Carbohydrate-responsive element-binding protein

Last updated
MLXIPL
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MLXIPL , CHREBP, MIO, MONDOB, WBSCR14, WS-bHLH, bHLHd14, MLX interacting protein like, MLX
External IDs OMIM: 605678 MGI: 1927999 HomoloGene: 32507 GeneCards: MLXIPL
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_032951
NM_032952
NM_032953
NM_032954
NM_032994

NM_021455
NM_001359237

RefSeq (protein)

NP_116569
NP_116570
NP_116571
NP_116572

NP_067430
NP_001346166

Location (UCSC) Chr 7: 73.59 – 73.62 Mb Chr 5: 135.12 – 135.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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. ChREBP.png
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.

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.

Related Research Articles

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

In chemistry, de novo synthesis is the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to recycling after partial degradation. For example, nucleotides are not needed in the diet as they can be constructed from small precursor molecules such as formate and aspartate. Methionine, on the other hand, is needed in the diet because while it can be degraded to and then regenerated from homocysteine, it cannot be synthesized de novo.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">Cholesterol 7 alpha-hydroxylase</span> Protein-coding gene in the species Homo sapiens

Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.

<span class="mw-page-title-main">CREB-binding protein</span> Nuclear protein that binds to CREB

CREB-binding protein, also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the CREBBP gene in humans, located on chromosome 16p13.3. CBP has intrinsic acetyltransferase functions; it is able to add acetyl groups to both transcription factors as well as histone lysines, the latter of which has been shown to alter chromatin structure making genes more accessible for transcription. This relatively unique acetyltransferase activity is also seen in another transcription enzyme, EP300 (p300). Together, they are known as the p300-CBP coactivator family and are known to associate with more than 16,000 genes in humans; however, while these proteins share many structural features, emerging evidence suggests that these two co-activators may promote transcription of genes with different biological functions.

<span class="mw-page-title-main">Sterol regulatory element-binding protein 1</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.

<span class="mw-page-title-main">Liver X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.

<span class="mw-page-title-main">USF1</span> Protein-coding gene in the species Homo sapiens

Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.

<span class="mw-page-title-main">PDK4</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase lipoamide kinase isozyme 4, mitochondrial (PDK4) is an enzyme that in humans is encoded by the PDK4 gene. It codes for an isozyme of pyruvate dehydrogenase kinase.

<span class="mw-page-title-main">Insulin-induced gene 1 protein</span> Protein-coding gene in the species Homo sapiens

Insulin induced gene 1, also known as INSIG1, is a protein which in humans is encoded by the INSIG1 gene.

<span class="mw-page-title-main">LPIN1</span> Protein-coding gene in the species Homo sapiens

Lipin-1 is a protein that in humans is encoded by the LPIN1 gene.

<i>MLX</i> (gene) Protein-coding gene in the species Homo sapiens

Max-like protein X is a protein that in humans is encoded by the MLX gene.

<span class="mw-page-title-main">MXD4</span> Protein-coding gene in the species Homo sapiens

Max-interacting transcriptional repressor MAD4 is a protein that in humans is encoded by the MXD4 gene.

<span class="mw-page-title-main">MNT (gene)</span> Protein-coding gene in the species Homo sapiens

MNT is a Max-binding protein that is encoded by the MNT gene

<span class="mw-page-title-main">INSIG2</span> Protein-coding gene in the species Homo sapiens

Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.

<span class="mw-page-title-main">Forkhead box protein O1</span> Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000009950 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000005373 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. 1 2 3 "Entrez Gene: MLXIPL MLX interacting protein-like".
  7. 1 2 3 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.
  8. 1 2 3 4 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.
  9. 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.
  10. 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.
  11. 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