Metabolic Pathways May Be Studied At Different Levels Of Organization

In addition to studies in the whole organism, the location and integration of metabolic pathways is revealed by studies at several levels of organization. At the tissue and organ level, the nature of the substrates entering and metabolites leaving tissues and organs is defined. At the subcellular level, each cell organelle (eg, the mitochondrion) or compartment (eg, the cytosol) has specific roles that form part of a subcellular pattern of metabolic pathways.

At the Tissue and Organ Level, the Blood Circulation Integrates Metabolism

Amino acids resulting from the digestion of dietary protein and glucose resulting from the digestion of carbohydrate are absorbed and directed to the liver via the hepatic portal vein. The liver has the role of regulating the blood concentration of most water-soluble metabolites (Figure 15-5). In the case of glucose, this is achieved by taking up glucose in excess of immediate requirements and converting it to glycogen (glycogene-

Figure 15-4. Overview of amino acid metabolism showing the major pathways and end products.
Figure 15-5. Transport and fate of major carbohydrate and amino acid substrates and metabolites. Note that there is little free glucose in muscle, since it is rapidly phosphorylated upon entry.

sis) or to fat (lipogenesis). Between meals, the liver acts to maintain the blood glucose concentration from glycogen (glycogenolysis) and, together with the kidney, by converting noncarbohydrate metabolites such as lactate, glycerol, and amino acids to glucose (gluco-neogenesis). Maintenance of an adequate concentration of blood glucose is vital for those tissues in which it is the major fuel (the brain) or the only fuel (the erythrocytes). The liver also synthesizes the major plasma proteins (eg, albumin) and deaminates amino acids that are in excess of requirements, forming urea, which is transported to the kidney and excreted.

Skeletal muscle utilizes glucose as a fuel, forming both lactate and CO2. It stores glycogen as a fuel for its use in muscular contraction and 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 in starvation.

Lipids in the diet (Figure 15-6) are mainly triacyl-glycerol and are hydrolyzed to monoacylglycerols and fatty acids in the gut, then reesterified in the intestinal mucosa. Here they are packaged with protein and secreted into the lymphatic system and thence into the blood stream as chylomicrons, the largest of the plasma lipoproteins. Chylomicrons also contain other lipid-soluble nutrients, eg, vitamins. Unlike glucose and amino acids, chylomicron triacylglycerol is not taken up directly by the liver. It is first metabolized by tissues that have lipoprotein lipase, which hydrolyzes the triacyl-glycerol, releasing fatty acids that are incorporated into tissue lipids or oxidized as fuel. The other major source of long-chain fatty acid is synthesis (lipogenesis) from carbohydrate, mainly in adipose tissue and the liver.

Adipose tissue triacylglycerol is the main fuel reserve of the body. On hydrolysis (lipolysis) free fatty acids are released into the circulation. These are taken up by most tissues (but not brain or erythrocytes) and esterified to acylglycerols or oxidized as a fuel. In the liver, triacyl-glycerol arising from lipogenesis, free fatty acids, and chylomicron remnants (see Figures 25-3 and 25-4) is secreted into the circulation as very low density lipoprotein (VLDL). This triacylglycerol undergoes a fate similar to that of chylomicrons. Partial oxidation of fatty acids in the liver leads to ketone body production (keto-

Figure 15-6. Transport and fate of major lipid substrates and metabolites. (FFA, free fatty acids; LPL, lipoprotein lipase; MG, monoacylglycerol; TG, triacylglycerol; VLDL, very low density lipoprotein.)

genesis). Ketone bodies are transported to extrahepatic tissues, where they act as a fuel source in starvation.

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 15-7 depicts the subcellular compartmentation of metabolic pathways in a hepatic parenchymal cell.

The central role of the mitochondrion is immediately apparent, since it acts as the focus of carbohydrate, lipid, and amino acid metabolism. It contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and ketogenesis, as well as the respiratory chain and ATP synthase.

Glycolysis, the pentose phosphate pathway, and fatty acid synthesis are all found in the cytosol. In gluconeo-genesis, substrates such as lactate and pyruvate, which are formed in the cytosol, enter the mitochondrion to yield oxaloacetate before formation of glucose.

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

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