Dietary cholesterol reduces plasma triacylglycerol in apolipoprotein E-null mice: Suppression of lipin-1 and -2 in the glycerol-3-phosphate pathway

Takashi Obama, Sayaka Nagaoka, Kazuki Akagi, Rina Kato, Naomi Horiuchi, Yasushi Horai, Toshihiro Aiuchi, Satoru Arata, Tomohiro Yamaguchi, Mitsuhiro Watanabe, Hiroyuki Itabe

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of triacylglycerol (TG) synthesis remains to be elucidated. Lipin, which catalyzes the conversion of phosphatidate to diacylglycerol, is a key enzyme involved in de novo TG synthesis in the liver via the glycerol-3-phosphate (G3P) pathway. However, the regulatory mechanisms for the expression of lipin in the liver are not well understood. Methodology/Principal Findings: Apolipoprotein E-knock out (apoE-KO) mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet). Cholesterol and bile acids were highly increased in the liver within a week. However, the amount of TG in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost eradicated in the long term. DNA microarray and real-time RT-PCR analyses revealed that the mRNA expression of all the genes in the G3P pathway in the liver was suppressed in the high-Chol diet apoE-KO mice. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which up-regulates the transcription of lipin-1, was also suppressed. In vitro analysis using HepG2 cells revealed that the protein expression of lipin-2 was suppressed by treatment with taurocholic acid. Conclusions/Significance: These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver.

Original languageEnglish
Article numbere22917
JournalPLoS One
Volume6
Issue number8
DOIs
Publication statusPublished - 2011

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Dietary Cholesterol
apolipoprotein E
Apolipoproteins E
glycerol
Liver
Triglycerides
triacylglycerols
cholesterol
phosphates
Plasmas
liver
mice
Cholesterol
Knockout Mice
Nutrition
Metabolites
Metabolism
protein synthesis
taurocholic acid
metabolites

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dietary cholesterol reduces plasma triacylglycerol in apolipoprotein E-null mice : Suppression of lipin-1 and -2 in the glycerol-3-phosphate pathway. / Obama, Takashi; Nagaoka, Sayaka; Akagi, Kazuki; Kato, Rina; Horiuchi, Naomi; Horai, Yasushi; Aiuchi, Toshihiro; Arata, Satoru; Yamaguchi, Tomohiro; Watanabe, Mitsuhiro; Itabe, Hiroyuki.

In: PLoS One, Vol. 6, No. 8, e22917, 2011.

Research output: Contribution to journalArticle

Obama, T, Nagaoka, S, Akagi, K, Kato, R, Horiuchi, N, Horai, Y, Aiuchi, T, Arata, S, Yamaguchi, T, Watanabe, M & Itabe, H 2011, 'Dietary cholesterol reduces plasma triacylglycerol in apolipoprotein E-null mice: Suppression of lipin-1 and -2 in the glycerol-3-phosphate pathway', PLoS One, vol. 6, no. 8, e22917. https://doi.org/10.1371/journal.pone.0022917
Obama, Takashi ; Nagaoka, Sayaka ; Akagi, Kazuki ; Kato, Rina ; Horiuchi, Naomi ; Horai, Yasushi ; Aiuchi, Toshihiro ; Arata, Satoru ; Yamaguchi, Tomohiro ; Watanabe, Mitsuhiro ; Itabe, Hiroyuki. / Dietary cholesterol reduces plasma triacylglycerol in apolipoprotein E-null mice : Suppression of lipin-1 and -2 in the glycerol-3-phosphate pathway. In: PLoS One. 2011 ; Vol. 6, No. 8.
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abstract = "Background: Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of triacylglycerol (TG) synthesis remains to be elucidated. Lipin, which catalyzes the conversion of phosphatidate to diacylglycerol, is a key enzyme involved in de novo TG synthesis in the liver via the glycerol-3-phosphate (G3P) pathway. However, the regulatory mechanisms for the expression of lipin in the liver are not well understood. Methodology/Principal Findings: Apolipoprotein E-knock out (apoE-KO) mice were fed a chow supplemented with 1.25{\%} cholesterol (high-Chol diet). Cholesterol and bile acids were highly increased in the liver within a week. However, the amount of TG in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78{\%}. The epididymal adipose tissue was almost eradicated in the long term. DNA microarray and real-time RT-PCR analyses revealed that the mRNA expression of all the genes in the G3P pathway in the liver was suppressed in the high-Chol diet apoE-KO mice. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which up-regulates the transcription of lipin-1, was also suppressed. In vitro analysis using HepG2 cells revealed that the protein expression of lipin-2 was suppressed by treatment with taurocholic acid. Conclusions/Significance: These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver.",
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AU - Akagi, Kazuki

AU - Kato, Rina

AU - Horiuchi, Naomi

AU - Horai, Yasushi

AU - Aiuchi, Toshihiro

AU - Arata, Satoru

AU - Yamaguchi, Tomohiro

AU - Watanabe, Mitsuhiro

AU - Itabe, Hiroyuki

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