Introduction
Diacylglycerol O-acyltransferase 1 (DGAT1) is an enzyme that catalyzes the final step in the synthesis of triacylglycerol (TAG), a key component of cellular energy stores and lipid transport. DGAT1 is encoded by the DGAT1 gene located on chromosome 19 in humans. The enzyme functions primarily in the endoplasmic reticulum (ER) membrane, where it facilitates the acylation of diacylglycerol (DAG) with a fatty acyl-CoA to form TAG. Through its role in lipid metabolism, DGAT1 influences a broad spectrum of physiological processes, including adipogenesis, hepatic lipid accumulation, intestinal fat absorption, and the maintenance of cellular membrane integrity. Dysregulation of DGAT1 activity has been implicated in metabolic disorders such as obesity, fatty liver disease, and congenital diarrheal disorders, making it a target of intense research interest in both basic biology and therapeutic development.
Gene and Protein
Gene Structure and Location
The DGAT1 gene spans approximately 10 kilobases of genomic DNA and consists of 14 exons. It is located on the short arm of chromosome 19, specifically at 19p13.12. The gene exhibits a single transcription start site and produces a primary mRNA transcript that is 2.4 kilobases in length. Alternative splicing events have been reported, but the predominant isoform encodes the full-length protein used in most functional studies.
Protein Architecture
DGAT1 is a polytopic ER membrane protein composed of 492 amino acids. Structural analysis reveals the presence of multiple transmembrane domains interspersed with short luminal and cytosolic loops. The N-terminus contains a signal anchor that directs the nascent polypeptide to the ER, while the C-terminus remains cytosolic. Within the transmembrane region, conserved motifs essential for catalytic activity have been identified, including a HXXXXD catalytic dyad that participates in the acyl transfer reaction. The protein is predicted to form a homodimer or higher-order oligomer, a configuration that may be critical for substrate binding and enzymatic stability.
Subcellular Localization
DGAT1 resides predominantly in the ER membrane. Immunofluorescence microscopy using DGAT1-specific antibodies demonstrates co-localization with ER markers such as calnexin and protein disulfide isomerase. In hepatocytes and adipocytes, DGAT1 also associates with lipid droplets, suggesting a dynamic redistribution that may facilitate TAG synthesis at sites of neutral lipid accumulation. Live-cell imaging indicates that DGAT1 trafficking between the ER and lipid droplets is regulated by nutritional cues, notably the presence of fatty acids.
Tissue Expression Profile
Quantitative RT-PCR and proteomic analyses reveal a broad distribution of DGAT1 across multiple tissues. High expression levels are found in adipose tissue, liver, and small intestine, reflecting the enzyme’s role in lipid storage, hepatic lipid synthesis, and intestinal triglyceride assembly. Additional expression is detected in the pancreas, reproductive tissues, and the brain, albeit at lower levels. Notably, DGAT1 expression is upregulated during adipocyte differentiation and in response to high-fat diet feeding, indicating a role in adipose tissue expansion and metabolic adaptation.
Biochemical Function
Catalytic Mechanism
DGAT1 catalyzes the esterification of a fatty acyl-CoA to diacylglycerol, yielding triacylglycerol and coenzyme A. The reaction proceeds through a nucleophilic attack of the fatty acyl-CoA on a catalytic histidine residue, forming a transient acyl-enzyme intermediate. Subsequently, the intermediate reacts with the 3-hydroxyl group of diacylglycerol, releasing TAG and regenerating the free enzyme. Structural studies have identified key residues that coordinate the fatty acyl-CoA substrate and stabilize the transition state.
Substrate Specificity
DGAT1 displays a preference for long-chain fatty acyl-CoAs, particularly those containing 16–18 carbon atoms. The enzyme accepts saturated and monounsaturated fatty acids with similar efficiencies, while polyunsaturated substrates are incorporated less efficiently. Saturated fatty acids such as palmitoyl-CoA and stearoyl-CoA serve as robust substrates in vitro, whereas arachidonoyl-CoA exhibits reduced turnover. The enzyme’s specificity extends to the diacylglycerol moiety, favoring glycerol backbones with saturated fatty acyl chains at the sn-1 and sn-2 positions.
Role in Triacylglycerol Synthesis
DGAT1 operates in concert with DGAT2, the second enzyme capable of TAG synthesis. While both enzymes contribute to the final step of TAG biosynthesis, they display complementary substrate preferences and subcellular localizations. DGAT1 is particularly important for TAG synthesis in the intestine and adipose tissue, whereas DGAT2 predominates in the liver. Knockout studies in mice have shown that loss of DGAT1 reduces intestinal TAG synthesis, impairs fat absorption, and leads to decreased hepatic TAG stores, underscoring the enzyme’s physiological relevance.
Physiological Roles
Energy Homeostasis and Adipogenesis
In adipocytes, DGAT1 is critical for the accumulation of lipid droplets. During adipogenesis, upregulation of DGAT1 facilitates the esterification of fatty acids into TAG, promoting the expansion of storage organelles. Mice lacking DGAT1 exhibit reduced adiposity, decreased TAG accumulation in adipose tissue, and increased fatty acid oxidation. These findings suggest that DGAT1 activity modulates the balance between lipid storage and utilization, thereby influencing overall energy homeostasis.
Liver Lipid Metabolism
DGAT1 contributes to hepatic TAG synthesis and secretion. In hepatocytes, the enzyme is involved in the formation of very-low-density lipoproteins (VLDL) by incorporating TAG into nascent lipoproteins. Deletion of DGAT1 in liver-specific knockouts reduces VLDL secretion, leading to hepatic steatosis in the context of a high-fat diet. Conversely, pharmacological inhibition of DGAT1 has been shown to lower plasma TAG levels, highlighting its therapeutic potential in dyslipidemia management.
Intestinal Fat Absorption
In enterocytes, DGAT1 catalyzes the re-esterification of dietary fatty acids into TAG, a key step in chylomicron assembly. Genetic ablation or pharmacologic inhibition of DGAT1 in mice impairs chylomicron formation, resulting in reduced fat absorption and subsequent weight loss. This effect underscores the enzyme’s essential role in dietary fat processing and systemic lipid transport.
Reproductive Physiology
DGAT1 is expressed in ovarian tissue and in testicular Leydig cells, suggesting a role in steroidogenesis and gamete development. In the ovary, TAG synthesis via DGAT1 may provide energy reserves for oocyte maturation. Studies in murine models indicate that DGAT1 deficiency can impair follicular development and reduce fertility, although the precise mechanisms remain under investigation.
Neuronal Function
Although expressed at lower levels in the brain, DGAT1 may contribute to neuronal membrane lipid remodeling and signaling pathways. Emerging evidence points to a role for DGAT1-derived TAGs in modulating synaptic plasticity and neuroinflammatory responses. Further research is required to elucidate the enzyme’s involvement in neurophysiology and neuropathology.
Genetic Variants and Human Disease
Congenital Diarrheal Disorder
A recessive loss-of-function mutation in DGAT1 causes a rare congenital diarrheal disorder characterized by chronic watery diarrhea, failure to thrive, and steatorrhea. The disease results from impaired intestinal TAG synthesis, leading to malabsorption of dietary lipids. Clinical management involves lipid supplementation and dietary modifications. Identification of pathogenic variants in patients has facilitated genetic counseling and targeted therapy development.
Lipid Metabolism Disorders
Polymorphisms in DGAT1 have been associated with altered plasma TAG levels and insulin sensitivity. Certain single nucleotide polymorphisms (SNPs) correlate with reduced TAG synthesis and lower risk of type 2 diabetes, suggesting a protective effect. Conversely, other variants may predispose individuals to hypertriglyceridemia and cardiovascular disease. Genome-wide association studies have highlighted DGAT1 as a locus of interest in metabolic trait analysis.
Other Clinical Associations
Emerging reports link DGAT1 activity to non-alcoholic fatty liver disease (NAFLD), where overexpression may exacerbate hepatic steatosis. Additionally, altered DGAT1 expression has been observed in certain cancers, including colorectal and breast carcinoma, where it may contribute to tumor cell lipid metabolism and survival. However, the causal relationships in these contexts remain to be clarified.
Animal Models
Mouse
Global knockout of DGAT1 in mice leads to growth retardation, reduced body fat, and increased fatty acid oxidation. Tissue-specific knockouts reveal distinct phenotypes: intestinal deletion impairs fat absorption, liver deletion alters VLDL secretion, and adipose deletion reduces lipid droplet formation. Conditional knockouts enable the dissection of DGAT1’s role in adult metabolism versus developmental processes.
Rat
DGAT1-deficient rats exhibit phenotypic traits similar to mice, including reduced adiposity and impaired fat absorption. Pharmacological studies in rat models have demonstrated that DGAT1 inhibitors lower plasma TAG levels and improve insulin sensitivity, supporting translational relevance of the enzyme as a drug target.
Zebrafish
Morpholino-mediated knockdown of dgata1 in zebrafish embryos results in defective lipid accumulation and increased apoptosis in the liver. These models provide a rapid platform for assessing DGAT1 function in vertebrate development and for screening chemical modulators of TAG synthesis.
Regulation
Transcriptional Control
DGAT1 expression is regulated by a network of transcription factors responsive to metabolic cues. Sterol regulatory element-binding protein 1c (SREBP-1c) upregulates DGAT1 in response to insulin signaling and fatty acid levels. Peroxisome proliferator-activated receptor gamma (PPARγ) also enhances transcription during adipocyte differentiation. In contrast, negative regulation by liver X receptor (LXR) occurs under cholesterol overload conditions, balancing lipid synthesis with storage.
Post-Translational Modifications
Phosphorylation of DGAT1 influences its enzymatic activity and stability. Casein kinase 2 (CK2) phosphorylates serine residues within the cytosolic tail, enhancing catalytic efficiency. Ubiquitination targets DGAT1 for proteasomal degradation, allowing rapid turnover in response to metabolic shifts. Glycosylation within luminal loops may affect protein folding and ER localization.
Hormonal Regulation
Insulin and leptin stimulate DGAT1 activity via signaling cascades that modulate transcription and post-translational modifications. Glucagon and epinephrine exert opposite effects, decreasing DGAT1 expression and promoting fatty acid mobilization. These hormonal controls integrate DGAT1 function with systemic energy balance.
Structure and Mechanism
Domain Architecture
Computational modeling and limited experimental data suggest that DGAT1 possesses a central catalytic core flanked by transmembrane helices that form a pocket accommodating the fatty acyl-CoA substrate. The catalytic dyad (His and Asp residues) resides within a conserved motif that aligns with the active sites of other acyltransferases. The ER luminal loops contribute to substrate specificity and may interact with accessory proteins.
Crystallography and High-Resolution Studies
Attempts to crystallize DGAT1 have been hampered by its membrane-bound nature. Cryo-electron microscopy (cryo-EM) has recently provided insights into the protein’s conformation, revealing a dimeric arrangement with a central lipid-binding cavity. These studies are instrumental in guiding the design of small-molecule inhibitors that occupy the catalytic site.
Key Residues and Mutagenesis
Site-directed mutagenesis of the His residue in the catalytic dyad abolishes activity, confirming its essential role. Substitutions in neighboring residues alter substrate preference, providing evidence for a finely tuned active site architecture. Analysis of human pathogenic variants indicates that missense mutations often disrupt folding or catalytic function, leading to loss-of-function phenotypes.
Therapeutic Implications
DGAT1 Inhibitors
Selective DGAT1 inhibitors have entered clinical development for the treatment of hypertriglyceridemia and type 2 diabetes. Preclinical studies show that oral inhibitors reduce plasma TAG levels, improve insulin sensitivity, and attenuate hepatic steatosis. Phase II trials indicate tolerable safety profiles, although some gastrointestinal adverse effects, such as steatorrhea, emerge from impaired intestinal TAG synthesis.
Gene Therapy
Gene replacement strategies aim to correct DGAT1 deficiency in congenital diarrheal disorders. Viral vectors delivering functional DGAT1 cDNA to enterocytes have restored intestinal TAG synthesis in animal models. Challenges include achieving targeted expression and long-term safety.
Metabolic Disease Management
Modulating DGAT1 activity offers a dual benefit of lowering plasma TAG and reducing ectopic fat deposition. Nutrient-based interventions that modulate enzyme expression, such as dietary fatty acid composition and caloric restriction, complement pharmacologic approaches. The enzyme’s role in adipocyte expansion also positions DGAT1 as a target for anti-obesity therapies.
Cancer Therapeutics
Since certain tumors exhibit elevated DGAT1 expression, inhibitors may impair lipid supply critical for rapidly proliferating cancer cells. Early studies in breast and colorectal cancer cell lines demonstrate reduced proliferation upon DGAT1 knockdown. However, the therapeutic window and specificity require further validation.
Research Applications
Biotechnological Production of TAGs
DGAT1 is employed in metabolic engineering to enhance TAG production in microorganisms and plants. Overexpression in yeast increases oil yield, while engineered plants with elevated DGAT1 produce higher seed oil content. These strategies hold promise for biofuel and nutraceutical production.
Modeling Human Lipid Disorders
Recombinant expression of DGAT1 variants in cultured cells permits functional analysis of disease-associated mutations. CRISPR/Cas9-mediated introduction of pathogenic variants into induced pluripotent stem cells (iPSCs) allows differentiation into intestinal or hepatic organoids, providing disease models for drug screening.
Structure-Based Drug Design
The emerging cryo-EM structures of DGAT1 guide rational inhibitor development. Computational docking of compound libraries into the catalytic cavity facilitates identification of high-affinity inhibitors. Iterative medicinal chemistry refines potency, selectivity, and pharmacokinetic properties.
Conclusion
DAG-ACP O-acyltransferase 1 (DGAT1) is a pivotal enzyme in triglyceride biosynthesis, with broad physiological functions spanning energy storage, lipid absorption, and endocrine regulation. Genetic mutations in DGAT1 underpin a rare congenital diarrheal syndrome and influence metabolic risk profiles. A multitude of animal models and emerging structural data support its candidacy as a therapeutic target for metabolic and possibly oncologic diseases. Continued research into its regulatory mechanisms, structural nuances, and translational applications will advance both basic science and clinical interventions.
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