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The Role of FoxO1in Intrahepatic Lipid Accumulation in Catch-up Growth

Payal Buckoreelall  
【摘要】:Objective: Catch-up growth (CUG) has been shown to result in systemicinsulin resistance (IR), lipid over-accumulation and raised intrahepatictriglyceride (TG) content. The objective of the present study was to assess therisk for development of non-alcoholic fatty liver disease (NAFLD). Then weinvestigated the role of forkhead box transcription factor1(FoxO1) andmicrosomal triglyceride transfer protein (MTTP) in lipid metabolism in CUG. Research Design and Methods: Male Sprague-Dawley rats were randomlydivided into control group (NC), high-fat diet group (HF), and catch-up growthby refeeding with either normal chow (RN) or high-fat diet (RH) for8weeks.Fasting blood glucose (FBG) and insulin were measured and IR assessed byHOMA-IR. In addition, we measured intrahepatic TG concentration andperformed histopathological analysis of liver samples. FoxO1and MTTP geneexpression level were assessed by RT-PCR and western blot method. We alsodetermined protein expression of phosphorylated FoxO1.Immunohistochemistry was performed to determine subcellular localization ofFoxO1. Results: Fasting insulin, HOMA-IR and intrahepatic TG were increased in bothCUG and HF groups compared to control (P0.05), whereas FBG showed nosignificant change. Histopathological analysis did not reveal any structuralabnormality in RN and minimal steatosis in RH whereas HF group showedborderline steatohepatitis. While FoxO1was increased in CUG and HF groupscompared to control (P0.05), surprisingly it was significantly higher in CUGthan HF, and even higher in RN compared to RH. Furthermore, there was an increased proportion of phosphorylated FoxO1in re-feeding groups comparedto HF (P0.05), associated with increased cytoplasmic localization. However inHF, FoxO1was localized mainly in the hepatonuclear compartment and thephosphorylated proportion was decreased compared to NC and CUG groups. Asfor MTTP gene expression, it was significantly higher in HF compared to theother groups (P0.05), consistent with increased transcriptional activity ofFoxO1. There were no significant difference in MTTP expression between RNand NC. Conclusion: Our study shows that CUG by normal chow does not result inNAFLD. Since MTTP is not up-regulated in RN, excessive TG is not exported,resulting in lipid accumulation in the liver. Furthermore, CUG by high-fat dietincreases the risks for liver damage. The difference in FoxO1activity mayexplain why although systemic IR and intrahepatic TG accumulation occur inboth models, CUG does not result in NAFLD. Further studies are needed todetermine the impact of long term CUG on hepatic lipid metabolism.

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1 K. Naghabushana Nayidu;[D];华中农业大学;2008年
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