Diacylglycerol O-acyltransferase 2 (DGAT2) is an enzyme fundamental to how mammals manage and store energy. It is a member of the Diacylglycerol O-acyltransferase (DGAT) family, which represents the final step in the body’s fat-storage pathway. This enzyme converts smaller fat molecules into the larger, inert form used for long-term storage, a process necessary for maintaining energy balance throughout the body. Understanding the role of DGAT2 offers significant insight into systemic energy regulation and the development of common metabolic conditions.
The Core Biochemical Reaction
The primary function of DGAT2 is to catalyze the final and committed step in the synthesis of triacylglycerol (TAG), more commonly known as triglycerides. This reaction converts a simpler lipid, diacylglycerol (DAG), into the larger, storage-ready TAG molecule. The enzyme achieves this by attaching a third fatty acid chain to the DAG backbone.
The process requires a fatty acid chain to be activated by coenzyme A, forming fatty acyl-CoA, which acts as the donor molecule. DGAT2 transfers the fatty acyl portion of fatty acyl-CoA to the remaining free hydroxyl group on the DAG structure. The resulting product, TAG, is chemically inert and is the most common form of stored energy, packaged into lipid droplets.
Because DGAT2 is responsible for this last step, its activity is considered rate-limiting for fat storage in many tissues. The reaction handles excess energy by quickly sequestering fatty acids into storage pools. This prevents the buildup of toxic lipid intermediates, such as DAG, which can interfere with cellular signaling pathways if left unchecked.
Cellular Location and Tissue Distribution
DGAT2 is an integral membrane protein found primarily in the endoplasmic reticulum (ER). The enzyme is embedded in the ER membrane, with its active site oriented toward the cytoplasm, where the necessary precursor molecules are found.
The location in the ER is strategic, as this organelle is the hub for lipid synthesis and processing within the cell. DGAT2 can also be found at the interface where the ER physically contacts mitochondria and on the surface of cytosolic lipid droplets (CLDs). This unique localization allows the enzyme to synthesize new TAG directly onto the growing fat storage structures.
The enzyme is widely distributed throughout the body, but its expression is highest in tissues that specialize in lipid metabolism. These include the liver, where it manages fat export and storage, and adipose tissue, which serves as the body’s main energy reservoir. High expression is also noted in the small intestine, where it processes dietary fats, and in the lactating mammary gland for milk fat production.
Distinguishing DGAT2 from DGAT1
While DGAT2 and its counterpart, DGAT1, both catalyze the same final step in triglyceride synthesis, they are structurally and functionally distinct, having evolved separately. DGAT2 belongs to a gene family that includes other acyltransferases, while DGAT1 is evolutionarily unrelated and shares no sequence homology. This difference in origin results in variations in their physical structure; for example, DGAT2 has far fewer membrane-spanning regions than DGAT1.
Their separate evolution has led to distinct physiological roles and preferred substrates. DGAT2 appears to be the dominant enzyme for overall systemic triglyceride storage; loss of the DGAT2 gene is incompatible with life in mammals due to extremely low body fat content. DGAT1, in contrast, is more specialized in synthesizing triglycerides for the assembly of lipoproteins, which transport fats out of the intestine and liver.
DGAT2 is thought to preferentially utilize fatty acids that are newly synthesized within the cell, known as de novo lipogenesis. DGAT1, however, seems to have a higher preference for exogenous fatty acids derived from the diet. This difference in substrate preference suggests that DGAT2 is more involved in handling carbohydrate and protein overconsumption that gets converted to fat, while DGAT1 is more active after a high-fat meal.
The two isoforms also differ in their cellular regulation and specific subcellular placement within the ER network. This functional specialization means that although they perform the same chemical reaction, they contribute to different aspects of cellular and systemic energy management.
Significance in Metabolic Health
DGAT2 activity regulates the body’s neutral lipid stores and is linked to metabolic health. When energy intake exceeds expenditure, increased DGAT2 activity leads to excessive triglyceride accumulation in tissues like the liver and muscle. This overproduction and improper storage of fat are strongly associated with the development of obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD).
In the liver, high DGAT2 activity can lead to hepatic steatosis, or fatty liver, where excess triglycerides build up. This accumulation can be accompanied by an increase in the precursor molecule, diacylglycerol (DAG). Elevated DAG levels can interfere with insulin signaling by activating a protein called Protein Kinase C-epsilon (PKCε), which subsequently impairs the cell’s ability to respond to insulin, leading to insulin resistance.
Similar mechanisms link DGAT2 to insulin resistance in skeletal muscle. Overexpression of DGAT2 in muscle tissue promotes lipid deposition, which impairs the muscle cells’ ability to take up and utilize glucose in response to insulin. The resulting insulin resistance in both the liver and muscle is a feature of Type 2 diabetes.
Due to its role as the committed step in fat storage, DGAT2 has become a major target for therapeutic intervention in metabolic disorders. Inhibiting the enzyme reduces the synthesis of triglycerides, thereby decreasing fat accumulation in the liver and improving overall metabolic function. Early clinical trials with DGAT2 inhibitors have demonstrated a significant reduction in liver fat content in patients with NAFLD.