a/silent information regulator T1 (SIRT1) axis, C57BL/6J mice (n = 12/group) were isocaloric pair-fed with Lieber-DeCarli liquid diet containing either high fat (HFLD) or high carbohydrate (HCLD) for 16 weeks. As compared to the HFLD fed mice, despite the similar final body weights, HCLD feeding: (1) induced more severe hepatic steatosis; (2) up regulated hepatic expression of miR 34a accompanied with significant decrease of SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT), SIRT1 activity and phosphorylation of AMPK; (3) up regulated de novo lipogenesis (DNL) related proteins expression (ACC, SCD1), and down-regulated expressions of miR-122, miR-370 and miR-33; (4) decreased mRNA expressions of genes Cpt1, Ppar alpha and Pgc1 alpha related to fatty acid oxidation; (5) increased hepatic total cholesterol concentration and decreased expression of cholesterol metabolism related genes Abcg5, Abcg8, Abcg11, Cyp7a1 and Cyp8b1; and (6) induced higher hepatic inflammatory response accompanied with significant increased mRNA expressions of Il1 beta, Tnf alpha and Mcp1. Thus, isocaloric HCLD feeding induced greater severity in hepatic steatosis and inflammatory response than HFLD feeding, potentially through miR-34a/SIRT1 axis mediated promotion of DNL, inhibition of fatty acid oxidation and cholesterol metabolism.