Protein found in humans
Carbohydrate-responsive element-binding protein (ChREBP ) also known as MLX-interacting protein-like (MLXIPL) is a
protein that in humans is encoded by the MLXIPL
gene .
[5]
[6] The protein name derives from the protein's interaction with carbohydrate response element sequences of DNA.
Function
Domains of ChREBP. The N-terminal glucose-sensing module consists of the low glucose inhibitory domain (LID) and the glucose activated conserved element (GRACE). The C-terminal regions consists of a polyproline-rich, a bHLH/LZ and a leucine-zipper-like (Zip-like) domain. Phosphorylation sites in red, acetylation sites in blue and O-GlcNAcylation sites in green.
[7]
This gene encodes a
basic helix-loop-helix leucine zipper
transcription factor of the
Myc /
Max /
Mad superfamily. This protein forms a heterodimeric complex and binds and activates, in a glucose-dependent manner,
carbohydrate response element (ChoRE) motifs in the promoters of
triglyceride synthesis genes.
[6]
ChREBP is activated by glucose, independent of
insulin .
[8] In
adipose tissue , ChREBP induces
de novo
lipogenesis from glucose in response to a glucose flux into
adipocytes .
[9]
[8] In the liver, glucose induction of ChREBP promotes
glycolysis and
lipogenesis .
[8]
Clinical significance
This gene is deleted in
Williams-Beuren syndrome , a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23.
[6]
Excess expression of ChREBP in the liver due to
metabolic syndrome or
type 2 diabetes can lead to
steatosis in the liver.
[8] In
non-alcoholic fatty liver disease , about 25% of total liver
lipids result from
de novo synthesis (synthesis of lipids from glucose).
[7] High blood glucose and insulin enhance
lipogenesis in the liver by activation of ChREBP and
SREBP-1c , respectively.
[7]
Chronically elevated blood glucose can activate ChREBP in the
pancreas can lead to excessive lipid synthesis in
beta cells , increasing lipid accumulation in those cells, leading to
lipotoxicity , beta-cell
apoptosis , and type 2 diabetes.
[10]
Interactions
MLXIPL has been shown to
interact with
MLX .
[11]
Role in glycolysis
ChREBP is translocated to the nucleus and binds to DNA after dephosphorylation of a p-Ser and a p-Thr residue by
PP2A , which itself is activated by
xylulose-5-phosphate . Xu5p is produced in the
pentose phosphate pathway when levels of
Glucose-6-phosphate are high (the cell has ample glucose). In the liver, ChREBP mediates activation of several regulatory enzymes of glycolysis and lipogenesis including L-type pyruvate kinase (L-PK), acetyl CoA carboxylase, and fatty acid synthase.
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000009950 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000005373 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ Meng X, Lu X, Li Z, Green ED, Massa H, Trask BJ, et al. (November 1998). "Complete physical map of the common deletion region in Williams syndrome and identification and characterization of three novel genes". Human Genetics . 103 (5): 590–599.
doi :
10.1007/s004390050874 .
PMID
9860302 .
S2CID
23530406 .
^
a
b
c
"Entrez Gene: MLXIPL MLX interacting protein-like" .
^
a
b
c Ortega-Prieto P, Postic C (2019).
"Carbohydrate Sensing Through the Transcription Factor ChREBP" . Frontiers in Genetics . 10 : 472.
doi :
10.3389/fgene.2019.00472 .
PMC
6593282 .
PMID
31275349 .
^
a
b
c
d Xu X, So JS, Park JG, Lee AH (November 2013).
"Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP" . Seminars in Liver Disease . 33 (4): 301–311.
doi :
10.1055/s-0033-1358523 .
PMC
4035704 .
PMID
24222088 .
^ Czech MP, Tencerova M, Pedersen DJ, Aouadi M (May 2013).
"Insulin signalling mechanisms for triacylglycerol storage" . Diabetologia . 56 (5): 949–964.
doi :
10.1007/s00125-013-2869-1 .
PMC
3652374 .
PMID
23443243 .
^ Song Z, Yang H, Zhou L, Yang F (October 2019).
"Glucose-Sensing Transcription Factor MondoA/ChREBP as Targets for Type 2 Diabetes: Opportunities and Challenges" . International Journal of Molecular Sciences . 20 (20): E5132.
doi :
10.3390/ijms20205132 .
PMC
6829382 .
PMID
31623194 .
^ Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A (March 2001).
"WBSCR14, a gene mapping to the Williams--Beuren syndrome deleted region, is a new member of the Mlx transcription factor network" . Human Molecular Genetics . 10 (6): 617–627.
doi :
10.1093/hmg/10.6.617 .
PMID
11230181 .
Further reading
de Luis O, Valero MC, Jurado LA (March 2000).
"WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog" . European Journal of Human Genetics . 8 (3): 215–222.
doi :
10.1038/sj.ejhg.5200435 .
PMID
10780788 .
Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K (November 2001).
"Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein" . Proceedings of the National Academy of Sciences of the United States of America . 98 (24): 13710–13715.
Bibcode :
2001PNAS...9813710K .
doi :
10.1073/pnas.231370798 .
PMC
61106 .
PMID
11698644 .
Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K (February 2002).
"Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase" . The Journal of Biological Chemistry . 277 (6): 3829–3835.
doi :
10.1074/jbc.M107895200 .
PMID
11724780 .
Hillman RT, Green RE, Brenner SE (2005).
"An unappreciated role for RNA surveillance" . Genome Biology . 5 (2): R8.
doi :
10.1186/gb-2004-5-2-r8 .
PMC
395752 .
PMID
14759258 .
Merla G, Howald C, Antonarakis SE, Reymond A (July 2004).
"The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14-3-3" . Human Molecular Genetics . 13 (14): 1505–1514.
doi :
10.1093/hmg/ddh163 .
PMID
15163635 .
Li MV, Chang B, Imamura M, Poungvarin N, Chan L (May 2006).
"Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module" . Diabetes . 55 (5): 1179–1189.
doi :
10.2337/db05-0822 .
PMID
16644671 .
(1) Basic domains
(1.1) Basic
leucine zipper (
bZIP )(1.2) Basic helix-loop-helix (
bHLH )
Group A Group B Group C bHLH-
PAS Group D Group E Group F bHLH-COE
(1.3)
bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2)
Zinc finger DNA-binding domains
(2.1)
Nuclear receptor (Cys4 )
subfamily 1 subfamily 2 subfamily 3 subfamily 4 subfamily 5 subfamily 6 subfamily 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4) β-Scaffold factors with minor groove contacts
(0) Other transcription factors