Triacylglycerol Synthesis and Lipolysis
- Compartment
- Cytosol / ER
- Main tissue
- Adipose tissue, liver
- Rate-limiting
- Diacylglycerol acyltransferase (DGAT1 or DGAT2)
- Steps
- 11
Reaction steps
In source order, 11 total
-
1
Fatty acid + CoA-SH + ATP → fatty acyl-CoA + AMP + PPi
› Notes
Acyl-CoA synthetases activate each fatty acid destined for esterification. This effectively irreversible activation costs two ATP equivalents per acyl chain because ATP is cleaved to AMP and PPi.
-
2
Glycerol + ATP → glycerol-3-phosphate + ADP
› Notes
In liver and kidney, glycerol kinase produces glycerol-3-phosphate, requiring ATP. This route is minor in adipocytes because glycerol kinase expression is low.
-
3
Dihydroxyacetone phosphate + NADH + H+ ⇌ glycerol-3-phosphate + NAD+
› Notes
Cytosolic glycerol-3-phosphate dehydrogenase supplies glycerol-3-phosphate from glycolytic DHAP, the predominant adipocyte source. This reaction couples TAG synthesis to glucose uptake and glycolysis.
-
4
Glycerol-3-phosphate + fatty acyl-CoA → lysophosphatidic acid (1-acyl-glycerol-3-phosphate) + CoA-SH
› Notes
Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first acylation, usually at sn-1. This is an important regulatory/committing step of the glycerol-3-phosphate pathway.
-
5
Lysophosphatidic acid + fatty acyl-CoA → phosphatidic acid (1,2-diacyl-glycerol-3-phosphate) + CoA-SH
› Notes
1-Acylglycerol-3-phosphate acyltransferase (AGPAT) adds the second acyl chain at sn-2.
-
6
Phosphatidic acid + H2O → diacylglycerol (DAG) + Pi
› Notes
Phosphatidic acid phosphatase (PAP; lipin) dephosphorylates phosphatidic acid. Lipin activity directs phosphatidic acid toward TAG synthesis rather than phospholipid signaling pathways.
-
7
DAG + fatty acyl-CoA → TAG + CoA-SH
› Notes
Diacylglycerol acyltransferase (DGAT1 or DGAT2) catalyzes the terminal acylation. This is the final committed step of TAG assembly; TAG is packaged into lipid droplets or, in liver/intestine, into apoB-containing lipoproteins.
-
8
TAG + H2O → DAG + free fatty acid
› Notes
During lipolysis, adipose triglyceride lipase (ATGL; PNPLA2) catalyzes the first and often rate-setting TAG hydrolysis. Its activity is strongly enhanced by CGI-58/ABHD5 released from phosphorylated perilipin, and is restrained by G0S2.
-
9
DAG + H2O → monoacylglycerol (MAG) + free fatty acid
› Notes
Hormone-sensitive lipase (HSL; LIPE) hydrolyzes DAG most efficiently; it also has TAG and cholesteryl-ester hydrolase activity. PKA phosphorylation of HSL and perilipin promotes access to the lipid droplet.
-
10
MAG + H2O → glycerol + free fatty acid
› Notes
Monoacylglycerol lipase (MGL; MGLL) completes hydrolysis. Released NEFAs bind serum albumin for transport; glycerol travels mainly to liver for glycerol-3-phosphate production, gluconeogenesis, or glycolysis.
-
11
Glycerol + ATP → glycerol-3-phosphate + ADP; glycerol-3-phosphate ⇌ DHAP
↪ glycerol-3-phosphate + ADP; glycerol-3-phosphate → DHAP
Glycerol kinase + glycerol-3-phosphate dehydrogenase (hepatic) 2.7.1.30 / 1.1.1.8 ST-0115 Reversible ATP› Notes
Hepatic glycerol kinase and glycerol-3-phosphate dehydrogenase metabolize adipose-derived glycerol. These downstream reactions permit glycerol carbon to enter gluconeogenesis or glycolysis during fasting.
Showing all 11 steps.
Regulation
What speeds each enzyme up and what slows it down
GPAT
Substrate glycerol-3-phosphate and acyl-CoA; lipogenic feeding state
Limited glycerol-3-phosphate/acyl-CoA; AMPK effects on selected isoforms
Insulin promotes lipogenic gene expression and substrate supply; fasting suppresses synthesis
DGAT1/DGAT2
DAG and acyl-CoA availability
Limited acyl-CoA; pharmacologic DGAT inhibition
Insulin and feeding favor TAG assembly; glucagon/epinephrine indirectly reduce it by mobilizing stores
ATGL
CGI-58/ABHD5; phosphorylation-dependent perilipin remodeling
G0S2; insulin-mediated suppression
Catecholamines activate cAMP/PKA and mobilize ATGL coactivation; insulin suppresses lipolysis
Hormone-sensitive lipase (HSL)
PKA phosphorylation; phosphorylation of perilipin; catecholamines/natriuretic peptides
Dephosphorylation; insulin; phosphodiesterase 3B lowering cAMP
Epinephrine and norepinephrine activate; insulin strongly inhibits; glucagon has a modest/direct role in human adipocytes compared with catecholamines
Overview
Triacylglycerol (TAG) synthesis esterifies three fatty acyl chains to glycerol, creating the principal long-term energy store in adipose tissue and a major export lipid in hepatic VLDL. Lipolysis reverses this storage process by sequentially hydrolyzing TAG to release nonesterified fatty acids (NEFAs) and glycerol. These pathways are reciprocally regulated by nutritional state: insulin promotes synthesis and storage, whereas fasting and adrenergic signaling mobilize fatty acids.
Cellular location
TAG synthesis occurs mainly on the cytosolic leaflet of the smooth ER in hepatocytes, enterocytes, and adipocytes; nascent lipid droplets bud from the ER and are coated by proteins including perilipins. Adipocyte lipolysis occurs at the surface of cytosolic lipid droplets. The liver can use glycerol directly because it expresses glycerol kinase; adipocytes have very low glycerol kinase activity and depend heavily on glucose-derived glycerol-3-phosphate for re-esterification.
Net energetics
Synthesis of one TAG from glycerol plus three preformed fatty acids requires 1 ATP for glycerol kinase (when glycerol is the precursor) and 3 ATP → AMP activations, costing 6 ATP equivalents, for a total of 7 ATP equivalents; if glycerol-3-phosphate comes from DHAP, its formation consumes NADH rather than the glycerol-kinase ATP. No ATP is generated by TAG assembly. Complete adipocyte lipolysis yields 3 fatty acids plus glycerol; ATP is generated only when the fatty acids and glycerol are subsequently oxidized, while hydrolysis itself requires water and no ATP.
Clinical significance
Adipose TAG is the body’s largest mobilizable energy reserve, while hepatic TAG production and VLDL secretion distribute endogenous lipid. Insulin resistance increases adipose NEFA release and hepatic TAG synthesis, contributing to hypertriglyceridemia, ectopic lipid deposition, and metabolic dysfunction-associated steatotic liver disease. Defects in ATGL or CGI-58 cause neutral lipid storage diseases, with myopathy/cardiomyopathy or ichthyosis, respectively. Dysregulated HSL/ATGL activity also contributes to excess NEFA flux in type 2 diabetes and obesity.
Recent literature
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