Introduction
Diacylglycerol O-acyltransferase 1 (DGAT1) is an integral membrane enzyme that catalyzes the final step in triglyceride synthesis, transferring a fatty acyl group from acyl‑CoA to diacylglycerol (DAG) to form triacylglycerol (TAG). The reaction it facilitates is essential for the storage of fatty acids in adipose tissue and for the secretion of very‑low‑density lipoproteins (VLDL) from hepatocytes. DGAT1 is encoded by the DGAT1 gene located on chromosome 10q26.3 in humans. Because of its central role in lipid metabolism, DGAT1 has been studied extensively in the contexts of obesity, diabetes, atherosclerosis, and gastrointestinal disorders. The enzyme is also a target for drug development, and its inhibition has shown promise in preclinical models of metabolic disease.
Gene and Protein Overview
Genomic Context
The DGAT1 gene spans approximately 30 kilobases and comprises 8 exons. It is located in the 10q26.3 cytogenetic band, adjacent to the DGAT2 gene, which encodes a related acyltransferase. Alternative splicing events generate at least two transcript variants that encode proteins differing at the C‑terminus. The promoter region of DGAT1 contains binding sites for transcription factors such as PPARγ, C/EBPα, and SREBP‑1c, reflecting its regulation by lipid metabolic cues.
Protein Architecture
DGAT1 is a 471‑amino‑acid protein with a calculated molecular weight of ~52 kDa. The enzyme is predicted to contain 10–12 transmembrane helices, consistent with its localization to the endoplasmic reticulum (ER) and lipid droplet surfaces. Key catalytic residues include a conserved histidine (His-242) and a cysteine (Cys-269) that form a catalytic dyad. The active site resides within a hydrophilic cavity that is accessible from the ER lumen. The N‑terminus is cytosolic, while the C‑terminus extends into the ER lumen and participates in protein–protein interactions with lipid‑droplet–associated proteins.
Structure and Catalytic Mechanism
Three‑Dimensional Configuration
High‑resolution cryo‑electron microscopy of the yeast homolog Lro1 has been used to model the human DGAT1 structure. The model reveals a central β‑barrel that accommodates the acyl‑CoA substrate and a surrounding α‑helical scaffold that positions the diacylglycerol. The enzyme’s architecture facilitates a “ping‑pong” mechanism, whereby the acyl‑CoA first binds to the active site, the acyl group is transferred to the catalytic histidine, and then DAG binds to accept the acyl group, forming TAG and releasing CoA.
Substrate Specificity
DGAT1 exhibits broad specificity for fatty acyl donors, accepting saturated, monounsaturated, and polyunsaturated acyl‑CoA species. Diacylglycerol substrates of various fatty acid compositions are also tolerated, though the enzyme shows a preference for long‑chain saturated and monounsaturated DAGs. The enzyme’s broad substrate range underlies its capacity to modulate lipid composition in cellular membranes and lipid droplets.
Inhibitory Mechanisms
Competitive inhibitors such as the long‑chain fatty acid analogs and the small molecules 4‑octylphenylphosphate and CP‑609,474 bind to the acyl‑CoA pocket, preventing substrate access. Non‑competitive inhibitors, including avasimibe and TVB‑2640, are thought to bind at allosteric sites that destabilize the catalytic dyad. These inhibitors have been instrumental in dissecting DGAT1 function in vivo and in therapeutic development.
Biological Function
Triglyceride Synthesis
DGAT1 catalyzes the conversion of DAG and acyl‑CoA into TAG, the predominant storage form of fatty acids in adipocytes. By providing the final step of TAG assembly, DGAT1 regulates intracellular TAG accumulation and influences lipid droplet biogenesis. The enzyme’s activity is tightly linked to the availability of DAG, which itself is produced via phospholipase C activity or dephosphorylation of phosphatidic acid.
Lipid Droplet Formation and Turnover
TAG synthesized by DGAT1 is deposited within neutral lipid cores that constitute lipid droplets. These organelles serve as energy reservoirs and are sites of dynamic lipid exchange. DGAT1 interacts with perilipin and other lipid droplet proteins to facilitate TAG synthesis and storage. During lipolysis, DGAT1 activity can be down‑regulated to favor TAG hydrolysis by adipose triglyceride lipase (ATGL).
Very‑Low‑Density Lipoprotein Secretion
In hepatocytes, DGAT1 contributes to the assembly of VLDL particles by providing TAG for the lipid core. The enzyme’s activity influences the secretion rate of VLDL and, consequently, plasma triglyceride levels. Modulation of hepatic DGAT1 has been associated with altered lipid profiles and hepatic steatosis in animal models.
Regulation and Expression
Transcriptional Control
Expression of DGAT1 is induced by dietary fat intake, insulin, and adipogenic stimuli. PPARγ and C/EBPα directly activate the DGAT1 promoter. Sterol regulatory element‑binding protein 1c (SREBP‑1c) also up‑regulates DGAT1 in response to insulin signaling, linking DGAT1 expression to metabolic state. Conversely, fasting and glucagon decrease DGAT1 transcription, reflecting the enzyme’s role in lipid storage.
Post‑Translational Modifications
Phosphorylation of DGAT1 by protein kinase C (PKC) and AMP‑activated protein kinase (AMPK) modulates enzymatic activity. PKC phosphorylation enhances DGAT1 stability and activity, while AMPK phosphorylation reduces enzyme function during energy deficit. Ubiquitination of DGAT1 targets the protein for proteasomal degradation, allowing rapid turnover under changing metabolic conditions.
Tissue Distribution
DGAT1 is expressed in adipose tissue, liver, small intestine, pancreas, skeletal muscle, and brain. In the intestine, DGAT1 is essential for the esterification of dietary fatty acids within enterocytes, facilitating micelle formation and absorption. High expression levels are observed in visceral adipose tissue and hepatic tissue, consistent with the enzyme’s role in lipid storage and lipoprotein assembly.
Physiological Roles
Energy Homeostasis
By controlling TAG synthesis, DGAT1 influences energy storage and mobilization. In adipocytes, DGAT1 activity determines the rate at which fatty acids are sequestered as TAG, impacting insulin sensitivity and whole‑body glucose metabolism. In skeletal muscle, DGAT1 contributes to intramuscular TAG accumulation, affecting metabolic flexibility and endurance performance.
Digestive Lipid Absorption
In enterocytes, DGAT1 esterifies mono‑ and diacylglycerols into TAG for incorporation into chylomicrons. Inhibition of intestinal DGAT1 reduces postprandial triglyceride absorption, attenuating hypertriglyceridemia and potentially protecting against atherosclerosis.
Neurophysiology
DGAT1 is expressed in neuronal tissues, where it participates in membrane lipid remodeling and synaptic vesicle formation. Knockdown studies in zebrafish and rodent models suggest a role in neuronal development and behavior, although the mechanistic details remain under investigation.
Pathophysiology and Disease Associations
Obesity and Metabolic Syndrome
Hyperactive DGAT1 activity can promote excessive TAG accumulation in adipose tissue, contributing to obesity. Mouse models with DGAT1 knockout display leanness and increased energy expenditure, indicating that DGAT1 inhibition may counteract weight gain. However, the degree to which DGAT1 inhibition affects long‑term body weight in humans remains to be fully elucidated.
Non‑Alcoholic Fatty Liver Disease (NAFLD)
Hepatic DGAT1 contributes to triglyceride deposition in the liver. In mouse models, hepatic overexpression of DGAT1 exacerbates steatosis, while liver‑specific DGAT1 deletion reduces hepatic TAG levels and improves insulin sensitivity. These findings suggest that DGAT1 modulation could be a therapeutic strategy for NAFLD and non‑alcoholic steatohepatitis (NASH).
Gastrointestinal Disorders
Patients with congenital diarrheal disorders have been reported to carry loss‑of‑function mutations in DGAT1. These mutations impair intestinal TAG synthesis, leading to malabsorption of dietary fats, protein‑losing enteropathy, and severe growth failure. The phenotype is typically consistent with a recessively inherited disorder characterized by persistent diarrhea and failure to thrive.
Cardiovascular Disease
Elevated plasma triglyceride levels are a risk factor for atherosclerosis. Inhibition of intestinal DGAT1 reduces postprandial lipemia, potentially lowering cardiovascular risk. Clinical trials of DGAT1 inhibitors have shown modest reductions in triglyceride concentrations and improvements in lipoprotein profiles.
Genetic Variants and Inheritance
Loss‑of‑Function Mutations
Recessive missense and nonsense mutations in DGAT1 have been identified in individuals with protein‑losing enteropathy. These mutations often cluster in the transmembrane domains or the catalytic dyad, abolishing enzymatic activity. The condition follows an autosomal recessive inheritance pattern, and affected individuals display early‑onset diarrhea, failure to thrive, and protein loss in stool.
Polymorphisms in Metabolic Traits
Common single‑nucleotide polymorphisms (SNPs) in the DGAT1 gene have been associated with variations in plasma lipid levels and adiposity in genome‑wide association studies. The rs2267494 SNP, located in the 3′ untranslated region, has been linked to higher triglyceride concentrations and increased waist circumference in several cohorts.
Founder Mutations
In certain isolated populations, specific loss‑of‑function alleles show higher carrier frequencies. For instance, a c.1153T>G (p.Val385Gly) variant has been reported with increased prevalence in a small Norwegian community, providing an opportunity for targeted screening and early intervention.
Clinical Implications
Diagnosis of DGAT1‑Related Enteropathy
Clinical suspicion arises in infants presenting with persistent watery diarrhea, hypoproteinemia, and failure to thrive. Endoscopic biopsy reveals villous atrophy and steatotic enterocytes. Genetic testing for biallelic pathogenic variants in DGAT1 confirms the diagnosis. Screening for other enteropathies, such as cystic fibrosis and autoimmune enteropathy, remains essential.
Therapeutic Strategies
Dietary modification to include medium‑chain triglycerides (MCTs) that bypass DGAT1 can improve fat absorption in patients with loss‑of‑function mutations. Pharmacological inhibition of DGAT1 in the intestine is a therapeutic approach for hyperlipidemia and obesity, although its clinical efficacy varies among patient populations. Long‑term safety data for DGAT1 inhibitors are still emerging.
Potential Biomarkers
Circulating levels of DGAT1 mRNA in peripheral blood mononuclear cells and urinary excretion of TAG species may serve as biomarkers for disease severity in DGAT1‑related disorders. Measurement of plasma triglyceride reduction after DGAT1 inhibitor administration provides a pharmacodynamic readout in clinical trials.
Therapeutic Targeting and Pharmacology
Small‑Molecule Inhibitors
- CP‑609,474 – a potent, orally bioavailable inhibitor that reduces plasma triglycerides in rodent models.
- Avasimibe – a bisphosphonate derivative that selectively inhibits DGAT1 activity, currently in phase II clinical trials for hypertriglyceridemia.
- TVB‑2640 – an orally active, highly selective DGAT1 inhibitor that lowered postprandial lipids in early human studies.
- GSK2194069 – a compound with high selectivity for DGAT1 over DGAT2, demonstrating efficacy in reducing hepatic steatosis in preclinical models.
Peptide and Antibody Modulators
Peptidomimetic inhibitors derived from the catalytic domain of DGAT1 have shown promising in vitro potency. Monoclonal antibodies targeting extracellular loops of DGAT1 are under investigation for intestinal delivery, aiming to minimize systemic exposure and reduce off‑target effects.
Gene Therapy and RNA‑Based Approaches
CRISPR‑Cas9‑mediated correction of loss‑of‑function mutations in intestinal stem cells has been demonstrated in murine models, restoring DGAT1 activity and normalizing fat absorption. Antisense oligonucleotides (ASOs) designed to modulate DGAT1 splicing patterns are also under preclinical evaluation, providing a strategy to reduce enzyme activity in metabolic disease contexts.
Research Methods and Models
Cell‑Based Assays
Human adipocyte and enterocyte cell lines overexpressing or lacking DGAT1 are used to assess TAG synthesis rates, lipid droplet morphology, and lipolysis. Radiolabeled fatty acids allow quantitative measurement of enzymatic activity in vitro.
Animal Models
- DGAT1 knockout mice (global deletion) display reduced body weight, increased insulin sensitivity, and altered lipid profiles.
- Hepatocyte‑specific DGAT1 knockout mice exhibit decreased hepatic TAG and protection against diet‑induced steatosis.
- Intestinal DGAT1 knockout rats show impaired dietary fat absorption and reduced postprandial triglyceridemia.
- Zebrafish models carrying human DGAT1 mutations recapitulate features of enteropathy, offering a platform for drug screening.
Human Studies
Genome‑wide association studies have linked DGAT1 variants to lipid phenotypes, while targeted sequencing of affected families identifies pathogenic mutations in enteropathy. Clinical trials of DGAT1 inhibitors assess changes in plasma triglycerides, body mass index, and metabolic parameters in overweight or obese participants.
Applications in Biotechnology
Biofuel Production
Microbial engineering of yeast and algae to overexpress DGAT1 enhances TAG accumulation, improving lipid yield for biodiesel synthesis. Optimizing DGAT1 expression alongside upstream fatty acid synthesis pathways has led to increased productivity in genetically modified microorganisms.
Pharmaceutical Manufacturing
DGAT1 modulators serve as lead compounds in drug discovery programs targeting metabolic diseases. High‑throughput screening of compound libraries against recombinant DGAT1 has facilitated the identification of novel scaffolds with improved selectivity and oral bioavailability.
Food Science
Modification of DGAT1 activity in plant cells can alter triglyceride composition, producing functional oils with desirable melting points and shelf‑life properties. For example, overexpression of DGAT1 in oilseed crops increases the proportion of unsaturated TAG species, potentially benefiting cardiovascular health.
Future Directions
Elucidating Neuro‑DGAT1 Function
Detailed studies on the role of DGAT1 in the central nervous system, including investigations of synaptic plasticity and neurodegeneration, may uncover novel therapeutic targets for neurological disorders.
Combination Therapies
Pairing DGAT1 inhibitors with lifestyle interventions, such as diet modification or exercise, could enhance clinical outcomes in obesity and hyperlipidemia. Research on synergistic effects with other lipid‑metabolism drugs (e.g., CETP inhibitors, PCSK9 antibodies) is ongoing.
Precision Medicine
Genotype‑guided therapy for DGAT1‑related enteropathy, including individualized dietary regimens and potential gene‑editing interventions, represents an emerging paradigm in rare disease management.
Long‑Term Safety Studies
Extended monitoring of patients receiving DGAT1 inhibitors will inform risk–benefit assessments, particularly regarding potential gastrointestinal adverse events and effects on essential fatty acid metabolism.
Conclusion
DGAT1 is a pivotal enzyme in triglyceride metabolism, with far‑reaching implications for energy balance, lipid absorption, and disease. The dichotomous role of DGAT1 – promoting storage while facilitating absorption – provides a unique therapeutic window for targeting metabolic disorders and enteropathy. Continued investigation into the genetic basis of DGAT1 dysfunction, coupled with advances in pharmacology and gene editing, will shape future diagnostic and treatment approaches across diverse biomedical fields.
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