Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice

Albert G. Linden, Shili Li, Hwa Y. Choi, Fei Fang, Masashi Fukasawa, Kosaku Uyeda, Robert E Hammer, Jay D Horton, Luke Engelking, Guosheng Liang

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Lipogenesis in liver is highest in the postprandial state; insulin activates SREBP-1c, which transcriptionally activates genes involved in FA synthesis, whereas glucose activates carbohydrate-responsive element-binding protein (ChREBP), which activates both glycolysis and FA synthesis. Whether SREBP-1c and ChREBP act independently of one another is unknown. Here, we characterized mice with liverspecific deletion of ChREBP (L-Chrebp-/- mice). Hepatic ChREBP deficiency resulted in reduced mRNA levels of glycolytic and lipogenic enzymes, particularly in response to sucrose refeeding following fasting, a dietary regimen that elicits maximal lipogenesis. mRNA and protein levels of SREBP-1c, a master transcriptional regulator of lipogenesis, were also reduced in L-Chrebp-/- livers. Adenoassociated virus-mediated restoration of nuclear SREBP-1c in L-Chrebp-/- mice normalized expression of a subset of lipogenic genes, while not affecting glycolytic genes. Conversely, ChREBP overexpression alone failed to support expression of lipogenic genes in the livers of mice lacking active SREBPs as a result of Scap deficiency. Together, these data show that SREBP-1c and ChREBP are both required for coordinated induction of glycolytic and lipogenic mRNAs. Whereas SREBP-1c mediates insulin's induction of lipogenic genes, ChREBP mediates glucose's induction of both glycolytic and lipogenic genes. These overlapping, but distinct, actions ensure that the liver synthesizes FAs only when insulin and carbohydrates are both present.

Original languageEnglish (US)
Pages (from-to)475-487
Number of pages13
JournalJournal of Lipid Research
Volume59
Issue number3
DOIs
StatePublished - Jan 1 2018

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Sterol Regulatory Element Binding Protein 1
Lipogenesis
Glycolysis
Liver
Carrier Proteins
Carbohydrates
Genes
Messenger RNA
Insulin
Glucose
Protein Deficiency
Viruses
Restoration
Sucrose
Fasting
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. / Linden, Albert G.; Li, Shili; Choi, Hwa Y.; Fang, Fei; Fukasawa, Masashi; Uyeda, Kosaku; Hammer, Robert E; Horton, Jay D; Engelking, Luke; Liang, Guosheng.

In: Journal of Lipid Research, Vol. 59, No. 3, 01.01.2018, p. 475-487.

Research output: Contribution to journalArticle

Linden, Albert G. ; Li, Shili ; Choi, Hwa Y. ; Fang, Fei ; Fukasawa, Masashi ; Uyeda, Kosaku ; Hammer, Robert E ; Horton, Jay D ; Engelking, Luke ; Liang, Guosheng. / Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice. In: Journal of Lipid Research. 2018 ; Vol. 59, No. 3. pp. 475-487.
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AU - Linden, Albert G.

AU - Li, Shili

AU - Choi, Hwa Y.

AU - Fang, Fei

AU - Fukasawa, Masashi

AU - Uyeda, Kosaku

AU - Hammer, Robert E

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AB - Lipogenesis in liver is highest in the postprandial state; insulin activates SREBP-1c, which transcriptionally activates genes involved in FA synthesis, whereas glucose activates carbohydrate-responsive element-binding protein (ChREBP), which activates both glycolysis and FA synthesis. Whether SREBP-1c and ChREBP act independently of one another is unknown. Here, we characterized mice with liverspecific deletion of ChREBP (L-Chrebp-/- mice). Hepatic ChREBP deficiency resulted in reduced mRNA levels of glycolytic and lipogenic enzymes, particularly in response to sucrose refeeding following fasting, a dietary regimen that elicits maximal lipogenesis. mRNA and protein levels of SREBP-1c, a master transcriptional regulator of lipogenesis, were also reduced in L-Chrebp-/- livers. Adenoassociated virus-mediated restoration of nuclear SREBP-1c in L-Chrebp-/- mice normalized expression of a subset of lipogenic genes, while not affecting glycolytic genes. Conversely, ChREBP overexpression alone failed to support expression of lipogenic genes in the livers of mice lacking active SREBPs as a result of Scap deficiency. Together, these data show that SREBP-1c and ChREBP are both required for coordinated induction of glycolytic and lipogenic mRNAs. Whereas SREBP-1c mediates insulin's induction of lipogenic genes, ChREBP mediates glucose's induction of both glycolytic and lipogenic genes. These overlapping, but distinct, actions ensure that the liver synthesizes FAs only when insulin and carbohydrates are both present.

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