ABHD2

Official Full Name

abhydrolase domain containing 2, acylglycerol lipase

Organism

Homo sapiens

GeneID

11057

Background

This gene encodes a protein containing an alpha/beta hydrolase fold, which is a catalytic domain found in a wide range of enzymes. The encoded protein is an acylglycerol lipase that catalyzes the hydrolysis of endocannabinoid arachidonoylglycerol from the cell membrane. This leads to activation of the sperm calcium channel CatSper, which results in sperm activation. Alternative splicing of this gene results in two transcript variants encoding the same protein. [provided by RefSeq, Jan 2017]

Synonyms

HS1-2; LABH2; PHPS1-2;

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Detailed Information

ABHD2, a member of the hydrolase protein family, has hydrolase activity and is involved in the regulation of lipid metabolism. ABHD2 gene is expressed in alveolar type II epithelial cells and bronchial smooth muscle cells, and ABHD2 knockout mice can naturally develop emphysema. Clinical studies have found that mutations in the rs12442260 gene in the human ABHD2 gene increase the risk of developing chronic obstructive pulmonary disease (COPD). Therefore, ABHD2 plays an important role in the occurrence and development of emphysema and COPD. Screening for ABHD2 susceptibility genes is expected to be a target for early detection, early prevention, and treatment of people with the predisposition to COPD.

ABHD2 Features

ABHD2 is a hydrolase protein expressed in humans. In 2002, Edgar and Polak cloned three cDNA sequences encoding hydrolase proteins from mouse lung cDNA libraries and named them lung hydrolase (Labh), now known as hydrolase domains 1, 2 and 3. Human ABHD2, the lung α/β hydrolase 2, consists of 425 residual proteins. The expression of ABHD2 is expressed in various tissues in mice, especially in the lung, adrenal gland and brain. ABHD2 is a unidirectional type II membrane protein with hydratase catalytic activity and is involved in the migration of vascular smooth muscle cells. ABHD2 is first expressed in endothelial cells and then transferred to smooth muscle cells to inhibit cell migration and intimal hyperplasia. The ABHD2 gene is expressed in lung type II cells and is involved in alveolar phospholipid metabolism.

The ABHD2 knockout mice constructed by gene capture technology have decreased type II cells, decreased phosphatidylcholine content on the alveolar surface, and increased pulmonary macrophage infiltration, and are closely related to age. Reimann et al. found that spontaneous formation of emphysema in ABHD2 knockout mice was due to increased macrophage infiltration on the alveolar surface, protease/antiprotease imbalance, and excessive expression of proinflammatory cytokines. In unstable angina, the expression of ABHD2 is increased. It regulates lipid metabolism, causes plaque rupture, and promotes the progression of atherosclerotic lesions, which is a key factor in the progression of unstable angina. Atherosclerosis is a chronic inflammatory response caused by a variety of factors, of which the role of smooth muscle cells is particularly important.

ABHD2 gene deletion promotes vascular smooth muscle cell migration and promotes neointimal hyperplasia. Studies have shown that the number of alveolar type II epithelial cells in ABHD2 gene-deficient mice is reduced, the phosphatidylcholine (PC) content in bronchoalveolar lavage fluid (BALF) is decreased, and the PC content in lung homogenate is not significantly changed. This suggests that the decrease in PC content in BALF is due to a decrease in PC secretion levels or a disturbance in phospholipid metabolism on the alveolar surface, independent of a decrease in the number of alveolar epithelial cells. A clinical histological analysis of colorectal cancer gene expression data suggests that the ABHD2 gene may be involved in the development of colorectal cancer. Insertion of retroviruses in mice drives high expression of the ABHD2 gene in expression analysis of genes involved in the progression of brain tumors (gliomas). Related studies in the spread of human hepatitis B virus have shown that the ABHD2 gene blocks the spread of human hepatitis B virus. Thus, ABHD2 plays an important role in the occurrence and development of various diseases.

Abhd2 Figure 1. The function of ABHD2. (Robert Sanders. 2016).

ABHD2 and Emphysema

The pathological changes of emphysema are mainly the excessive expansion of the alveoli and the decrease of its elasticity. Related studies have shown that ABHD2 has hydrolase activity and is a member of the hydrolase protein family. The hydrolase protein family is screened from emphysema tissue genes. The team used the replaceable gene capture technology to find that the ABHD2 gene is expressed in smooth muscle cells, hepatic portal veins, alveolar cells, and bronchial smooth muscle cells. The smooth muscle cell migration and the intimal hyperplasia of ABHD2 knockout homozygous mice. By constructing ABHD2 gene-trapped mice (ABHD2Gt/Gt), compared with wild-type mice (ABHD2^+/+), it was found that the 12-month-old ABHD2 gene trapped mice had disordered alveolar surfactant metabolism and increased macrophage infiltration. Moreover, the inflammatory factors of the trachea are excessively secreted, the number of alveolar type II epithelial cells is decreased, abnormal apoptosis, alveolar structure destruction, and spontaneous formation of an age-related emphysema phenotype. This process is similar to the occurrence of human emphysema. Consistent with later related studies, ABHD2 is a down-regulated gene of emphysema.

ABHD2 and COPD

The main pathophysiological changes in COPD are pulmonary ventilation dysfunction caused by persistent airflow limitation. The combination of ventilation/blood flow imbalance and diffusion disorder leads to obstacles in ventilation function. The amino acid sequence encoded by the mouse ABHD2 gene is 99% identical to the human homologous gene product. It can be speculated that mouse ABHD2 should have a similar function to human ABHD2. Liu et al. analyzed the association of single-nucleotide polymorphisms (SNPs) in humans with the risk of COPD in the Han population and found that the rs12442260 polymorphism of ABHD2 gene may increase the risk of COPD. This study extracted genomic DNA from patients with COPD and normal controls, screened for SNPs in the ABHD2 gene, and compared their frequency with their smoking status and lung function. The results showed that the CT/CC genotype of the ABHD2 gene at rs12442260 increased the risk of COPD by 83%, especially in former smokers. This finding further supports the hypothesis that the ABHD2 gene plays an important role in the development of COPD. Rs12442260 is located in the fifth intron of the human ABHD2 gene, 489 bp upstream of the sixth exon.

References:

Reimann, S., Fink, L., Wilhelm, J., Hoffmann, J., Bednorz, M., & Seimetz, M., et al. (2015). Increased s100a4 expression in the vasculature of human copd lungs and murine model of smoke-induced emphysema. Respir Res, 16(1), 127.
Barnawi, J., Hai, T., Jersmann, H., Pitson, S., Roscioli, E., & Hodge, G., et al. (2015). Potential link between the sphingosine-1-phosphate (s1p) system and defective alveolar macrophage phagocytic function in chronic obstructive pulmonary disease (copd). Plos One, 10(10), e0122771.
Ivan, B., Steven, B., & Ross, V. (2015). Targeting oxidant-dependent mechanisms for the treatment of copd and its comorbidities. Pharmacology & Therapeutics, 155, 60-79.
Liu, L., Li, X., Yuan, R., Zhang, H., Qiang, L., & Shen, J., et al. (2015). Associations of abhd2 genetic variations with risks for chronic obstructive pulmonary disease in a chinese han population. Plos One, 10(4), e0123929.

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