title: Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.
abstract: Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.
authors.affiliation: Institute for Adult Diseases, Asahi Life Foundation, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ono
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Motonobu
authors.initials: M
authors.lastname: Anai
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Amelia Y I
authors.initials: AY
authors.lastname: Viana
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Miho
authors.initials: M
authors.lastname: Abe
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shojima
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004798:Enzymes / Q000235:genetics; D005234:Fatty Liver / Q000209:etiology; D005943:Gluconeogenesis; D006019:Glycolysis; D006529:Hepatomegaly / Q000209:etiology*; D006801:Humans; D015228:Hypertriglyceridemia / Q000209:etiology*; D007003:Hypoglycemia / Q000209:etiology*; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004798:Enzymes; D008055:Lipids; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt