Lipolysis occurs in almost all tissues and cell types, but this process is most common in white and brown adipose tissue.
General Information
The body uses fat stores as the main energy source during fasting, preserving protein.
Overall, fats are quantitatively the most important energy source in the body, and the duration of time a person can survive without food depends primarily on the amount of fat stored in adipose tissue.
Therefore, lipolysis is especially important in the fasted metabolic state when blood glucose levels decrease. [1]
Glycerol, produced as a result of lipolysis, is a carbon source for gluconeogenesis in the liver.
Free fatty acids are transported in the blood bound to albumin and are either oxidized in tissues through a process called beta-oxidation or converted into ketone bodies.
By-products of beta-oxidation, ATP and NADH, contribute to gluconeogenesis. Free fatty acids are converted into ketone bodies in the liver, which serve as an energy source for the brain, thereby reducing further consumption of already depleted blood glucose.
Free fatty acids are used throughout the body for energy production or biosynthetic pathways, except in white adipose tissue, where they are stored.
In the "fasting" metabolic state, when the body is deprived of nutrients, white adipose tissue releases free fatty acids and glycerol to supply non-adipose tissues. [2]
The main enzymes involved in lipolysis are adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase.
Functions and Biological Significance
Fatty acids are transported by blood albumin. In tissues such as muscles and kidneys, fatty acids are oxidized for energy. In the liver, fatty acids are converted into ketone bodies, which are oxidized by tissues such as muscles and kidneys.
During fasting (after fasting has lasted about three or more days), the brain uses ketone bodies for energy. The fuel source is ketone bodies, acetoacetate, and β-hydroxybutyrate.
The liver uses glycerol as a carbon source for gluconeogenesis, which produces glucose for tissues, including the brain and red blood cells.
To begin with, the mechanism of triglyceride synthesis is briefly reviewed, followed by their hydrolysis, i.e., the process of lipolysis itself.
Triglyceride Synthesis
Triacylglycerols, also known as triglycerides, providing the body with a significant energy source, are obtained from food or synthesized endogenously, primarily in the liver. They are transported in the blood as lipoproteins and stored in adipose tissue.
The major classes of blood lipoproteins involved include high-density lipoproteins (HDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and chylomicrons.
Chylomicrons are synthesized in the small intestine and transport dietary triglycerides from the small intestine to tissues such as muscles and adipose tissue. The liver synthesizes VLDL, which transports triglycerides from the liver to tissues.
High-density lipoproteins (HDL) perform numerous functions related to lipid metabolism, including playing an integral role in the conversion of VLDL to LDL. HDL also serves as a reservoir for essential apoproteins, such as apolipoprotein C2 (Apo C-II).
Apo C-II activates lipoprotein lipase, the enzyme responsible for digesting and breaking down triglycerides.
The synthesis of triglyceride stores in adipose tissue occurs in the fed state after a meal. Triglycerides are synthesized in two ways:
- from free fatty acids formed as a by-product of lipoprotein lipase action on chylomicrons and VLDL
- from the glycerol part derived from glucose
In the liver and adipose tissue, glycerol-3-phosphate provides the glycerol part. The liver can convert glycerol to glycerol-3-phosphate either from an intermediate or directly, thanks to the enzyme glycerol kinase.
In adipose cells, this enzyme is absent, so glycerol-3-phosphate is formed exclusively from an intermediate.
Storage of triglycerides in adipose tissue is mediated by insulin, which stimulates adipose cells to secrete lipoprotein lipase and absorb glucose, which is converted to glycerol (through the intermediate dihydroxyacetone phosphate) for further triacylglycerol synthesis.
In this process, glucose is converted to dihydroxyacetone phosphate, which is reduced by NADH coenzyme (nicotinamide adenine dinucleotide) to form glycerol-3-phosphate.
Ultimately, glycerol-3-phosphate reacts with two molecules of acyl-CoA to form phosphatidic acid. The phosphate group is cleaved to form diacylglycerol, which reacts with other acyl-CoA molecules, resulting in the formation of triacylglycerol.
Lipolysis: Triglyceride Hydrolysis
Lipolysis proceeds in an orderly and controlled manner, with different enzymes acting at each stage. During energy deficiency, white adipose tissue is stimulated by hormonal and biochemical signals to increase lipolysis activity.
Catecholamines, especially norepinephrine, are the main activators of fasting-induced lipolysis, while other hormones also influence this process. These include cortisol, glucagon, growth hormone (GH), and adrenocorticotropic hormone (ACTH). Dietary compounds such as caffeine and calcium also stimulate lipolysis.
Each of these substances binds to the corresponding membrane receptors and acts on them, causing a signaling cascade with the sole purpose of activating hormone-sensitive lipase.
Hormone-sensitive lipase is the most important of the three enzymes involved in the initiation of lipolysis because it is enzymatically active at all stages of hydrolysis.
Adipose triglyceride lipase performs the first stage of triglyceride hydrolysis (thus, it is rate-limiting), forming diacylglycerol and fatty acids.
Hormone-sensitive lipase performs the second stage and hydrolyzes diacylglycerol to form monoacylglycerol and free fatty acids. Monoglyceride lipase is selective for monoacylglycerols and, in turn, produces glycerol and also fatty acids.
Clinical Significance
Changes in lipolysis are often associated with obesity. These changes include an increase in basal lipolysis rate, which may contribute to the development of insulin resistance, and a decrease in response to stimulated lipolysis. [3]
The combination of increased lipolysis and impaired lipogenesis ultimately contributes to insulin resistance due to the release of cytokines and lipid metabolites.
Additionally, the adipose tissue of insulin-resistant individuals shows a deficiency of proteins involved in mitochondrial function. Mitochondrial energy sources are involved in lipogenesis in adipose tissue. [4]
Obesity is primarily characterized by an excess of white adipose tissue, which is characterized by adipocyte hypertrophy resulting from increased triglyceride stores.
Obesity is a major public health issue worldwide due to its association with a number of diseases, including insulin resistance, type II diabetes, hypertension, and atherosclerosis.
