Triacylglycerol Synthesis and Lipolysis

1. 1

   Fatty acid + CoA-SH + ATP → fatty acyl-CoA + AMP + PPi

   Acyl-CoA synthetases 6.2.1.3 ST-0105 Irreversible ATP CoA-SH PPi
   In Fatty acid CoA-SH ATP

   Out 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. 2

   Glycerol + ATP → glycerol-3-phosphate + ADP

   Glycerol kinase (liver/kidney) 2.7.1.30 ST-0106 Irreversible/directional ATP
   In Glycerol ATP

   Out 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. 3

   Dihydroxyacetone phosphate + NADH + H+ ⇌ glycerol-3-phosphate + NAD+

   Cytosolic glycerol-3-phosphate dehydrogenase (GPD1) 1.1.1.8 ST-0107 Reversible NAD+ NADH
   In Dihydroxyacetone phosphate NADH H+

   Out 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. 4

   Glycerol-3-phosphate + fatty acyl-CoA → lysophosphatidic acid (1-acyl-glycerol-3-phosphate) + CoA-SH

   Glycerol-3-phosphate acyltransferase (GPAT) 2.3.1.15 ST-0108 Irreversible/directional CoA-SH
   In Glycerol-3-phosphate Fatty acyl-CoA

   Out Lysophosphatidic acid 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. 5

   Lysophosphatidic acid + fatty acyl-CoA → phosphatidic acid (1,2-diacyl-glycerol-3-phosphate) + CoA-SH

   1-Acylglycerol-3-phosphate acyltransferase (AGPAT) 2.3.1.51 ST-0109 Irreversible/directional CoA-SH
   In Lysophosphatidic acid Fatty acyl-CoA

   Out Phosphatidic acid CoA-SH
   › Notes

   1-Acylglycerol-3-phosphate acyltransferase (AGPAT) adds the second acyl chain at sn-2.

6. 6

   Phosphatidic acid + H2O → diacylglycerol (DAG) + Pi

   Phosphatidic acid phosphatase (PAP; lipin) ST-0110 Irreversible/directional H2O Pi
   In Phosphatidic acid H2O

   Out 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. 7

   DAG + fatty acyl-CoA → TAG + CoA-SH

   Diacylglycerol acyltransferase (DGAT1 or DGAT2) 2.3.1.20 ST-0111 Irreversible/directional CoA-SH
   In Diacylglycerol Fatty acyl-CoA

   Out Triacylglycerol (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. 8

   TAG + H2O → DAG + free fatty acid

   Adipose triglyceride lipase (ATGL; PNPLA2) 3.1.1.3 ST-0112 Irreversible/directional H2O
   In Triacylglycerol (TAG) H2O

   Out Diacylglycerol 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. 9

   DAG + H2O → monoacylglycerol (MAG) + free fatty acid

   Hormone-sensitive lipase (HSL; LIPE) 3.1.1.79 ST-0113 Irreversible/directional H2O
   In Diacylglycerol H2O

   Out Monoacylglycerol (MAG) 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. 10

    MAG + H2O → glycerol + free fatty acid

    Monoacylglycerol lipase (MGL; MGLL) ST-0114 Irreversible/directional H2O
    In Monoacylglycerol H2O

    Out Glycerol 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. 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
    In Glycerol ATP

    Out Glycerol-3-phosphate ADP
    › 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.

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.