Substrate preparation and transport
The process of fat creation begins with the breakdown of glucose. During glycolysis, which takes place in the cell cytosol, a glucose molecule is converted into pyruvate. The resulting pyruvate must move into the mitochondrion. There, it undergoes changes, turning into acetyl-CoA and oxaloacetate, which then fuse to form citrate.
Since subsequent molecule assembly takes place in the cytosol, citrate is transported out of the mitochondrion. Once in the cytoplasm, it breaks back down, supplying the cell with acetyl-CoA and oxaloacetate once again.
For synthesis reactions to proceed successfully, the cell vitally needs reducing equivalents in the form of NADPH. The body obtains them from two main sources:
- The pentose phosphate pathway (starting with the transformation of glucose-6-phosphate);
- The reaction converting malate to pyruvate, catalyzed by a specific malic enzyme.
Tissue specificity of fat backbone formation
To assemble a complete triacylglycerol molecule, two components must be joined: glycerol-3-phosphate (acting as the backbone) and acyl-CoA (activated fatty acids). The origin of glycerol-3-phosphate strictly depends on the type of tissue where synthesis is occurring.
In liver cells, two mechanisms for obtaining this substrate operate simultaneously:
- Reduction of dihydroxyacetone phosphate, which is an intermediate metabolite of glycolysis.
- Phosphorylation of free glycerol brought by the bloodstream. This reaction is carried out by the enzyme glycerol kinase.
In adipose tissue, the situation is different. The enzyme glycerol kinase is completely absent in adipocytes. For this reason, adipose tissue has only one way to obtain the fat backbone — from dihydroxyacetone phosphate. This is of fundamental clinical importance: for adipocytes to store fats, glucose must enter them and glycolysis must proceed uninterrupted.
Mechanism of fat deposition in adipocytes
During the absorptive period, adipose tissue actively begins to store triacylglycerols. Unlike the liver, adipocytes prefer not to synthesize fatty acids from scratch, but rather to take up preformed ones from the bloodstream. In the blood, fats circulate as part of special transport complexes: chylomicrons (CM), very-low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL).
On the inner wall of blood capillaries supplying adipose tissue lies the enzyme lipoprotein lipase (LPL). It hydrolyzes passing triacylglycerols, breaking them down into free fatty acids and glycerol.
The subsequent fate of these products differs:
- Fatty acids penetrate into the adipocyte and are immediately activated, converting into the form of acyl-CoA.
- The released glycerol cannot be utilized by the adipocyte (due to a lack of the enzyme) and is carried away by the bloodstream to the liver.
Simultaneously, glucose enters the cell via insulin-dependent GLUT-4 transporters. Inside the cell, it is broken down into dihydroxyacetone phosphate, which is reduced to glycerol-3-phosphate. At the final stage, acyl-CoA and glycerol-3-phosphate combine to form triacylglycerol molecules, which are stored in the lipid droplet.
Regulatory role of insulin
Insulin acts as the master conductor of fat anabolism, stimulating this process through two parallel pathways:
- Activation of glucose transport. The hormone stimulates the function of GLUT-4 transporters, significantly accelerating the entry of glucose into adipocytes. Without this step, the cell could not synthesize glycerol-3-phosphate.
- Activation of lipolysis in the blood. Insulin induces the synthesis and subsequent placement of LPL on the surface of adipose tissue capillaries, thereby ensuring a constant and powerful influx of fatty acids into cells for storage.
Briefly: answers to topical questions
What intermediate metabolites are formed during the conversion of glycerol-3-phosphate into the final triacylglycerol?
The intermediate metabolites in the synthesis of triacylglycerol from glycerol-3-phosphate are phosphatidic acid and diacylglycerol.
The formation of metabolites occurs in the following sequence:
- Phosphatidic acid is formed as a result of the acylation of glycerol-3-phosphate by two molecules of acyl-CoA (fatty acids).
- Diacylglycerol (DAG) is formed by the dephosphorylation (hydrolysis) of phosphatidic acid, which is accompanied by the cleavage of inorganic phosphate.
Then, DAG is acylated by a third acyl-CoA molecule, resulting in the synthesis of the final product — triacylglycerol (TAG).
Class and exam questions
Why can't adipose tissue use free glycerol from the blood?
Adipocytes lack the enzyme glycerol kinase. Because of this, glucose undergoing glycolysis becomes the sole source of the fat backbone (glycerol-3-phosphate).
How do preformed fatty acids from the blood enter the adipocyte?
Triacylglycerols within blood lipoproteins are hydrolyzed by the enzyme lipoprotein lipase (LPL) located on the capillary wall. The released fatty acids enter the cell and are activated to acyl-CoA.
What else to study on this topic
- The pentose phosphate pathway and its significance
- The role of malic enzyme in metabolism
- Structure and functions of lipoproteins (CM, VLDL, IDL)
- Stages of glycolysis and formation of dihydroxyacetone phosphate
- Mechanism of action of GLUT-4 transporters
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