How the liver synthesizes fats
The synthesis of triacylglycerols (TAGs) in hepatocytes is activated postprandially. Cells use glucose not only for energy, but also as a building material. The entire process can be divided into three successive stages:
- Fatty acid preparation. Excess acetyl-CoA obtained by the cell during glycolysis is directed toward building fatty acid chains. Ultimately, they are activated, converting into acyl-CoA.
- Formation of the glycerol backbone. The cell requires glycerol-3-phosphate, which is synthesized via two pathways. The first is the reduction of a glycolysis intermediate (dihydroxyacetone phosphate) with the obligatory participation of the coenzyme NADH. The second is the direct phosphorylation of free glycerol, requiring the expenditure of ATP.
- Molecule assembly. Fatty acid radicals (acyl-CoA) attach to glycerol-3-phosphate, forming phosphatidic acid. It is then dephosphorylated (losing phosphoric acid) to become diacylglycerol (DAG). Final acylation of DAG completes the process, forming a TAG molecule.
Since the liver does not store synthesized fat, TAG molecules are packaged into very-low-density lipoproteins (VLDLs) and secreted into the bloodstream.
Regulation and storage in adipose tissue
Adipocytes (fat tissue cells) specialize in energy storage. This process occurs during the absorptive period, when insulin dominates in the blood.
Adipose tissue is insulin-dependent, and the hormone affects it in a comprehensive manner:
- Stimulates glucose uptake. Insulin causes cells to insert GLUT-4 transporters into the membrane, opening the way for glucose to enter.
- Activates glycolysis. Glucose breakdown provides the cell with ATP for synthesis reactions and glycerol-3-phosphate (the framework for future fat).
- Triggers the pentose phosphate pathway. This shunt supplies NADPH, which is critically important for de novo fatty acid synthesis.
- Regulates blood enzymes. Insulin initiates the synthesis and translocation of the enzyme lipoprotein lipase to the capillary surface. It breaks down lipoproteins circulating in the blood, allowing adipocytes to take up fatty acids for storage.
Distribution of fatty acids to tissues
The fate of fatty acids extracted from the blood via lipoprotein lipase depends directly on tissue function:
- In adipose tissue, they are re-esterified (converted back into TAGs) and deposited into stores.
- In myocardium and skeletal muscles, they serve as priority fuel: here, fatty acids undergo oxidation, generating massive amounts of ATP for muscle contraction.
If the body requires energy and fats are hydrolyzed (broken down), two functionally different products are formed. Fatty acids are used for oxidation by most tissues. Glycerol is sent to the liver for gluconeogenesis—the synthesis of new glucose, which is vital for the brain and other glucose-dependent cells during starvation.
Energy depots: fats vs. glycogen
Both fats and glycogen serve as energy reservoirs, but their characteristics differ significantly. Fats vastly outperform carbohydrates in caloric content.
Capacity and lifespan:
- Glycogen stores last for approximately one day of starvation.
- Fat stores are capable of sustaining life for many weeks.
Consumption and turnover rate:
- Glycogen turns over rapidly (in less than two days) and is continuously consumed by cells (except for a couple of hours post-meal).
- Fat depots are inert: only a hundredth of the reserve is renewed per day. With a rhythmic, regular diet, stored fats may not be consumed at all, as organs manage to obtain fatty acids from circulating lipoproteins (chylomicrons and VLDLs). Energetically, these transport forms of lipoproteins act as a short-term reserve and function more like glycogen than true fat.
Class and exam questions
Where does the liver get building blocks for fats?
The primary carbon source for fat synthesis is glucose breakdown products. Specifically, this is excess acetyl-CoA formed during glycolysis.
How does insulin affect adipose tissue?
Insulin activates the insertion of GLUT-4 receptors into the adipocyte membrane, stimulates glycolysis and the pentose phosphate pathway, and promotes the exposure of lipoprotein lipase on capillaries to capture fats from the blood.
What is the fate of glycerol during fat breakdown?
Glycerol released during fat hydrolysis is used by the liver in gluconeogenesis. It is converted into glucose, supplying energy to the brain during starvation.
Why are fats more efficient than glycogen as a long-term depot?
Fats possess a much greater energy density (caloric value). Furthermore, they are consumed extremely slowly, allowing the body's energy supply to be maintained for many weeks, whereas glycogen is depleted within a day.
What else to study on this topic
- Mechanism of action and regulation of lipoprotein lipase (LPL)
- Pentose phosphate pathway: phases and significance of NADPH generation
- Biochemical stages of fatty acid β-oxidation
- Structure, functions, and metabolism of VLDLs and chylomicrons
- Gluconeogenesis: synthesis of glucose from non-carbohydrate precursors
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