Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice.
CCAAT/enhancer binding protein alpha (C/EBP alpha) is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBP alpha-null mice that do not survive beyond the first day after birth because of severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBP alpha in leptin-deficient mouse (ob/ob) liver, a C/EBP alpha-liver null mouse on an ob/ob background (ob/ob-C/EBP alpha/Cre(+)) was produced using a floxed C/EBP alpha allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBP alpha-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBP alpha/Cre(-)). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-coenzyme A carboxylase, stearoyl-coenzyme A desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBP alpha/Cre(+) mouse liver. Induction of these lipogenic genes by a high-carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride, and cholesterol contents in ob/ob-C/EBP alpha/Cre(-) mice but not in ob/ob-C/EBP alpha/Cre(+) mice. Deficiency in hepatic C/EBP alpha expression caused an exacerbation of hyperglycemia because of decreased insulin secretion. Taken together, these results indicate that hepatic C/EBP alpha plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kimihiko
K
Matsusue
Oksana
O
Gavrilova
Gilles
G
Lambert
H Bryan
HB
Brewer
Jerrold M
JM
Ward
Yusuke
Y
Inoue
Derek
D
LeRoith
Frank J
FJ
Gonzalez
D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000483:Alleles; D000821:Animal Feed; D000818:Animals; D001056:Apolipoproteins C / Q000378:metabolism; D001786:Blood Glucose / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000097:blood / Q000378:metabolism; D020738:Leptin / Q000172:deficiency*; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000033:anatomy & histology / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017384:Sequence Deletion; D013230:Stearoyl-CoA Desaturase / Q000235:genetics
C484352:Apoc4 protein, mouse; D001056:Apolipoproteins C; D001786:Blood Glucose; D022763:CCAAT-Enhancer-Binding Protein-alpha; D007328:Insulin; D020738:Leptin; D008055:Lipids; D012333:RNA, Messenger; D002784:Cholesterol; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D064429:Fatty Acid Synthases; D001275:ATP Citrate (pro-S)-Lyase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose