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J Lipid Res. 2018 Mar;59(3):475-487. doi: 10.1194/jlr.M081836. Epub 2018 Jan 15.

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

Author information

1
Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Veterans Affairs Medical Center, Dallas, TX 75216.
4
Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390 luke.engelking@utsouthwestern.edu guosheng.liang@utsouthwestern.edu.

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 liver-specific 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. Adeno-associated 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.

KEYWORDS:

adeno-associated virus; carbohydrate-responsive element-binding protein; sterol regulatory element-binding protein -1c

PMID:
29335275
PMCID:
PMC5832931
DOI:
10.1194/jlr.M081836
[Indexed for MEDLINE]
Free PMC Article

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