Figure 2-7. Diagram of hepatic fatty acid metabolism. Both dietary and newly synthesized fatty acids are esterified and

subsequently degraded in the mitochondria for energy, first as reducing equivalents, then adenosine triphosphate via the electron

transport chain. Acetyl CoA, in red, plays a central role in lipid metabolism.

3 Free fatty acids are a direct source of energy for cardiac and skeletal muscles and under basal

conditions, most free fatty acids are catabolized for energy. Under conditions of adipocyte lipolysis, the

liver can take up and metabolize fatty acids. Although fatty acid synthesis occurs in the cytosol, fatty

acid oxidation occurs in the mitochondria. Fatty acid-CoA esters bind carnitine, a carrier molecule, and

in the absence of cytosolic malonyl CoA, they enter the mitochondria, where they undergo betaoxidation to acetyl CoA and reducing equivalents (Fig. 2-7). Acetyl CoA can then take one of the

following routes: (a) enter the tricarboxylic acid cycle and be degraded to carbon dioxide, (b) be

converted to citrate for fatty acid synthesis, or (c) be converted into 3-hydroxy-3-methylglutaryl CoA

(HMG-CoA), a precursor of cholesterol and ketone bodies. The mitochondrial hydrolysis of fatty acids is

a source of large quantities of ATP. The conversion of stearic acid to carbon dioxide and water, for

instance, generates 136 molecules of ATP and demonstrates the highly efficient storage of energy as fat.

By a process called beta-oxidation, acetyl-CoA molecules are cleaved from fatty acids. The acetyl CoA is

then metabolized through the citric acid cycle under normal circumstances.

In times of significant lipolysis – starvation, uncontrolled diabetes, or other conditions of triglyceride

mobilization from adipocyte stores – the predominant ketone bodies 3-hydroxybutyrate and

acetoacetate are formed in hepatic mitochondria from free fatty acids and are a source of energy for

extrahepatic tissues. Ketogenesis is regulated primarily by the rate of mobilization of free fatty acids.

Once in the liver mitochondria, the relative proportion of acyl CoA destined to undergo beta-oxidation

is limited by the activity of an enzyme, carnitine palmitoyltransferase-1. Lastly, there are mechanisms

that keep the levels of acetyl CoA entering the citric acid cycle constant, so that only at high

mitochondrial levels will acetyl CoA be converted to ketone bodies. Even the brain, in times of

starvation, can use ketone bodies for half of its energy requirements. At some point, however, the

ability of liver to perform beta-oxidation may be inadequate. Under such circumstances, hepatic storage

of triglyceride or fatty infiltration of the liver can be significant, leading to the development of

nonalcoholic steatohepatitis. Triglyceride storage by itself does not appear to be a cause of hepatic

fibrosis, but fatty infiltration may be a marker for the derangement of normal processes by alcohol or

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drug toxicity, diabetes, or long-term total parenteral nutrition. A specific type of microvesicular fatty

accumulation is also seen in a variety of diseases, such as Reye syndrome, morbid obesity, and acute

fatty liver of pregnancy.

Figure 2-8. The LDL receptor, an example of a transmembrane receptor that participates in receptor-mediated endocytosis. The

LDL receptor specifically binds lipoproteins that contain apolipoprotein B-100 or E. Once internalized, the lipoproteins are

degraded. AA, amino acids; EGF, epidermal growth factor.

As noted above, fatty acids are critical elements of all mammalian cells; as energy substrate, in

cellular structure, and for intracellular signaling. Evolutionarily, storage of excess fat in adipose tissue

mitigated starvation. But in most modern societies the ready availability of calorie-dense foods has led

to an epidemic of obesity as is discussed in detail in other chapters. In terms of intermediary

metabolism, excess dietary fatty acids are now known to cause insulin resistance in muscle through

intramyocellular triglyceride content leading to type II diabetes. This effect is likely due to intracellular

perturbations in active lipid metabolites such as diacylglycerols or ceramides. Other studies have

documented mitochondrial abnormalities possibly through interference with serine kinases.8

CHOLESTEROL METABOLISM

Cholesterol is an important regulator of membrane fluidity and is a substrate for bile acid and steroid

hormone synthesis. Cholesterol may be available by dietary intake or by de novo synthesis. In

mammals, mostly new cholesterol is synthesized in the liver from its precursor, acetyl CoA. Dietary

cholesterol intake can suppress endogenous synthesis by inhibiting the rate-limiting enzyme in the

cholesterol biosynthetic pathway, HMG-CoA reductase. A competitive antagonist, lovastatin, can also

block HMG-CoA reductase and effectively lower plasma cholesterol by blocking cholesterol synthesis,

stimulating LDL receptor synthesis, and allowing an increased hepatic uptake and metabolism of

cholesterol-rich LDL lipoproteins. The structure of the LDL receptor is known and serves as a model for

the structure and function of other cell membrane receptors (Fig. 2-8).

Cholesterol is lipophilic and hydrophobic, and most plasma cholesterol is in lipoproteins esterified

with oleic or palmitic acid. The liver can process cholesterol esters from all classes of lipoproteins.

Hepatocytes can also take up chylomicron remnants containing dietary cholesterol esters. Abnormally

elevated levels of cholesterol in VLDLs or LDLs are associated with atherosclerosis, whereas high HDL

levels are protective. Newly synthesized hepatic cholesterol is also used to synthesize bile acids for

further intestinal absorption of dietary fats. A large proportion of the bile acids secreted by the liver

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into bile are returned to the liver via the enterohepatic circulation (Fig. 2-9).

Phospholipids

The three major classes of phospholipids synthesized by the liver are lecithins, cephalins, and

sphingomyelins. Although most cells in the body are capable of some phospholipid synthesis, the liver

produces 90%. Phospholipid formation is controlled by the overall rate of fat metabolism and by the

availability of choline and inositol. The main role of phospholipids of all types is to form plasma and

organelle membranes. The amphiphilic nature of phospholipids makes them essential for reducing

surface tension between membranes and surrounding fluids. Phosphatidylcholine, one of the lecithins, is

the major biliary phospholipid and is important in promoting the secretion of free cholesterol into bile.

Thromboplastin, one of the cephalins, is needed to initiate the clotting cascade. The sphingomyelins are

necessary for the formation of the myelin nerve sheath.

Figure 2-9. The enterohepatic circulation of bile acids. The primary bile acids, cholic acid, and chenodeoxycholic acid, are

synthesized in the liver from cholesterol. Deoxycholic acid and lithocholic acid are formed in the colon (blue lines) during bacterial

degradation of the primary bile acids. All four bile acids are conjugated with glycine or taurine in the liver. Most of the lithocholic

acid is also sulfated, which decreases reabsorption and increases fecal excretion. Bile acids are absorbed passively in the epithelium

of the small and large intestine and actively in the distal ileum.

PROTEIN METABOLISM

Formation and Catabolism of Plasma Proteins

4 Hepatic protein synthesis, when excess amino acids are available, includes albumin, fibrinogen, and

apolipoproteins and can reach 50 g/day. Of the total hepatic protein synthesized, 75% is destined for

export in plasma. Most newly synthesized proteins are not stored in the liver, and the rate of protein

synthesis is primarily determined by the intracellular levels of amino acids. The tertiary structure of

many proteins undergoes posttranslational modification after they have been synthesized in the liver’s

rough endoplasmic reticulum (ER). Glycosylation, or the addition of carbohydrate moieties, occurs in

the smooth ER. Sialation, or the addition of sialic acid, occurs in the Golgi. Glycosylation is important in

allowing some proteins to bind with specific receptors for subsequent hepatic uptake and processing.

Removal of sialic acid residues, or desialation, from the terminal galactose molecules of glycoproteins

allows them to bind to the asialoglycoprotein (ASGP) receptor in the liver and undergo degradation.

Desialation, therefore, is important in the clearance of senescent proteins from the plasma.

Intracellular proteases hydrolyze proteins into peptides, and the peptides are in turn hydrolyzed by

peptidases. Ultimately, free amino acids are generated. Unlike carbohydrate and lipids, excess amino

acids are degraded if they are not immediately reincorporated into new proteins. Protein degradation

occurs primarily by one of two routes. ASGPs are internalized into lysosomes via receptor-mediated

endocytosis. The lysosomal enzymes do not require ATP and are nonselective in their activities; more

than 20 known hydrolytic enzymes are present in lysosomes. A second pathway involves the covalent

attachment of ubiquitin, named for the fact that it exists in all mammalian cells, targeting proteins for

destruction. This pathway is ATP dependent and generally is used for proteins with shorter half-lives.9

Amino Acid Synthesis

Essentially, all the end products of dietary protein digestion are amino acids, which are absorbed by the

enterocytes into the portal circulation in an ionized state. Liver amino acid uptake occurs by one of

several active transport mechanisms. Amino acids are not stored in the liver but are rapidly used in the

production of plasma proteins, purines, heme proteins, and hormones. Under certain conditions, the

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