title: Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice.
abstract: OBJECTIVE
  Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis.
  
  
  RESULTS
  Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively.
  
  
  CONCLUSIONS
  Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles.
authors.affiliation: Department of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takahashi
authors.forename: Ryo
authors.initials: R
authors.lastname: Saito
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.forename: Masaki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Shoko
authors.initials: S
authors.lastname: Miyahara
authors.forename: Saori
authors.initials: S
authors.lastname: Koyasu
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Ishii
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takekoshi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010316:Particle Size; D049294:Phospholipid Transfer Proteins / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D049294:Phospholipid Transfer Proteins; D011973:Receptors, LDL; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C510091:phospholipid transfer protein, mouse; D002784:Cholesterol