MTTP Gene: Microsomal Triglyceride Transfer Protein
The MTTP gene encodes the large subunit of the microsomal triglyceride transfer protein, which is essential for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Mutations in MTTP cause abetalipoproteinemia, a rare autosomal recessive disorder of fat malabsorption and vitamin deficiency.
Gene Information Card
| Symbol | MTTP |
|---|---|
| Full Name | Microsomal Triglyceride Transfer Protein |
| Gene Type | Protein coding |
| Chromosomal Location | 4q23 |
| NCBI Gene ID | 4547 ncbi.nlm.nih.gov/gene/4547 |
| Ensembl ID | ENSG00000138823 |
| UniProt ID | P55157 |
| OMIM ID | 157147 |
| HGNC ID | 7467 |
| Aliases | ABL, MTP |
Description
The MTTP gene encodes the large subunit of the microsomal triglyceride transfer protein (MTP), a heterodimeric lipid transfer protein. The MTP complex, consisting of the MTTP large subunit and protein disulfide isomerase (PDI), is localized to the endoplasmic reticulum (ER) of hepatocytes and enterocytes. Its primary function is to transfer neutral lipids (triglycerides and cholesteryl esters) onto apolipoprotein B (apoB) during the assembly of very low-density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. This lipid transfer activity is essential for the lipidation and proper folding of apoB, preventing its degradation and enabling the secretion of these lipoproteins into the circulation. The MTTP gene is also expressed in other tissues, including the heart and kidney, where its function is less well-defined but may be involved in local lipid metabolism.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Abetalipoproteinemia (ABL) | Loss-of-function mutations in MTTP abolish or severely reduce the lipid transfer activity of MTP. This prevents the assembly and secretion of apoB-containing lipoproteins (chylomicrons and VLDL) in the intestine and liver, leading to a complete absence of these lipoproteins in plasma. | OMIM #200100; ClinVar; Multiple case reports and functional studies confirm that biallelic pathogenic variants in MTTP cause ABL. |
| Non-alcoholic fatty liver disease (NAFLD) / Hepatic steatosis | Common genetic variants (e.g., rs1800804, rs1800591) in the MTTP promoter region can reduce MTTP expression, leading to decreased VLDL secretion and subsequent accumulation of triglycerides in hepatocytes, contributing to the development of hepatic steatosis. | ClinVar; Genome-wide association studies (GWAS) and candidate gene studies have linked MTTP polymorphisms to increased risk of NAFLD. |
| Hyperlipidemia (modifier) | Variants that increase MTTP expression or activity could potentially increase VLDL secretion, contributing to hyperlipidemia. However, this is less established than the loss-of-function phenotype. | ClinVar; Some studies suggest a role for MTTP variants in modulating plasma lipid levels. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 27.4 | High |
| Small Intestine | 18.2 | High |
| Kidney | 3.1 | Low |
| Heart | 2.5 | Low |
| Adipose Tissue | 0.8 | Not detected |
| Brain | 0.5 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (Liver) | 35.2 | High expression; used as a model for hepatic lipoprotein production. |
| Caco-2 (Colon) | 12.8 | Moderate expression; used as a model for intestinal lipid absorption. |
| A549 (Lung) | 0.2 | Very low expression. |
| MCF7 (Breast) | 0.1 | Very low expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1862T>C (p.Leu621Pro) | Missense | Rare (found in ABL patients) | Disrupts MTP function, leading to abetalipoproteinemia. |
| c.2151+1G>A | Splice site | Rare (found in ABL patients) | Causes aberrant splicing, leading to a non-functional protein. |
| c.1282C>T (p.Arg428Cys) | Missense | Rare (found in ABL patients) | Impairs lipid transfer activity. |
| c.493G>A (p.Gly165Ser) | Missense | Rare (found in ABL patients) | Reduces MTP activity and apoB secretion. |
| rs1800804 (promoter) | SNP | Common (MAF ~0.2) | Associated with reduced MTTP expression and increased risk of NAFLD. |
Mutation functional classification
Loss of Function (LOF)
The majority of disease-causing MTTP mutations are loss-of-function. These mutations, including missense, nonsense, frameshift, and splice-site variants, result in reduced or absent MTP activity. This leads to a failure in the assembly and secretion of apoB-containing lipoproteins, causing abetalipoproteinemia. The severity of the phenotype correlates with the residual MTP activity.
Gain of Function (GOF)
No clear gain-of-function mutations have been identified for MTTP. Some promoter polymorphisms that increase expression have been suggested to influence lipid levels, but these are not considered classic gain-of-function mutations.
Dominant Negative (DN)
Abetalipoproteinemia is inherited in an autosomal recessive manner, and carriers with one functional allele are asymptomatic. This indicates that MTTP mutations do not act in a dominant-negative manner, as a single wild-type allele is sufficient for normal function.
View complete mutation data：
Gene Ontology (GO)
| • lipid transfer activity | • lipid binding |
| • protein homodimerization activity | • enzyme binding |
| • endoplasmic reticulum | • microsome |
| • lipid transport | • lipoprotein metabolic process |
| • chylomicron assembly | • very-low-density lipoprotein particle assembly |
| • triglyceride homeostasis | • response to nutrient |
Pathways
• Lipoprotein metabolism (Reactome: R-HSA-174824)
• VLDL assembly (Reactome: R-HSA-8964043)
• Chylomicron assembly (Reactome: R-HSA-174800)
• Lipid digestion
• mobilization
• and transport (Reactome: R-HSA-73923)
Protein Summary
The MTTP protein (P55157) is a 97 kDa large subunit of the microsomal triglyceride transfer protein complex. It is a multifunctional protein that binds to various lipid molecules, including triglycerides, cholesteryl esters, and phospholipids. The protein is localized to the lumen of the endoplasmic reticulum, where it forms a heterodimer with protein disulfide isomerase (PDI). The MTTP/PDI complex is essential for the transfer of lipids to nascent apoB proteins, a critical step in the assembly of VLDL and chylomicrons. The protein has three main structural domains: an N-terminal β-barrel domain, a central α-helical domain, and a C-terminal lipid-binding domain. The C-terminal domain is thought to be the primary site for lipid binding and transfer. Mutations in this domain often lead to severe loss of function.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MTTP Knockout HEK293 Cell Line | EDJ-KQ3757 | Human | 4547 | Details Get a Quote |
| MTTP Knockout HeLa Cell Line | EDJ-KQ53921 | Human | 4547 | Details Get a Quote |
| MTTP Knockout A-549 Cell Line | EDJ-KQ62414 | Human | 4547 | Details Get a Quote |
| MTTP Knockout HCT 116 Cell Line | EDJ-KQ70881 | Human | 4547 | Details Get a Quote |
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