Diacylglycerol O-acyltransferase 2, or DGAT2, is an enzyme that plays a specific part in the body’s metabolism. It functions as an acyltransferase, meaning it helps transfer a fatty acid group from one molecule to another. DGAT2 facilitates the joining of a diacylglycerol (DAG) with a fatty acyl-CoA to create triglycerides, a type of fat. This process is a foundational step in how the body manages and stores energy.
How DGAT2 Works
DGAT2 performs a specific reaction in the body, which is the final step in the synthesis of triglycerides. This enzyme takes two main ingredients: diacylglycerol (DAG) and fatty acyl-CoA, and combines them to produce a triglyceride molecule. This reaction takes place mainly in the endoplasmic reticulum, a network of membranes within cells.
Once formed, triglycerides serve as the body’s primary way to store energy. They are packed into lipid droplets within the cell, particularly in tissues like the liver and adipose (fat) tissue, which are specialized for fat storage. When the body needs energy, these stored triglycerides can be broken down.
DGAT2 also has the ability to associate with lipid droplets directly, especially when cells are exposed to fatty acids. This association allows DGAT2 to catalyze triglyceride synthesis right where the lipid droplets are expanding.
DGAT2 and Metabolic Health
The activity of DGAT2 has direct connections to a person’s metabolic health. When there is too much DGAT2 activity, it can lead to an overproduction and buildup of triglycerides within the body. This excessive accumulation of fat is a factor in several metabolic conditions.
One such condition is non-alcoholic fatty liver disease (NAFLD), where too much fat accumulates in the liver. NAFLD can progress to more severe stages like steatohepatitis and even liver cirrhosis if not managed. DGAT2 contributes to NAFLD by increasing the synthesis of triglycerides in the liver.
Increased DGAT2 activity is also linked to obesity and type 2 diabetes. In both NAFLD and type 2 diabetes, there’s often an underlying issue of insulin resistance, which can further promote the accumulation of free fatty acids in the liver and impair fat breakdown in adipose tissue. This imbalance in lipid metabolism, partly driven by DGAT2, contributes to the development and progression of these interconnected health concerns.
Targeting DGAT2 for Treatment
Researchers are investigating DGAT2 as a potential target for developing new treatments for metabolic diseases. The idea is to adjust DGAT2’s activity to help manage conditions like non-alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes. Inhibiting DGAT2, for example, could reduce the excessive synthesis of triglycerides.
By directly blocking the DGAT2 enzyme, scientists aim to decrease the overall production of triglycerides. This reduction in triglyceride synthesis can lead to less fat accumulation in tissues such as the liver and adipose tissue. Lowering circulating triglyceride levels in the bloodstream is also a potential benefit, which could help reduce risks associated with cardiovascular diseases.
Preclinical studies have shown promise for DGAT2 inhibitors, with some compounds demonstrating effectiveness in animal models of metabolic disease. Certain small-molecule DGAT2 inhibitors have been developed. These efforts represent a forward-looking approach to addressing the challenges posed by metabolic disorders.