Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter III. METABOLISM OF MAJOR CLASSES OF BIOMOLECULES

CHAPTER 14. LIPID METABOLISM. I. CATABOLISM OF TRIACYLGLYCEROLS AND FATTY ACIDS

14.2. CATABOLISM OF TRIACYLGLYCEROLS

Triacylglycerols (neutral fats, fats) enter The Human Body as components of animal and plant foods. Lipids of this Class are broken down in the digestive tract into monoglycerides, free Fatty acids, and glycerol, which, after intestinal absorption and complex biochemical transformations in enterocytes, Blood, and the Liver, are deposited in adipose tissue. The accumulation of neutral fat reserves is the most efficient mechanism for storing metabolic energy. Because of the high degree of reduction of the fatty acid residues that make up triacylglycerol molecules, their oxidation releases significantly more chemical energy than the Catabolism of CARBOHYDRATES and Proteins (Chapter 26).

The primary Location of reserve triglycerides in the human body is the adipocytes of adipose tissue (lipocytes), a significant part of whose Cytoplasm is occupied by a giant spherical lipid droplet (Fig. 14.1).

Fig. 14.1. Adipose tissue Cell (adipocyte).

In significantly smaller amounts, triglycerides are present in the Cells of other Organs, notably liver hepatocytes, where they occur as cytoplasmic lipid droplets.

Adipose tissue, in which up to 65% of the mass accounts for neutral fats, is a highly specialized tissue that accumulates substantial amounts of metabolic fuel, the ENERGY VALUE OF which significantly exceeds the energy reserves of carbohydrates and proteins. The mass of adipose tissue in an average-weight adult is about 10 kg on average, and its total triglyceride content is sufficient to meet the body's energy demands for at least 40 days of fasting.

Catabolic reactions of triacylglycerols

Enzymatic Hydrolysis (lipolysis) of triacylglycerols in adipocytes and other cells where neutral fats accumulate is a physiological mechanism of major importance as a reserve energy source, especially under conditions of carbohydrate depletion and stress. The process of triacylglycerol breakdown with the release of fatty acids into the blood is termed mobilization of fatty acids from adipose tissue.

Intracellular lipolysis of triacylglycerols (TGs) proceeds in several stages, yielding diacylglycerols (diglycerides — DGs), monoacylglycerols (monoglycerides — MGs), glycerol, and free fatty acids as products:

Overall equation of lipolysis:

Free fatty acids (non-esterified fatty acids — NEFAs) serve as oxidation substrates for cells in many Tissues, particularly the myocardium, Cartilage, smooth Muscle, etc., except for the Brain. Upon entering Blood Plasma, high-molecular-weight fatty acids, which are insoluble in the aqueous phase of plasma, are transported in a molecular form bound to serum albumin.

MOLECULAR MECHANISMS OF lipolysis regulation

The stepwise lipolysis process described above, which takes place in adipose tissue adipocytes, is catalyzed by three Enzymes: triglyceride lipase, diglyceride lipase, and monoglyceride lipase. The activity of the latter two enzymes (E₂ and E₃) is dozens of times higher than that of the first enzyme (E₁). Typically, the overall rate of a multi-step metabolic pathway is controlled by the activity of The enzyme catalyzing the slowest (rate-limiting) step of the process. Therefore, such an enzyme is regulatory; indeed, the activity of tissue triglyceride lipase (TG lipase) is regulated by many Hormones, in particular adrenaline, Glucagon, Insulin, and somatotropin.

The molecular basis for regulating adipocyte triglyceride lipase activity is its covalent modification via reversible phosphorylation-dephosphorylation.

Fig. 14.2. Scheme of the cascade regulation of adipocyte triglyceride lipase activity.

E1 — adenylate cyclase, E2 — protein kinase, E3 — protein phosphatase.

The phosphorylated form of TG lipase is catalytically active, whereas the dephosphorylated form is inactive. Phosphorylation of the respective protein is carried out using ATP with the participation of cAMP-dependent protein kinase. In turn, an increase in the intracellular cAMP concentration results from the interaction of adrenaline or glucagon with specific receptors on the adipocyte Plasma Membranes, leading to the activation of membrane-bound adenylate cyclase. Dephosphorylation of the catalytically active TG lipase by phosphatase results in The formation of the inactive molecular form of the enzyme.

Overall, the process of controlling TG lipase activity in Adipose tissue is an example of the cAMP-dependent cascade mechanism of hormonal Regulation of cellular biochemical and physiological Functions, which was discussed earlier (Chapter 3) using Glycogen phosphorolysis in The Liver and Muscles as an example.

Neurohumoral regulation of Lipolysis

The Regulation of Lipid METABOLISM is driven by the PHYSIOLOGICAL AND BIOCHEMICAL effects of the neuroendocrine system on the rate-limiting reactions of this biomolecule class. Specific hormones and Neurotransmitters influence the catalytic activity and intracellular concentration of Key Enzymes involved in lipid breakdown and Biosynthesis. The most thoroughly studied is the neurohumoral regulation of lipolysis, which is the intracellular hydrolysis of storage triacylglycerols.

Epinephrine, Norepinephrine, Glucagon

Epinephrine and norepinephrine are catecholamines that activate lipolysis in adipose tissue by stimulating a cAMP-dependent cascade mechanism that regulates the activity of adipocyte triacylglycerol lipase. The lipolytic action of these hormones is triggered under physiological conditions (such as physical exertion or drops in ambient Temperature) and psychological stress (fear, anxiety). These states are accompanied by the release of epinephrine from The adrenal medulla, as well as The stimulation of the sympathetic Nervous system and the release of norepinephrine at Neuronal Synapses, which bind to adrenergic receptors on the adipocyte membrane.

Glucagon is a pancreatic hormone that stimulates the lipolytic system in adipose tissue through a mechanism similar to that of catecholamines—specifically by increasing cAMP levels in adipocytes via adenylate cyclase activation. The action of glucagon manifests when blood glucose concentrations drop due to decreased intestinal absorption or increased tissue utilization.

Overall, through these biochemical mechanisms, the metabolic effects of catecholamines and glucagon lead to the rapid stimulation of Glycogenolysis in the liver and muscles, as well as lipolysis in adipose tissue, thereby meeting the body's heightened energy demands during stress or fasting.

Insulin

Unlike the aforementioned humoral factors that activate adipocyte triacylglycerol lipase and promote the mobilization of NEFA from adipose tissue, the hormone insulin inhibits lipolysis and the release of fatty acids. The inhibitory effect of insulin on adipocyte lipolysis is mediated by two biochemical mechanisms:

a) a decrease in cAMP concentration, which may be linked to the activation of cAMP phosphodiesterase;

b) an increase in the permeability of adipocyte membranes to glucose, resulting in the activation of Glycolysis in adipose tissue and, consequently, the accumulation of glycolytic metabolites—dihydroxyacetone phosphate and 3-phosphoglyceraldehyde. These metabolites, in turn, serve as precursors for glycerol-3-phosphate, which is required for the re-Esterification of fatty acids during triacylglycerol biosynthesis. Thus, insulin-stimulated glucose uptake shifts fatty acid metabolism primarily toward synthetic pathways, reducing their release into the bloodstream.

These biochemical features of insulin action explain certain alterations in carbohydrate and Lipid Metabolism observed during starvation and Diabetes Mellitus. These conditions, characterized by low blood insulin levels, also feature impaired glucose uptake in adipocytes. By diminishing the glucose-dependent inhibition of fatty acid mobilization (see above), this promotes the release of fatty acids into blood plasma so they can be utilized as an energy source by other tissues. The administration of glucose and insulin to patients with diabetes mellitus or to fasted experimental animals inhibits adipocyte lipolysis and prevents excessive surges of plasma NEFA.

Somatotropin (Growth Hormone) is an anterior pituitary hormone that also stimulates lipolysis in adipose tissue during fasting; however, its lipolytic action differs significantly from that of catecholamines and glucagon. Somatotropin enhances lipolysis by upregulating the Synthesis of the relevant enzyme proteins. The metabolic effects of somatotropin develop slowly, highlighting its role in long-term adaptation to starvation.

Lipolysis in other tissues (such as muscles and the liver) is regulated by similar neurohumoral mechanisms.