The role of FoxO1 in intrahepatic lipid accumulation in catch-up growth.pdf

1、Objective：Catch-up growth(CUG)has been shown to result in systemic insulin resistance(IR)lipid over-accumulation and raised intrahepatic triglyceride(TG)content.The objective of the present study was to assess the risk f

2、or development of non-alcoholic fatty liver disease(NAFLD)．Then we investigated the role of forkhead box transcription factor 1(FoxO1) and microsomal triglyceride transfer protein(MTTP)in lipid metabolism in CUG．
　　Re

3、search Design and Methods：Male Sprague-Dawley rats were randomly divided into control group(NO，high-fat diet group(HF)，and catch-up growth by refeeding with either normal chow(RN)or high-fat diet(RH)for 8 weeks．Fasting b

4、lood glucose(FBG)and insulin were measured and IR assessed by HOMA-IR．In addition，we measured intrahepatic TG concentration and performed histopathological analysis of liver samples．FoxO1 and MTTP gene expression level w

5、ere assessed by RT-PCR and western blot method．We also determined protein expression of phosphorylated FoxO1．Immunohistochemistry was performed to determine subcellular localization of FoxO1．
　　Results：Fasting insulin

6、，HOMA-IR and intrahepatic TG were increased in both CUG and HF groups compared to control(P<0.05)，whereas FBG showed no significant change．Histopathological analysis did not reveal any structural abnormality in RN and mi

7、nimal steatosis in RH whereas HF group showed borderline steatohepatitis．While FoxO1 was increased in CUG and HF groups compared to control(P<0.05)，surprisingly it was significantly higher in CUG than HF，and even higher

8、in RN compared to RH．Furthermore，there was an increased proportion of phosphorylated FoxO1 in re-feeding groups compared to HF(P<0.05)，associated with increased cytoplasmic localization．However in HF，F(xiàn)oxO1 was localized

9、mainly in the hepatonuclear compartment and the phosphorylated proportion was decreased compared to NC and CUG groups．As for MTTP gene expression，it was significantly higher in HF compared to theother groups(P<0.05)，cons

10、istent 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 in NAFLD．Since MTTP

11、 is not up-regulated in RN，excessive TG is not exported，resulting in lipid accumulation in the liver．Furthermore，CUG by high-fat diet increases the risks for liver damage．The difference in FoxO1 activity may explain why