BIOCHEMISTRY: A TEXTBOOK FOR HIGHER EDUCATION - E. S. Severin - 2004

CHAPTER 8. LIPID METABOLISM

IV. Triacylglycerol Metabolism

Since food intake occurs at significant intervals, the body has developed mechanisms to store Energy Sources. Fats are the most efficient and primary form of energy storage. Glycogen reserves in the body do not exceed 300 g and can sustain energy needs for no more than a day. In contrast, stored fat can supply energy during prolonged fasting for up to 7–8 weeks. Fat synthesis is activated during the absorptive period and takes place mainly in adipose tissue and the Liver. While adipose tissue serves as the primary fat storage site, the liver plays a crucial role in converting a portion of dietary CARBOHYDRATES into fats, which are then secreted into the bloodstream as VLDL and delivered to other tissues (primarily adipose tissue). Fat synthesis in both The Liver and Adipose tissue is stimulated by Insulin. Fat mobilization is triggered when glucose is insufficient to meet the body's energy demands—such as in the postabsorptive period, during fasting, and during physical exertion—under the Action of Hormones such as Glucagon, epinephrine, and Growth Hormone. Fatty acids are released into the Blood and utilized by tissues as energy sources.

A. Fat Synthesis in Adipose Tissue and the Liver

Fat synthesis occurs during the absorptive period in the liver and adipose tissue. The direct substrates for fat synthesis are acyl-CoA and glycerol-3-phosphate. The metabolic pathway of fat synthesis is identical in both tissues, with the sole difference lying in the pathways of glycerol-3-phosphate formation.

Formation of Glycerol-3-Phosphate

Fat synthesis in the liver and adipose tissue proceeds via The formation of an intermediate product, phosphatidic acid (Fig. 8-21).

Class="center">Fig. 8-21. Fat synthesis in the liver and adipose tissue.

The precursor of Phosphatidic acid is glycerol-3-phosphate, which is formed in the liver via two pathways:

✵ reduction of dihydroxyacetone phosphate, an intermediate metabolite of Glycolysis;

✵ phosphorylation of free glycerol by glycerol kinase, which enters the liver from the blood (a product of lipoprotein lipase action on chylomicron and VLDL fats).

Adipose tissue lacks glycerol kinase, making the reduction of dihydroxyacetone phosphate the sole pathway for glycerol-3-phosphate formation. Consequently, fat synthesis in adipose tissue can occur only during the absorptive period, when glucose enters adipocytes via the GLUT-4 glucose transporter—which is active only in the presence of insulin—and is degraded via glycolysis.

Fat Synthesis in Adipose Tissue

In adipose tissue, fat synthesis predominantly utilizes fatty acids released from the Hydrolysis of chylomicron and VLDL fats (Fig. 8-22). These fatty acids enter adipocytes, are converted into CoA derivatives, and react with glycerol-3-phosphate to form first lysophosphatidic acid and then phosphatidic acid. Following dephosphorylation, phosphatidic acid is converted into diacylglycerol, which is further acylated to form triacylglycerol.

In addition to blood-derived fatty acids entering adipocytes, these Cells also synthesize fatty acids de novo from glucose breakdown products. To support fat synthesis reactions, glucose breakdown in adipocytes follows two pathways: glycolysis, which provides glycerol-3-phosphate and acetyl-CoA, and the Pentose Phosphate Pathway, whose oxidative reactions generate NADPH to serve as a hydrogen donor in fatty acid synthesis reactions.

Fig. 8-22. Fat storage in adipocytes during the absorptive period. Following a meal, elevated blood glucose concentrations stimulate insulin secretion. Insulin activates Glucose Transport into adipocytes via GLUT-4, as well as the synthesis of lipoprotein lipase in adipocytes and its exposure on the Capillary Wall surface. Vascular endothelium-associated lipoprotein lipase hydrolyzes fats within chylomicrons and VLDL. ApoC-II On the surface of chylomicrons and VLDL activates lipoprotein lipase. Fatty acids penetrate the adipocyte, while glycerol is transported to the liver. Because adipocytes lack the enzyme glycerol kinase, free glycerol cannot be utilized for TAG synthesis in this tissue. Activated fatty acids react with glycerol-3-phosphate (derived from dihydroxyacetone phosphate) and are converted via phosphatidic acid into TAGs, which are then stored in adipocytes. Abbreviations: TAG* — triacylglycerols in chylomicrons and VLDL; DHAP — dihydroxyacetone phosphate.

Fat molecules in adipocytes coalesce into large, Water-free lipid droplets, making them the most compact form for storing energy molecules. It has been calculated that if the energy stored in fats were instead kept in the form of highly hydrated glycogen molecules, human body weight would increase by 14–15 kg.

TAG Synthesis in the Liver. VLDL Formation in the Liver and Fat Transport to Other Tissues

The liver is the primary organ where fatty acids are synthesized from glycolysis products. In the smooth Endoplasmic reticulum of hepatocytes, fatty acids are activated and immediately utilized for fat synthesis by reacting with glycerol-3-phosphate. As in adipose tissue, fat synthesis proceeds through the formation of phosphatidic acid. Fats synthesized in the liver are packaged into VLDL and secreted into the bloodstream (Fig. 8-23).

Fig. 8-23. Synthesis and Secretion of VLDL in the liver. Proteins synthesized in the rough endoplasmic reticulum (1) and the Golgi apparatus (2) form a complex with TAGs known as VLDL. VLDL particles are packaged into secretory granules (3), transported to The Cell membrane, and secreted into the blood.

In addition to fats, VLDL particles contain Cholesterol, Phospholipids, and the protein apoB-100. This is a very large protein comprising 11,536 Amino Acids. A single molecule of apoB-100 covers the entire surface of the lipoprotein.

VLDLs are secreted from the liver into the blood (Fig. 8-23), where, like chylomicrons, they are acted upon by lipoprotein lipase. Fatty acids enter tissues, particularly adipocytes, and are used for fat synthesis. As fats are removed from VLDLs by lipoprotein lipase, VLDLs are first converted into IDLs and then into LDLs. In LDLs, the primary lipid components are cholesterol and its esters; therefore, LDLs function as Lipoproteins that deliver cholesterol to peripheral tissues. Glycerol released from lipoproteins is transported by the blood to the liver, where it can be reused for fat synthesis.

The rate of Fatty acid and fat synthesis in the liver depends significantly on dietary composition. If the diet contains more than 10% fat, the rate of hepatic fat synthesis drops sharply.

B. Mobilization of fats from adipose tissue

Adipocytes (the fat storage sites) are located mainly beneath the Skin, forming the subcutaneous fat layer, and in the Abdominal cavity, forming the greater and lesser omenta. The mobilization of fats—i.e., their hydrolysis into glycerol and fatty acids—occurs during the postabsorptive period, during fasting, and during vigorous physical exertion. The hydrolysis of intracellular fat is carried out by the enzyme hormone-sensitive lipase, or TAG lipase. This enzyme cleaves one fatty acid from the first carbon atom of glycerol to form diacylglycerol, after which other lipases hydrolyze it further into glycerol and fatty acids, which enter the bloodstream. Glycerol, being a water-soluble substance, is transported freely in the blood, whereas fatty acids (hydrophobic molecules) are transported in a complex with the plasma protein albumin.

C. Hormonal Regulation of fat synthesis and mobilization

Which process predominates in the body—fat synthesis (Lipogenesis) or fat breakdown (lipolysis)—depends on nutrient intake and physical activity. In the absorptive state, lipogenesis occurs under the Action of Insulin; in the postabsorptive state, lipolysis is activated by glucagon. Adrenaline, the secretion of which increases during physical activity, also stimulates lipolysis.

Regulation of fat synthesis. In the absorptive period, when the insulin/glucagon ratio increases, fat synthesis is activated in the liver. In adipose tissue, the synthesis of lipoprotein lipase is induced within adipocytes, and the enzyme is translocated to the endothelial surface; consequently, the uptake of fatty acids by adipocytes increases during this period. Simultaneously, insulin activates glucose transporter proteins, specifically GLUT-4. Glucose uptake into adipocytes and glycolysis are also stimulated. As a result, all the necessary components for fat synthesis are produced: glycerol-3-phosphate and active forms of fatty acids. In the liver, insulin acts through various mechanisms to activate Enzymes via dephosphorylation and to induce their synthesis. Consequently, there is an increase in the activity and synthesis of enzymes involved in converting a portion of dietary glucose into fat. These include regulatory glycolytic enzymes, the Pyruvate dehydrogenase complex, and enzymes involved in the synthesis of fatty acids from acetyl-CoA. The net effect of insulin action on carbohydrate and Lipid METABOLISM IN the liver is enhanced fat synthesis and its secretion into the blood as part of VLDLs. VLDLs deliver fats to the capillaries of adipose tissue, where the action of lipoprotein lipase ensures the rapid uptake of fatty acids into adipocytes, where they are stored as triacylglycerols.

The storage of fat in adipose tissue is the principal form of energy reserve in The Human Body (Table 8-6). Fat reserves in a 70-kg human amount to about 10 kg, though in many individuals the quantity of fat can be considerably larger.

Table 8-6. Energy reserves in the human body (mass 70 kg)

Fats form fat vacuoles within adipocytes. These fat vacuoles sometimes occupy a significant portion of the Cytoplasm. The rate of synthesis and mobilization of subcutaneous fat varies across different PARTS OF THE body, which is related to the uneven distribution of Hormone Receptors on adipocytes.

Regulation of fat mobilization. The mobilization of stored fat is stimulated by glucagon and adrenaline and, to a lesser extent, by certain Other Hormones (growth hormone, cortisol). During the postabsorptive period and fasting, glucagon acts on adipocytes via the adenylate cyclase system to activate protein kinase A, which phosphorylates and thereby activates hormone-sensitive lipase, initiating lipolysis and the release of Fatty Acids and glycerol into the blood. During physical activity, the secretion of adrenaline increases; it acts via $\beta$-adrenergic receptors on adipocytes to stimulate the adenylate cyclase system (Fig. 8-24). Currently, 3 types of $\beta$-receptors have been identified: $\beta_1$, $\beta_2$, $\beta_3$, the activation of which produces a lipolytic effect. Activation of $\beta_3$-receptors yields the strongest lipolytic response. Adrenaline simultaneously acts on $\alpha_2$-receptors of adipocytes, which are coupled to an inhibitory G-protein, thereby inactivating the adenylate cyclase system. The Effect of adrenaline is likely dual: at low blood concentrations, its antilipolytic effect via $\alpha_2$-receptors predominates, whereas at high concentrations, its lipolytic effect via $\beta$-receptors prevails.

Fig. 8-24. Hormonal regulation of fat mobilization during the postabsorptive period, fasting, and physical exertion. During fasting, glucagon secretion increases; during physical activity, adrenaline secretion increases. These hormones stimulate fat mobilization by acting through the adenylate cyclase system. *TAG lipase also has other names: hormone-sensitive lipase, tissue lipase.

During fasting or physical exertion, fatty acids become an important energy source for muscles, The Heart, Kidneys, and liver. The liver converts some of the fatty acids into Ketone Bodies, which are used as energy sources by the Brain, Nervous Tissue, and certain other tissues.

As a result of fat mobilization, the concentration of fatty acids in the blood approximately doubles (Fig. 8-25), although the absolute concentration of fatty acids in the blood remains low even during this period. The half-life (T¹_/2) of fatty acids in the blood is also very short (less than 5 min), indicating a rapid flux of fatty acids from adipose tissue to other Organs. When the postabsorptive period transitions back to the absorptive period, insulin activates a specific phosphatase that dephosphorylates hormone-sensitive lipase, halting fat breakdown.

Fig. 8-25. Changes in the blood concentration of fatty acids, ketone bodies, and glucose during fasting.

D. Disorders of Lipid Metabolism. Obesity

Adipose tissue accounts for 20–25% of total body weight in women and 15–20% in men. However, excessive fat accumulation in adipocytes (obesity) is widespread. Among the adult population in some countries, about 50% of individuals suffer from obesity. Obesity is a major risk factor for myocardial infarction, stroke, Diabetes Mellitus, arterial Hypertension, and cholelithiasis.

Obesity is defined as a condition in which body weight exceeds the "ideal" weight for a given individual by more than 20%. The formation of adipocytes occurs prenatally, beginning in the last trimester of Pregnancy, and ends in the prepubertal period. Thereafter, fat cells can increase in size during obesity or decrease during weight loss, but their total number remains unchanged throughout life.

Primary obesity

Primary obesity is characterized by numerous hormonal and metabolic peculiarities in affected individuals. In the most general terms, primary obesity develops as a result of nutritional imbalance—excessive caloric intake relative to Energy Expenditure.

The body's daily Energy Requirements consist of:

✵ Basal metabolism—the energy required to sustain life; basal metabolism is measured by oxygen consumption or heat production in a human at rest in the morning, after a 12-hour fast;

✵ energy required for physical activity.

Energy expenditure required for physical activity is divided into 3 levels:

I — 30% of basal metabolic rate (in sedentary individuals);

II — 60 — 70% of basal metabolic rate (in individuals engaging in moderate physical activity for 2 hours a day);

III — 100% or more of basal metabolic rate (in individuals engaged in heavy physical labor for several hours a day).

Depending on the intensity of activity and age, the daily energy requirement ranges from 2,000 to 3,000 kcal for women, and from 2,300 to 4,000 kcal for men.

The amount of food consumed is determined by many factors, including chemical regulators of hunger and satiety. These sensations are regulated by blood glucose levels and hormones that trigger satiety: cholecystokinin, neurotensin, bombesin, and leptin.

Causes of primary obesity:

✵ Genetic Disorders (up to 80% of obesity cases result from genetic disorders);

✵ composition and quantity of consumed food, as well as family dietary habits;

✵ level of physical activity;

✵ psychological factors.

Genetic factors in The Development of obesity. Metabolic differences between obese and lean individuals cannot yet be definitively characterized. Several theories explain these differences:

✵ genetically determined differences in the functioning of "futile" cycles (Substrate Cycles, section 7). These cycles consist of a pair of metabolites interconverted by two enzymes, where one of the reactions consumes ATP. For example,

✵ if these substrates are interconverted at equal rates, a "futile" consumption of ATP and energy sources (such as fats) occurs;

✵ obesity-prone individuals likely have a tighter coupling of Respiration and Oxidative Phosphorylation, i.e., a more efficient metabolism;

✵ differing ratios of aerobic and anaerobic glycolysis are possible; anaerobic glycolysis (being less efficient) "Burns" much more glucose, thereby reducing its conversion into fats;

✵ individual subjects exhibit variations in Na⁺/K⁺-ATPase activity, the operation of which accounts for up to 30% of cellular energy consumption.

The Role of leptin in The regulation of adipose tissue mass

Humans and animals possess the "obesity Gene" — the ob gene. The product of this gene's expression is the protein leptin, consisting of 167 amino acids, which is synthesized and secreted by adipocytes and interacts with hypothalamic receptors. Its action leads to a decrease in neuropeptide Y secretion. Neuropeptide Y stimulates feeding behavior, as well as the search for and consumption of food in animals. Other Peptides involved in the regulation of satiety, such as cholecystokinin, also influence neuropeptide Y secretion. Through this indirect pathway, leptin acts as a regulator of the fat mass required for GROWTH AND REPRODUCTION. Leptin levels in obese patients can vary.

In 80% of obese patients, blood leptin concentrations are 4 times higher than in individuals with normal body weight. In these cases, There is a genetic defect in hypothalamic leptin receptors; therefore, despite leptin production, the hypothalamic hunger center continues to secrete neuropeptide Y.

20% of patients have alterations in the Introduction/19.html">Primary Structure of leptin. To date, 5 single Mutations in the leptin gene have been described that lead to the development of obesity. These patients exhibit increased fat deposition in adipose tissue, excessive food intake, low physical activity, and the development of type II diabetes mellitus. The Pathogenesis of obesity associated with an ob gene defect may be as follows: low blood leptin levels serve as a signal of insufficient fat reserves in the body; this signal triggers mechanisms that lead to increased appetite and, consequently, weight gain.

Therefore, we can conclude that primary obesity is not merely the consequence of overeating, but the result of multiple factors; in other words, obesity is a polygenic disease.

Secondary obesity — obesity developing as a result of an underlying disease, most commonly of endocrine origin. For example, hypothyroidism, Cushing's syndrome, hypogonadism, and many other conditions lead to the development of obesity (see section 11).