At the whole organism level substrates are moved between organs that can either remove or add substrates to the blood perfusing the organ. The concentrations of the substrates entering and leaving tissues and organs can be measured to help describe how substrates move between organs. Within each organ substrates can be followed as they transverse the plasma membrane and enter the metabolic pathways. Depending on the specific pathway it could all occur in the cytosol (eg, glycolysis) or be compartmentalized in subcellular organelles (eg, citric acid cycle in the mitochondrion).

The Anatomical Location of an Organ & the Blood Circulation Integrates Metabolism

When food is digested in the intestine the substrates are either directly taken up and enter the portal vein or are packaged and secreted into the lymphatic system. The portal vein sends all of the absorbed substrates to the liver. Depending on the substrate, the liver can take up a small or large fraction of that which is delivered into the portal vein with the remaining allowed to pass into the systemic circulation. Substrates that enter the lymphatic circulation coalesce into a common thoracic duct which bypasses the liver and drains its contents into the systemic circulation.

Amino acids resulting from the digestion of dietary protein and glucose resulting from the digestion of carbohydrates are absorbed via the hepatic portal vein. The liver has the role of regulating the blood concentration of these water-soluble metabolites (Figure 1) by removing a variable portion of these substrates before they enter the systemic circulation. The uptake of glucose and amino acids is a regulated process.

Fig1. Uptake and fate of major carbohydrate and amino acid substrates and metabolites. Note: Brain and adipose tissue are not depicted.

In the case of glucose, in the fed state ~10 to 15% of the absorbed glucose is taken up by the liver . The majority is used to synthesize glycogen (glycogenesis). A small fraction is used for fatty acid synthesis (lipogenesis) and the remainder is broken down by glycolysis to generate pyruvate that can be oxidized in the citric acid cycle for pyruvate oxidation. The glucose not taken up by the liver is oxidized by the brain and many other tissues including skeletal muscle. Between meals, the liver rapidly switches to a producer of glucose. It is the primary source of glucose in the fasted setting . The glucose is derived from two sources; stored glycogen (glycogenolysis) and the synthesis of glucose from metabolites such as lactate, glycerol, and amino acids (gluconeogenesis).

The liver is a consumer of many dietary amino acids. Like glucose only a fraction of the total absorbed amino acids are removed by the liver. The remaining are removed by peripheral tissues. In the liver they are substrates for the synthesis of the major plasma proteins (eg, albumin, fibrinogen). A significant fraction is deaminated. While the carbon backbone of amino acids can be oxidized, the nitrogen is converted to urea, transported to the kidney and excreted . The remaining amino acids are taken up by peripheral tissues primarily for protein synthesis.

The main dietary lipids (Figure 2) are triacylglycerols that are hydrolyzed to monoacylglycerols and fatty acids in the gut, then reesterified in the intestinal mucosa. Here they are packaged with protein (ie, apolipoproteins) and secreted into the lymphatic system and thence into the bloodstream as chylomicrons, the largest of the plasma lipoproteins (see Chapter 25). Chylomicrons also contain other lipid-soluble nutrients from the diet, including vitamins A, D, E, and K . Unlike glucose and amino acids absorbed from the small intestine, chylomicron triacylglycerol is not taken up directly by the liver. It is first metabolized by tissues that have lipoprotein lipase, which hydrolyzes the triacylglycerol, releasing fatty acids that are incorporated into tissue lipids or oxidized as fuel. The chylomicron remnants are cleared by the liver. The other major source of long-chain fatty acids is synthesis (lipogenesis) from carbohydrate, in adipose tissue and the liver .

Fig2. Uptake and fate of major lipid substrates and metabolites. (LPL, lipoprotein lipase; MG, monoacylglycerol; NEFA, nonesterified fatty acids; TG, triacylglycerol; VLDL, very low-density lipoprotein.)

Adipose tissue triacylglycerol is the main fuel reserve of the body. It is hydrolyzed (lipolysis) and glycerol and nonesterified (free) fatty acids are released into the circulation. Glycerol is used as a substrate for gluconeogenesis .

The fatty acids are transported bound to serum albumin; they are taken up by most tissues (but not brain or erythrocytes) and either esterified to triacylglycerols for storage or oxidized as a fuel. In the liver, newly synthesized triacylglycerol, triacylglycerol from chylomicron remnants  and nonesterified (free) fatty acids from adipose tissue are pack aged in very low-density lipoprotein (VLDL) and secreted into the circulation. This triacylglycerol undergoes a fate simi lar to that of chylomicrons. Fatty acids can be partially oxidized  in the liver in the fasting setting to form ketone bodies . Ketone bodies are exported to extrahepatic tissues, where they provide an alternative fuel in prolonged fasting and starvation.

Skeletal muscle’s primary fuel is fatty acids in the fasted setting. In the fed state muscle glucose uptake increases markedly as its preferred substrate fatty acid decreases (see Figure 14–1). The glucose is oxidized to CO2 (aerobic) or anaerobically con verted to lactate. A large fraction (>50%) is stored as glycogen in the fed state. Skeletal muscle synthesizes muscle protein from plasma amino acids. Muscle accounts for approximately 50% of body mass and consequently represents a considerable store of protein that can be drawn upon to supply amino acids for gluconeogenesis and be oxidized in skeletal muscle in starvation (s. In long term  fasting ketones can be a significant contributor to muscle substrate oxidation.

At the Subcellular Level, Glycolysis Occurs in the Cytosol & the Citric Acid Cycle in the Mitochondria

Compartmentation of pathways in separate subcellular compartments or organelles permits integration and regulation of metabolism. Not all pathways are of equal importance in all cells. Figure 3 depicts the subcellular compartmentation of metabolic pathways in a liver parenchymal cell.

Fig3. Intracellular location and overview of major metabolic pathways in a liver parenchymal cell. (AA →, metabolism of one or more essential amino acids; AA ↔, metabolism of one or more nonessential amino acids.)

The liver performs many anabolic processes simultaneously (gluconeogenesis, lipogenesis, VLDL synthesis, and protein synthesis) each of these are energy requiring (ATP, NADH, NADPH). The central role of the mitochondrion is immediately apparent, since it acts as the focus of carbohydrate, lipid, and amino acid metabolism as well as a site for generation of energy to support these processes. It contains the enzymes of the citric acid cycle , β-oxidation of fatty acids and ketogenesis , as well as the respiratory chain and ATP synthase.

Glycolysis , the pentose phosphate pathway, and fatty acid synthesis all occur in the cytosol. Gluconeogenesis requires movement of molecules between cellular compartments. Substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate that then has to be moved to the cytosol to generate phosphoenolpyruvate, which serves as a precursor for the synthesis of glucose.

The membranes of the endoplasmic reticulum contain the enzyme system for triacylglycerol synthesis , and the ribosomes are responsible for protein synthesis.

مواضيع ذات صلة

The Flux Through Metabolic Pathways Must be Regulated In A Concerted Manner

Pathways To Process The Major Products Of our Diet

Overview of Substrate Metabolism in Fasting & Feasting

The selective permeability of the inner mitochondrial membrane necessitates exchange transporters

Many Poisons Inhibit the Respiratory Chain

The Respiratory Chain Provides Most Of The Energy Captured During Catabolism

Electron Transport Via The Respiratory Chain Creates A Proton Gradient Which Drives The Synthesis of ATP

The Respiratory Chain Oxidizes Reducing Equivalents & Acts as A Proton Pump

دورة الخلية وتخليق الدنا Cell Cycle & DNA Synthesis

Oxygenases Catalyze The Direct Transfer & Incorporation of Oxygen Into A Substrate Molecule

Hydroperoxidases Use Hydrogen Peroxide or an Organic Peroxide as Substrate

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