The Liver Plays an Important Role in the Metabolism of Lipids

The liver plays a pivotal role in lipid metabolism (Fig. 28.4). It takes up free fatty acids and lipoproteins (complexes of lipid and protein) from the plasma. Lipid is circulated in the plasma as lipoproteins because lipid and water are not mis-

The Metabolism of Monosaccharides. Monosaccharides are first phosphorylated by a reaction catalyzed by the enzyme hexokinase. In the liver (but not in the muscle), there is a specific enzyme (glucokinase) for the phosphorylation of glucose to form glucose 6-phosphate. Depending on the energy requirement, the glucose 6-phosphate is channeled to glycogen synthesis or used for energy production by the glycolytic pathway.

Fructose is taken up by the liver and phosphorylated by fructokinase to form fructose 1-phosphate. This molecule is either isomerized to form glucose 6-phosphate or metabolized by the glycolytic pathway. Fructose 1-phosphate is used by the glycolytic pathway more efficiently than glucose 6-phosphate.

Galactose is an important sugar used not only to provide energy but also in the biosynthesis of glycoproteins and glycolipids. When galactose is taken up by the liver, it is phosphorylated to form galactose 1-phosphate, which then reacts with uridine diphosphate-glucose, or UDP-glucose, to form UDP-galactose and glucose 1-phosphate. The UDP-galactose can be used for glycoprotein and glycolipid biosynthesis or converted to UDP-glucose, which can then be recycled.

Gluconeogenesis. Gluconeogenesis is the production of glucose from noncarbohydrate sources such as fat, amino

Plasma

Fatty acid bound to albumin

Lipoprotein Catabolism

Fatty acid bound to albumin

LDL, VLDL remnants, and chylomicron remnants

LDL, VLDL remnants, and chylomicron remnants

The regulation of lipid metabolism in the

"liver. LDL, low-density lipoprotein,- VLDL, very low density lipoprotein, TG, triglycerides, TCA, tricarboxylic acid.

cible,- the lipid droplets coalesce in an aqueous medium. The protein and phospholipid on the surface of the lipoprotein particles stabilize the hydrophobic triglyceride center of the particle.

During fasting, fatty acids are mobilized from adipose tissue and are taken up by the liver. They are used by the hepatocytes to provide energy via ^-oxidation, for the generation of ketone bodies, and to synthesize the triglyceride necessary for VLDL formation. After feeding, chylomicrons from the small intestine are metabolized peripherally, and the chylomicron remnants formed are rapidly taken up by the liver. The fatty acids derived from the triglycerides of the chylomicron remnants are used for the formation VLDLs or for energy production via ^-oxidation.

Fatty Acid Oxidation and Synthesis. Fatty acids derived from the plasma can be metabolized in the mitochondria of hepatocytes by ^-oxidation to provide energy. Fatty acids are broken down to form acetyl-CoA, which can be used in the tricarboxylic acid cycle for ATP production, in the synthesis of fatty acids, and in the formation of ketone bodies. Because fatty acids are synthesized from acetyl-CoA, any substances that contribute to acetyl-CoA, such as carbohydrate and protein sources, enhance fatty acid synthesis.

The liver is one of the main organs involved in fatty acid synthesis. Palmitic acid is synthesized in the hepatocellular cytosol; the other fatty acids synthesized in the body are derived by shortening, elongating, or desaturating the palmitic acid molecule.

Lipoprotein Synthesis. One of the major functions of the liver in lipid metabolism is lipoprotein synthesis. The four major classes of circulating plasma lipoproteins are chy-lomicrons, very low density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) (Table 28.1). These lipoproteins, which differ in chemical composition, are usually isolated from plasma according to their flotation properties.

Chylomicrons are the lightest of the four lipoprotein classes, with a density of less than 0.95 g/mL. They are made only by the small intestine and are produced in large quantities during fat ingestion. Their major function is to transport the large amount of absorbed fat to the bloodstream.

Very low density lipoproteins (VLDLs) are denser and smaller than chylomicrons. The liver synthesizes about 10 times more circulating VLDLs than the small intestine. Like chylomicrons, VLDLs are triglyceride-rich and carry most of the triglyceride from the liver to the other organs. The triglyceride of VLDLs is broken down by lipoprotein lipase to yield fatty acids, which can be metabolized to provide energy. The human liver normally has a considerable capacity to produce VLDLs, but in acute or chronic liver disorders, this ability is significantly compromised. Liver VLDLs are associated with an important class of proteins, the apo B proteins. The two forms of circulating apo B are B48 and B100. The human liver makes only apo B100, which has a molecular weight of about 500,000. Apo B100 is important for the hepatic secretion of VLDL. In abetalipoproteinemia, apo B synthesis and, therefore, the secretion of VLDLs is blocked. Large lipid droplets can be seen in the cytoplasm of the hepatocytes of abetalipopro-teinemic patients.

Although considerable amounts of circulating plasma LDLs and HDLs are produced in the plasma, the liver also produces a small amount of these two cholesterol-rich lipoproteins. LDLs are denser than VLDLs, and HDLs are denser than LDLs. The function of LDLs is to transport cholesterol ester from the liver to the other organs. HDLs are believed to remove cholesterol from the peripheral tissue and transport it to the liver.

The formation and secretion of lipoproteins by the liver is regulated by precursors and hormones, such as estrogen and thyroid hormone. For instance, during fasting, the fatty acids in VLDLs are derived mainly from fatty acids mobilized from adipose tissue. In contrast, during fat feeding, fatty acids in VLDLs produced by the liver are largely derived from chylomicrons.

As noted earlier, the fatty acids taken up by the liver can be used for ^-oxidation and ketone body formation. The relative amounts of fatty acid channeled for these various purposes are largely dependent on the individual's nutritional and hormonal status. More fatty acid is channeled to keto-genesis or ^-oxidation when the supply of carbohydrate is short (during fasting) or under conditions of high circulating glucagon or low circulating insulin (diabetes mellitus). In contrast, more of the fatty acid is used for synthesis of triglyceride for lipoprotein export when the supply of carbohydrate is abundant (during feeding) or under conditions of low circulating glucagon or high circulating insulin.

Lipoprotein Catabolism. The importance of the liver in lipoprotein metabolism is exemplified by familial hyperc-holesterolemia, a disorder in which the liver fails to produce the LDL receptor. When LDL binds its receptor, it is internalized and catabolized in the hepatocyte. Consequently, the LDL receptor is crucial for the removal of LDL from the plasma. Individuals suffering from familial hyper-cholesterolemia usually have very high plasma LDLs,

f table 28.1

Characteristics of Human Plasma Lipoproteins

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