Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice[S]
- Albert G. Linden1,*,
- Shili Li1,*,
- Hwa Y. Choi2,*,
- Fei Fang*,
- Masashi Fukasawa3,†,§,
- Kosaku Uyeda†,§,
- Robert E. Hammer†,
- Jay D. Horton*,**,
- Luke J. Engelking4,*,** and
- Guosheng Liang4,*
- Departments of Molecular Genetics,* University of Texas Southwestern Medical Center, Dallas, TX 75390
- Biochemistry,† University of Texas Southwestern Medical Center, Dallas, TX 75390
- Internal Medicine,** University of Texas Southwestern Medical Center, Dallas, TX 75390
- Veterans Affairs Medical Center,§ Dallas, TX 75216
- ↵4To whom correspondence should be addressed. e-mail: luke.engelking{at}utsouthwestern.edu (L.J.E.); guosheng.liang{at}utsouthwestern.edu (G.L.)
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.
- carbohydrate-responsive element-binding protein
- sterol regulatory element-binding protein -1c
- adeno-associated virus
Footnotes
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↵1 A. G. Linden and S. Li contributed equally to this work.
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↵2 Present address of H. Y. Choi: College of Veterinary Medicine, Texas A&M University, College Station, TX 77843.
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↵3 Present address of M. Fukasawa: Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan.
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- Abbreviations:
- AAV
- adeno-associated virus
- ACC
- acetyl-CoA carboxylase
- ACLY
- ATP citrate lyase
- bHLH-Zip
- basic helix-loop-helix leucine zipper
- ChoRE
- carbohydrate-responsive element
- ChREBP
- carbohydrate-responsive element-binding protein
- ELOVL6
- long-chain fatty acyl elongase 6
- GFP
- green fluorescent protein
- G6P
- glucose-6-phosphatase
- GPAT
- glycerol-3-phosphate acyltransferase
- KHK
- ketohexokinase
- L-PK
- L-pyruvate kinase
- LXR
- liver X receptor
- ME
- malic enzyme
- nSREBP
- nuclear SREBP
- 6PGDH
- 6-phosphogluconate dehydrogenase
- SCD-1
- stearoyl-CoA desaturase 1
- SRE
- sterol regulatory element
- TBG
- thyroid hormone-binding globulin
- TG
- triglyceride
- TK
- triose kinase
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This work was supported by National Institutes of Health Grants HL20948, 5K08DK102652 (L.J.E.), and ST32GM08014 (A.G.L., Medical Scientist Training Program Grant) and Foundation for the National Institutes of Health Grant 5T35OD010991 (H.Y.C., National Institutes of Health T35 Program). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no related financial interests to declare.
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↵[S] The online version of this article (available at http://www.jlr.org) contains a supplement.
- Received November 9, 2017.
- Revision received January 2, 2018.
Author’s Choice—Final version free via Creative Commons CC-BY license.
