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In May 2014, the CHUM Research Center at the University of Montreal found that an enzyme called abhydrolase domain containing 6, ABHD6, could destroy monoacylglycerol and negatively regulate insulin release. Thomas et al. found that inhibition of ABHD6 can enhance the response of β cells to glucose, increase the level of insulin expression in the blood, and increase the sensitivity of their tissues to insulin in order to reduce blood sugar. Therefore, ABHD6 is expected to be a unique new target for the treatment of type 2 diabetes.
ABHD6 is a protein of 337 amino acids with a relative molecular mass of 38,331. The amino acids 1 to 8 form the N-terminal extracellular region. The 9th to 29th amino acids constitute the helix region and are type II membrane protein signal anchors. The 30th to 337th amino acids constitute the intracellular region, in which 148th nucleophilic serine, 278th acid aspartic acid, and highly conserved 306th histidine form a highly conserved catalytic triad. ABHD6 is widely distributed in normal tissues of the human body, with higher contents such as brain, liver and brown adipose tissue.
ABHD6 Function and Mechanism of Action
As a newer target for metabolic diseases and inflammation, ABHD6 has been shown to have three main effects: 1. Regulating lipid metabolism and insulin secretion; 2. Regulating inflammation and neurological diseases through endogenous cannabinoid signaling; 3. Promoting white adipose issue (WAT) browning and regulating brown adipose issue (BAT) function, thereby regulating systemic energy homeostasis.
The process by which pancreatic beta cells secrete insulin requires the involvement of various cytokines and protein kinase substrates localized on the cell membrane. Monoacylglycerol (MAG) (especially long-chain saturated 1-MAG) plays a key role in this process. MAG can bind to the C1 domain of the Munc-13 protein, and transfer Munc-13 protein to the cell membrane to form a complex soluble NSF attachment protein receptor (SNARE) protein complex. In turn, the vesicles are matured and the efflux of insulin particles is accelerated. ABHD6 is capable of hydrolyzing MAG to produce glycerol and free fatty acids, thereby negatively regulating insulin secretion. Excessive glycerol and fatty acids produced by hydrolysis at the same time can also cause insulin resistance.
Figure 1. Model illustrating how the ABHD6/1-MAG/Munc13-1 network regulates insulin secretion in response to various classes of insulin secretagogues. (Zhao, et al. 2015).
Other studies have shown that diacylglycerol (DAG) is an important source of arachidonic acid (AA) in humans and is a major precursor of prostaglandins and an important signaling molecule in cells. DAG can activate protein kinase C (PKC) and enhance insulin secretion in vivo. DAG can be hydrolyzed by diacylglycerol lipase (DAGL) to form 2-arachidonoylglycero (2-AG), which is then hydrolyzed by ABHD6 to form glycerol and arachidonic acid. Inhibition of ABHD6 and inhibition of the hyper hydrolysis of 2-AG can negatively regulate DAG levels in the body, thereby increasing insulin secretion.
The endogenous cannabis system is composed of cannabinoid receptors, endocannabinoids and endogenous cannabinoid degrading enzymes, which regulates human body emotions and pain sensations, and also plays an important role in cardiovascular regulation and energy metabolism. Endogenous cannabinoids are N-arachidonic acid aminoethanol (anandamide, AEA) and 2-AG. 2-AG can be hydrolyzed by monoglyceride lipolytic enzyme (MAGL), ABHD6, ABHD12 in different tissues to produce AA. 2-AG is involved in the metabolic pathways of various inflammatory factors, such as the production of prostaglandins by the cyclooxygenase (COX) pathway; it is involved in the lipoxygenase (LOX) pathway, producing leukotriene family cytokines. ABHD6 regulates the levels of inflammatory factors such as anti-inflammatory bioactive lipids in the body by regulating the level of 2-AG in the body.
The downstream fat signal MAG activates PPARα (peroxisome proliferator-activated receptors α ) and PPARγ ( peroxisome proliferator-activated receptors γ ) pathways to promote BAT formation and enhance its effects. Energy consumption is increased by fatty acid oxidation and non-shivering heat production while increasing glucose tolerance and insulin sensitivity, and reducing fat content to maintain energy homeostasis. Townsend et al found that inhibition of ABHD6 can increase intracellular MAG content and regulate BAT content and function, which plays a crucial role in preventing and treating diabetes caused by obesity and obesity.
Small Molecule ABHD6 Inhibitor
ABHD6 has many potential advantages as a therapeutic target for diabetes: First, because of its small molecule inhibitors that regulate insulin secretion in a dose-dependent manner, the risk of hypoglycemia can be reduced or avoided. Secondly, the concentration and specificity of ABHD6 distribution in vivo also greatly reduce the adverse reactions of its inhibitors in reducing blood glucose. In view of the important role played by ABHD6 in lowering blood glucose, research institutions such as Scripps Research Institute and Montreal Medical Center have conducted extensive research. Several small molecule ABHD6 inhibitors have entered the preclinical research phase. However, the conversion of ABHD6 inhibitors into drugs still faces some challenges. For example, Prambanig et al. found that the role of ABHD6 in autoimmune cerebrospinal inflammation is not clear; Zhao et al found that ABHD6 inhibitors cannot be ignored in the central nervous system; whether it can be deeply analyzed from a molecular perspective; how to choose the best combination therapy methods, etc.