Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism

Abstract

Monoacyglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze two consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT enzymes that differ in catalytic properties, subcellular localization, tissue distribution, and physiological functions. MGAT and DGAT enzymes play fundamental roles in the metabolism of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiological functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT enzymes and the development of chemical inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT enzymes by synthetic compounds may provide novel treatment for obesity and its related metabolic complications.

Fig. 1.

The 2 metabolic pathways involved in the synthesis of triacylglycerol (TAG). The monoacylglycerol (MAG) pathway, also known as the remodeling pathway, begins with the acylation of MAG with fatty acyl-CoA catalyzed by monoacylglycerol acyltransferase (MGAT). This pathway dominates in the small intestine, a tissue primarily responsible for dietary fat absorption. The glycerol 3-phosphate (G-3-P) pathway is a de novo pathway involved in TAG synthesis in most tissues. The G-3-P pathway begins with the acylation of G-3-P by glycerol-3-phosphate acyltransferase (GPAT) with fatty acyl-CoA, producing lysophosphatidic acid (LPA), followed sequentially by further acylation by LPA acyltransferase (LPAAT) and dephosphorylation by phosphatidic acid (PA) phosphorylase (PAP) to yield diacylgycerol (DAG). The 2 pathways share the final step in converting DAG into TAG, which is catalyzed by diacylglycerol acyltransferase (DGAT). DAG is also used as a substrate for the synthesis of phosphatidic choline (PC) and phosphatidic ethanolamine (PE).

Fig. 2.

MGAT and DGAT enzymes are implicated in multiple pathways that regulate energy homeostasis. MGAT and DGAT enzymes play important roles in energy metabolism by regulating satiety in the brain (mediated by MAG), dietary fat absorption in the gut (in the form of TAG), phospholipid synthesis and VLDL secretion in the liver (in the form of DAG and TAG), fat storage in adipocytes (in the form of TAG), and insulin sensitivity in skeletal muscle (mediated by DAG).

Fig. 3.

The process of dietary lipid digestion and absorption. A: the digestion of dietary lipids begins in the stomach, where lipids are subjected to partial digestion by gastric lipase, forming large fat globules with a hydrophobic TAG core surrounded by polar molecules, including phospholipids (PL), free cholesterol (CL), fatty acids (FA), and ionizing proteins. The digestive processes are completed in the intestinal lumen, where large emulsions of fat globules are mixed with bile salts (BS) and pancreatic juice containing lipid digestive enzymes to form an aqueous suspension of small fatty droplets with maximized exposure to the pancreatic lipases for lipid hydrolysis. MAG, LPA, DAG, and free FA that are released from lipid and phospholipid hydrolysis join BS, CL, and fat-soluble vitamins to form mixed micelles for dietary fat absorption at the brush border of the enterocytes. B: after entering the enterocyte, MAG, LPA, and CL have to be reacylated before they can be absorbed. MAG is sequentially acylated by MGAT and DGAT enzymes to form TAG. LPA is acylated by LPAAT to PA followed by dephosphorylation by PAP to yield DAG. Dietary cholesterol (CL) is acylated by acyl-CoA:cholesterol acyltransferase (ACAT) to cholesteryl esters (CE). Facilitated by microsomal triglyceride transfer protein (MTP), TAG joins CE and apolipoprotein B (apoB) to form chylomicrons that are secreted to the lymph for circulation.

Fig. 4.

A hypothetical model for the regulation of insulin sensitivity by the MGAT and DGAT enzymes. Obesity is associated with increased free fatty acid (FFA) influx to skeletal muscle, resulting in increased levels of intramyocellular TAG and other intracellular lipotoxic FA derivatives, such as DAG and ceramide. FFA enters muscles cells, where it is converted to long-chain fatty acyl-CoAs that are used for either the synthesis of DAG, ceramide, or β-oxidation in the mitochondria. DAG can also be generated from hydrolysis of triglyceride or phospholipids catalyzed by phospholipase C (PLC). DAG and ceramide are known to cause hyperactivation of multiple isoforms of protein kinase Cs (PKCs) and c-Jun NH₂-terminal kinase (JNK), which phosphorylate serine residues on insulin receptor substrate-1 (IRS-1), leading to insulin resistance. Accordingly, inactivation of MGAT or overexpresion of DGAT in skeletal muscle is envisaged to improve insulin sensitivity by preventing the intracellular accumulation of DAG.