Down-regulation of hepatic HNF4alpha gene expression during hyperinsulinemia via SREBPs.
Mutations in the coding region of hepatocyte nuclear factor 4alpha (HNF4alpha), and its upstream promoter (P2) that drives expression in the pancreas, are known to lead to maturity-onset diabetes of the young 1 (MODY1). HNF4alpha also controls gluconeogenesis and lipid metabolism in the liver, where the proximal promoter (P1) predominates. However, very little is known about the role of hepatic HNF4alpha in diabetes. Here, we examine the expression of hepatic HNF4alpha in two diabetic mouse models, db/db mice (type 2, insulin resistant) and streptozotocin-treated mice (type 1, insulin deficient). We found that the level of HNF4alpha protein and mRNA was decreased in the liver of db/db mice but increased in streptozotocin-treated mice. Because insulin increases the activity of sterol regulatory element-binding proteins (SREBP)-1c and -2, we also examined the effect of SREBPs on hepatic HNF4alpha gene expression and found that, like insulin, ectopic expression of SREBPs decreases the level of hepatic HNF4alpha protein and mRNA both in vitro in primary hepatocytes and in vivo in the liver of C57BL/6 mice. Finally, we use gel shift, chromatin immunoprecipitation, small interfering RNA, and reporter gene analysis to show that SREBP2 binds the human HNF4alpha P1 promoter and negatively regulates its expression. These data indicate that hyperinsulinemia down-regulates HNF4alpha in the liver through the up-regulation of SREBPs, thereby establishing a link between these two critical transcription factor pathways that regulate lipid and glucose metabolism in the liver. These findings also provide new insights into diabetes-associated complications such as fatty liver disease.
Xie
Xuefen
X
Department of Physiology and Pathophysiology, Peking University, Health Sciences Center, Beijing 100083, China.
Liao
Hailing
H
Dang
Huaixin
H
Pang
Wei
W
Guan
Youfei
Y
Wang
Xian
X
Shyy
John Y-J
JY
Zhu
Yi
Y
Sladek
Frances M
FM
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D016415:Sequence Alignment; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D051779:Sterol Regulatory Element Binding Proteins