Conditions and substrates for triglyceride synthesis
Fat synthesis occurs during the absorptive state and is regulated by the main anabolic hormone — insulin, which induces key enzymes of lipogenesis. The synthesis of triacylglycerol (TAG) requires two substrates: glycerol-3-phosphate and acyl-CoA (an activated fatty acid attached to coenzyme A).
The production of glycerol-3-phosphate depends on the tissue:
- In the liver, two pathways are possible: the reduction of dihydroxyacetone phosphate (a glycolysis metabolite) involving NADH, and the direct phosphorylation of free glycerol by the enzyme glycerol kinase.
- In adipose tissue, glycerol kinase is absent, so the only source of glycerol-3-phosphate is the reduction of dihydroxyacetone phosphate, making TAG synthesis entirely dependent on glycolysis activity.
Stages of triacylglycerol synthesis
Acyl-CoA is formed from acetyl-CoA during fatty acid synthesis, which requires NADPH. Subsequent assembly of the TAG molecule occurs sequentially:
- Glycerol-3-phosphate is acylated by two molecules of acyl-CoA to form phosphatidic acid (diacylglycerol-3-phosphate).
- Dephosphorylation reaction: the removal of the phosphoric acid residue leads to the formation of diacylglycerol.
- The addition of a third fatty acid residue (R3) yields a mature triacylglycerol molecule.
Fat transport: VLDL
In the liver, synthesized TAGs are packaged into very-low-density lipoproteins (VLDL) and secreted into the blood. The immature VLDL particle contains the structural protein apoB-100 (unlike apoB-48 in chylomicrons).
In the bloodstream, immature VLDL receives apoproteins apoC-II and apoE from HDL, turning into a mature particle. ApoC-II activates lipoprotein lipase (LPL) anchored to the walls of blood capillaries. LPL hydrolyzes VLDL TAGs into free fatty acids and glycerol; the fatty acids are taken up by adipocytes, where they are resynthesized into TAG for storage.
Tissue-specific features of lipoprotein lipase
LPL isoforms in different tissues vary in their substrate affinity:
- Adipose tissue: high value of Michaelis constant (KM) — low affinity. The enzyme works efficiently only at high substrate concentration, i.e. after a meal, when VLDL and chylomicrons are abundant in the blood.
- Muscle tissue: low $K_m$ — high affinity. LPL is active even at low concentrations of circulating TAGs, providing muscles with an energy substrate.
Up to 60% of fats are stored in the liver, adipose tissue, and the lactating mammary gland.
Regulation of lipogenesis by insulin
Insulin exerts four main effects on fat synthesis in adipocytes:
- Induction of LPL and its display on the capillary wall, which enhances the uptake of fatty acids into adipocytes.
- Activation of the GLUT-4 transporter, increasing glucose uptake by adipose tissue.
- Activation of the pentose phosphate pathway, which provides NADPH for fatty acid synthesis.
- Activation of glycolysis — the sole source of dihydroxyacetone phosphate and, consequently, glycerol-3-phosphate in adipocytes.
Hepatic steatosis
When substrates are supplied in excess or VLDL secretion is impaired, TAGs accumulate in hepatocytes, causing hepatic steatosis (fatty liver disease). A balanced ratio between TAG synthesis and their export as part of VLDL is a key condition for normal lipid metabolism in the liver.
Obesity: classification and pathogenesis
Obesity is divided into primary (alimentary-constitutional, genetically determined) and secondary (associated with endocrine and other diseases). The pathogenetic mechanisms of primary obesity are related to specific features of energy metabolism:
- Decreased activity of "futile" (substrate) cycles. In such cycles, a metabolite is converted into another and back (e.g., glucose ⇄ glucose-6-phosphate), which is accompanied by non-productive ATP consumption. In lean individuals, these cycles are more active; in obese individuals, they are attenuated, and energy is stored as fat.
- Increased coupling of oxidative and substrate phosphorylation: metabolism operates more "economically", more energy is stored in ATP rather than dissipated as heat.
- Decreased proportion of anaerobic glycolysis. Anaerobic glycolysis is energetically inefficient and actively "burns" glucose; its reduction helps divert excess glucose toward lipogenesis.
- Defect in the ob gene encoding leptin. Decreased leptin levels increase neuropeptide Y activity, which enhances appetite and establishes pathological eating behavior; leptin-dependent regulation of fat metabolism is also impaired.
Key points
- TAG synthesis requires glycerol-3-phosphate and acyl-CoA; insulin is the main inducer of lipogenesis.
- Adipocytes lack glycerol kinase, so lipogenesis strictly depends on glycolysis.
- Hepatic TAGs are transported as part of VLDL containing apoB-100; apoC-II and apoE are transferred from HDL.
- Lipoprotein lipase on the capillary endothelium cleaves VLDL and chylomicron TAGs into fatty acids and glycerol.
- LPL isoforms differ in $K_m$: high in adipose tissue, low in muscle.
- Insulin stimulates LPL, GLUT-4, the pentose phosphate pathway, and glycolysis in adipocytes.
- Accumulation of TAGs in hepatocytes leads to hepatic steatosis.
- Primary obesity is associated with weakened futile cycles, increased phosphorylation coupling, decreased anaerobic glycolysis, and leptin deficiency.