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

Chapter VI. BIOCHEMISTRY OF PHYSIOLOGICAL FUNCTIONS AND SPECIALIZED TISSUES

CHAPTER 31. BIOCHEMICAL FUNCTIONS OF THE LIVER. DETOXIFICATION PROCESSES

Liver diseases are among the most common human pathologies. Acute and chronic hepatitis, as well as liver cirrhosis, develop As a result of the damaging effects on hepatocytes caused by various infectious agents (viral and bacterial), exogenous chemical compounds—xenobiotics, radiation injury, hemodynamic disorders (cardiovascular insufficiency, Shock of various origins), and dietary deficiencies of Proteins, Essential Amino Acids, and "lipotropic factors" (The amino acid L-Methionine, and the antioxidant α-tocopherol).

31.1. STRUCTURAL AND FUNCTIONAL ORGANIZATION OF THE LIVER. BIOCHEMICAL FUNCTIONS OF HEPATOCYTES

The liver occupies a central position in the regulation and integration of interorgan METABOLISM, acting as the "central biochemical laboratory of the body."

This unique Significance of the liver in regulating the biochemical Homeostasis of the whole Organism is primarily due to its Anatomical and physiological Location between the PORTAL VEIN SYSTEM (v. porta) and the systemic Circulation (Fig. 31.1).

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Fig. 31.1. Anatomical and physiological relationships between the liver, the gastrointestinal tract, and the portal vein;

1 — liver; 2 — intestine; 3 — Stomach; 4 — v. porta (adapted from E. Newsholme, C. Start, 1977).

Of the Blood passing through the liver, 70% comes from the v. porta (with the remainder supplied by the hepatic artery); consequently, all compounds absorbed in the gastrointestinal tract inevitably pass through the liver. Based on this, the liver (due to the biochemical Functions of hepatocytes as the primary Structural and functional Cells of the organ) performs two main physiological functions that are vital for the survival of higher animals:

1. The liver serves as the primary regulator of blood levels of Monosaccharides, amino acids, Fatty acids, and glycerol derived from the Digestion of dietary nutrients. Furthermore, owing to its ability to biosynthesize and secrete numerous classes of CARBOHYDRATES, Lipids, and blood proteins into the bloodstream, the liver acts as the main distribution center for nutrients in the Human and Animal body.

Since nutrient supply from the intestine is intermittent, the levels of glucose, amino acids, and fats in the portal vein blood undergo significant fluctuations throughout the day. Maintaining their stable concentration in the systemic circulation is achieved precisely through the regulatory function of the liver, which smooths out ("damps") these fluctuations in metabolite levels.

2. Following intestinal absorption, not only nutrients but also numerous foreign chemical substances (such as drugs and toxins) and certain toxic end-metabolites (Bile pigment metabolism products, hormone Catabolism products, and compounds formed during protein putrefaction in the Large Intestine) pass through the liver. Thanks to complex enzyme systems of biotransformation within hepatocytes, the liver performs a vitally important barrier function, protecting other Organs and tissues from the Adverse effects of toxic substances.

Features of the Morphological Organization OF THE Liver

The mass of the liver in a healthy adult is about 1500–2000 g (on average, 20–25 g/kg of body weight).

The histological framework and functional units of the liver are the hepatic lobules, which consist of parenchymal liver cells—hepatocytes. These cells form cellular cords (trabeculae) that converge toward the v. centralis (Fig. 31.2). Hepatocytes make up to 80% of the cellular COMPOSITION OF THE liver and carry out the primary biochemical functions characteristic of this organ.

Fig. 31.2. Cytology/cytology/92.html">SCHEMATIC Structure OF a hepatic lobule

(A — sinusoids; B — spaces of Disse; C — bile canaliculus).

Located between the individual hepatic cords are sinusoids (vessels representing terminal Branches of the portal vein), from which blood flows through the v. centralis into the hepatic Veins and, consequently, into the systemic circulation. The walls of the sinusoids are formed by elongated reticuloendothelial ("Kupffer") cells. Between the walls of these cells and the trabeculae (the Plasma Membranes of hepatocytes), slit-like spaces—the spaces of Disse—are formed, through which the exchange of substances takes place between the sinusoidal blood and the parenchymal cells of the liver. The lateral surfaces of hepatocytes opposite to the sinusoids (plasma membranes) form bile canaliculi, through which specific biochemical components are secreted into the bile.

Biochemical Functions of the Liver in the Body

Aside from its anatomical and physiological location, blood supply, and structural architecture, the functional role of the liver in humans and higher animals is determined by the specific enzymatic composition of its hepatocytes, enabling the organ to perform a series of intrinsic biochemical functions. Impairment of these functions under conditions of hepatocellular insufficiency, which can occur during various types of hepatocyte damage, leads to severe systemic disorders—particularly affecting the Central Nervous system (hepatic coma)—and represents a life-threatening condition.

1. Carbohydrate (Glycogenic) Function of the Liver

This function consists in the ability of hepatocytes to form labile carbohydrate reserves used to maintain required blood glucose concentrations and supply this sugar to other organs (primarily the Brain) during periods between meals.

Formation and Utilization of Glucose-6-Phosphate

The initiating step in incorporating glucose into metabolic pathways is its phosphorylation to glucose-6-phosphate (G-6-P):

This key reaction of Carbohydrate Metabolism can be catalyzed in the liver by two Enzymes: specific glucokinase and nonspecific hexokinase, which differ in their substrate affinity. The K_m values for these enzymes are 0.01-0.1 mM for hexokinase and 10 mM for glucokinase. Hence, it is evident that at physiological glucose concentrations (3.3-5.5 mmol/L), hexokinase is catalytically active, whereas the enzymatic action of glucokinase is triggered only upon a significant increase in glucose influx into hepatocytes following the consumption of a carbohydrate-rich diet (Fig. 31.3).

Fig. 31.3. Kinetic curves showing the dependence of The rate of glucose phosphorylation (V_max) on carbohydrate concentration under the action of hexokinase and glucokinase.

Postprandial activation of the glucokinase reaction establishes kinetic conditions for The production of substantial amounts of intracellular glucose-6-phosphate, which, in turn, can enter metabolic pathways via one of the routes indicated in the scheme (Fig. 31.4).

Fig. 31.4. Scheme of G-6-P transformations in hepatocytes and approximate quantitative relationships between individual metabolic pathways.

Biosynthesis and Breakdown of Glycogen

Due to The activity of glycogen synthase, hepatocytes continuously synthesize and store significant amounts of glycogen within their Cytoplasm in the form of insoluble cytosolic granules: 3-5% (g/100 g of organ mass), allowing the liver to perform the physiologically vital function of a whole-body glucose reservoir.

This metabolic function is mediated by the glycogen phosphorolysis system, the activation of which is stimulated by Glucagon (during drops in blood glucose levels), as well as by the presence of active glucose-6-phosphatase in The Endoplasmic reticulum membranes:

Impairments in the glycogen-related function of the liver—that is, its ability to build metabolic glycogen reserves and/or utilize them as metabolic fuel to support other organs—depend on various etiological factors, the primary ones being:

(a) depletion of glycogen reserves in hepatocytes caused by damaging agents of diverse origins that disrupt cellular anabolic reactions (viral or toxic hepatitis, cellular Hypoxia);

(b) impaired ability of hepatocytes to synthesize glycogen from glucose due to congenital enzymopathies (aglycogenosis);

(c) impaired ability of hepatocytes to mobilize glycogen reserves (Glycogen Storage Diseases), specifically resulting from a deficiency in hepatic Glycogen phosphorylase (Hers disease) or glucose-6-phosphatase, which converts glucose-6-phosphate into free glucose (Gierke disease).

Gluconeogenesis

The liver is the primary organ of gluconeogenesis, meaning the Synthesis of glucose from non-carbohydrate precursors (lactate, glucogenic amino acids, glycerol), which is activated when hepatic glycogen reserves (180-350 g of glycogen) are depleted and dietary sugar intake decreases (or ceases entirely).

In The Human Body, carbohydrate reserves are exhausted in approximately 12 hours; nevertheless, a person can endure fasting for several months. Under these conditions, the supply of glucose to tissues whose Energy Metabolism heavily relies on this monosaccharide (the brain, other neural tissues, erythrocytes, renal medulla, and Testes) is sustained precisely through hepatic and, partially, renal gluconeogenesis.

Conversion of Other Monosaccharides into Glucose

During a mixed diet, along with glucose, the Human digestive tract absorbs numerous other monosaccharides, notably D-fructose (derived from sucrose), D-galactose (from milk lactose), and D-manose (from plant-based foods). The integration of these sugars into general metabolism is facilitated by enzyme systems within hepatocytes that convert these monosaccharides into phosphorylated glucose esters and glycolytic intermediates.

2. Regulation of Blood Lipid Profile

The liver is the site of active Synthesis and degradation for most lipid classes, including fatty acids, acylglycerols, Cholesterol, Phospholipids (Glycerophospholipids and sphingophospholipids), and Glycolipids.

Aside from utilizing lipids for its own energetic and structural needs, the liver plays a decisive role in regulating fat oxidation by other tissues—a function carried out through the hepatic Synthesis and Secretion into the bloodstream of triacylglycerols (in the form of very-low-density Lipoproteins, VLDL) and Ketone Bodies. Furthermore, the liver produces the bulk of cholesterol utilized by peripheral tissues for the synthesis of physiologically active Steroids.

(1) Synthesis and Secretion of Triacylglycerols

In the human body, the primary storage site for high-energy triacylglycerols is adipose tissue. At the same time, the Biosynthesis of triacylglycerols from Higher Fatty Acids and glycerol occurs predominantly in hepatocytes by utilizing metabolites generated during glucose oxidation (acetyl-CoA, glycolytic intermediates).

Consequently, the body requires a transport mechanism to deliver Water-insoluble triacylglycerols through the bloodstream to adipocytes. This mechanism involves The formation of VLDL in hepatocytes, which are secreted into the blood and utilized by adipocytes via active lipoprotein lipase located in the capillary endothelium of adipose tissue. The biosynthesis and secretion of VLDL into the bloodstream by hepatocytes increase with an elevated flux of fatty acids directed from the intestine to the liver during the digestion of neutral fats, as well as under a high-carbohydrate diet, which enhances the endogenous synthesis of long-chain fatty acids in liver cells.

Impaired VLDL synthesis in hepatocytes due to viral or toxic liver damage leads to the abnormal accumulation of triacylglycerols within the organ—a condition known as «Fatty liver degeneration».

(2) Synthesis and Utilization of Ketone Bodies

Liver cells do not secrete free fatty acids into the bloodstream; instead, these are utilized within the liver itself via β-oxidation or incorporation into triacylglycerols (see above). The energy substrate («fatty fuel») that hepatocytes supply to other tissues consists of ketone bodies (primarily acetoacetate), which are actively produced in the liver through a specialized biosynthetic pathway involving the Condensation of individual acetyl-CoA molecules.

In a healthy organism, the utilization of ketone bodies synthesized in the liver occurs in most extrahepatic tissues, particularly in skeletal Muscles, the myocardium, the Kidneys, and (during prolonged fasting) the brain.

(3) Synthesis and Biotransformation of Cholesterol

The liver is the primary site of Cholesterol Biosynthesis from acetyl-CoA (averaging 250-500 mg/day).

The utilization of cholesterol involves the intrahepatic synthesis of bile acids and extrahepatic reactions yielding biologically active steroids: vitamin D₃ and its derivatives, corticosteroids of the adrenal cortex, and male and Female Sex Hormones.

3. Protein-Synthesizing Function of the Liver

The Role of the Liver in Protein metabolism of the whole organism involves the production of most Plasma Proteins, which perform vital biochemical and physiological functions; the Regulation of Amino acid distribution among individual organs and tissues; and the synthesis of urea as the final product of nitrogen catabolism.

(1) Hepatocytes synthesize all plasma albumins (13-18 g/day), which participate in maintaining normal plasma oncotic pressure and transporting numerous metabolites and other Biomolecules; hypoalbuminemia serves as an informative clinical and diagnostic marker of acute and chronic Liver failure.

(2) The liver synthesizes the majority (about 80%) of plasma globulins: hepatocytes participate in The biosynthesis of a certain fraction of α-globulins, reticuloendothelial cells produce β-globulins and a portion of γ-globulins (IMMUNOGLOBULINS); liver diseases accompanied by severe structural and functional impairments of the organ are characterized by decreased blood concentrations of α₁-, α₂-, and β-globulins; conversely, pathological processes involving the activation of immunocompetent liver cells lead to elevated levels of γ-globulins.

(3) Liver cells synthesize many protein factors involved in the Blood Coagulation, anticoagulation, and fibrinolytic systems: coagulation factors V, XI, XII, XIII, Components of the prothrombin complex (factors II, VII, IX, X), fibrinogen, antithrombin, antiplasmin, and heparin.

(4) Due to the active course of Amino acid metabolism reactions (Transamination, deamination, decarboxylation), the liver participates in maintaining the relative biochemical Stability of the blood amino acid pool; impaired protein-synthesizing function of hepatocytes (particularly under The Influence of chemical and biological damaging factors on the ribosomal Translation system) is accompanied by a significant increase in the concentration of free amino acids in Blood Plasma; the plasma amino nitrogen level (normally 2.9-4.3 mmol/L) can rise up to 21 mmol/L in patients with severe liver failure, accompanied by marked Aminoaciduria.

4. Urea-Synthesizing Function of the Liver

The liver is the sole organ containing the complete set of enzymes required for urea synthesis from the products of nitrogen (primarily protein) catabolism. Impairments in The Urea Cycle function caused by exogenous damaging factors or hereditary enzymopathies (Genetic Defects in the Synthesis of specific urea cycle enzymes) lead to the accumulation of free ammonia in the blood and tissues.

Brain Neurons are the most sensitive to this pathobiochemical state, wherein excess ammonia is capable of inhibiting The Tricarboxylic Acid Cycle through the interaction of NH₄⁺ with α-ketoglutarate in the reductive amination reaction. The inhibition of TCA cycle reactions and the corresponding decrease in ATP levels in Nervous Tissue trigger neuronal membrane depolarization and impaired synaptic transmission, which clinically manifests as The Development of hepatic encephalopathy and a comatose state.

5. Bile-Forming and Pigment Functions of the Liver

Crucial for human physiology and pathology is the role the liver plays in the catabolism of Hemoglobin and other heme-containing proteins, The breakdown of which yields bile pigments—bilirubin and biliverdin—excreted via the intestine (see section 31.3). These compounds, along with other organic substances (bile acids, cholesterol, phospholipids) produced by hepatocytes, form the constituents of bile, imparting its characteristic golden-yellow color.

Biochemical Composition of Bile

Bile is a fluid secretion of liver cells that serves both to deliver surface-active compounds (bile acids, phospholipids) necessary for the DIGESTION AND ABSORPTION of neutral fats into the duodenum, and to excrete the End products of biomolecule catabolism and xenobiotics from the body. An adult human produces 500-700 mL of bile per day; the concentrations of the main bioorganic compounds in hepatic and Gallbladder bile are presented in Table 31.1.

Table 31.1. Biochemical composition of human bile (g/L)

6. Liver Detoxification Function

One of the most vital BIOLOGICAL FUNCTIONS OF the liver is the neutralization—detoxification—of chemical compounds that are not normal body metabolites and can cause adverse effects, exhibiting general toxic, necrogenic, mutagenic, and carcinogenic actions. The biochemical essence of the detoxification process occurring in hepatocytes lies in the conversion (biotransformation) of a chemical compound, through specific enzymatic reactions, into a molecular form with significantly reduced toxic properties. As a rule, the products of toxin biotransformation in the liver are more water-soluble (hydrophilic) substances that can be excreted from the body by various elimination systems (kidneys, intestines, Lungs, Skin).

Due to its utmost importance for maintaining the chemical homeostasis of the internal environment in humans and animals, this function will be discussed in detail below.