Medical Physiology, 3rd Edition

The Liver as a Metabolic Organ

The liver is a metabolically active and highly aerobic organ. It receives ~28% of the total blood flow and extracts ~20% of the oxygen used by the body. The liver is responsible for the synthesis and degradation of carbohydrates, proteins, and lipids. The small molecules that are products of digestion are efficiently sorted in the liver for metabolism, storage, or distribution to extrahepatic tissues for energy. The liver provides energy to other tissues mainly by exporting two substrates that are critical for oxidization in the peripheral tissues, glucose and ketone bodies (e.g., acetoacetate).

The liver can serve as either a source or a sink for glucose

The liver is one of the key organs that maintain blood glucose concentrations within a narrow range, in a dynamic process involving endogenous glucose production and glucose utilization. The fasting blood [glucose] is normally 4 to 5 mM. Between meals, when levels of insulin are relatively low (see p. 1036) and levels of glucagon are high (see p. 1052), the liver serves as a source of plasma glucose, both by synthesizing glucose and by generating it from the breakdown of glycogen. The de novo synthesis of glucose from lactate, pyruvate, and amino acids—gluconeogenesis (see p. 1176)—is one of the liver's most important functions; it is essential for maintaining a normal plasma concentration of glucose, which is the primary energy source for most tissues.

The second way in which the liver delivers glucose to blood plasma is by glycogenolysis (see p. 1182). Stored glycogen may account for as much as 7% to 10% of the total weight of the liver. Glycogenolysis in the liver yields glucose as its major product, whereas glycogen breakdown in muscle produces lactic acid (see Fig. 58-9).

After a meal, when levels of insulin are relatively high, the liver does just the opposite: it acts as a sink for glucose by taking it up from the portal blood and either breaking it down to pyruvate or using it to synthesize glycogen (see Fig. 51-8 and pp. 1179–1181). Glucose oxidation has two phases. In the anaerobic phase, glucose is broken down to pyruvic acid (glycolysis). In the aerobic phase, pyruvic acid is completely oxidized to H2O and CO2 through the citric acid cycle.

The liver also consumes glucose by using it for glycogen synthesis. Carbohydrate that is not stored as glycogen or oxidized is metabolized to fat.

All the aforementioned processes are regulated by hormones such as insulin (see Fig. 51-8) and glucagon (see Fig. 51-12), which enable rapid responses to changes in the metabolic requirements of the body.

The liver synthesizes a variety of important plasma proteins (e.g., albumin, coagulation factors, and carriage proteins) and metabolizes dietary amino acids

Protein Synthesis

One of the major functions of the liver is to produce a wide array of proteins for export to the blood plasma (Table 46-3). These products include major plasma proteins that are important for maintaining the colloid osmotic pressure of plasma (see p. 470). Other products include factors involved in hemostasis (blood clotting) and fibrinolysis (breakdown of blood clots), carriage proteins that bind and transport hormones and other substances in the blood, prohormones, and lipoproteins (Table 46-4). The liver synthesizes plasma proteins at a maximum rate of 15 to 50 g/day. imageN46-12

TABLE 46-3

Proteins Made by the Liver for Export

Major Plasma Proteins



Plasma fibronectin (an α2-glycoprotein)

C-reactive protein


Various other globulins

Factors Involved in Hemostasis/Fibrinolysis

Coagulation: fibrinogen and all others except for factor VIII

Inhibitors of coagulation: α1-antitrypsin and antithrombin III, α2-macroglobulin, protein S, protein C

Fibrinolysis: plasminogen

Inhibitors of fibrinolysis: α2-antiplasmin

Complement C3

Carriage Proteins (Binding Proteins)

Ceruloplasmin (see pp. 970–971)

Corticosteroid-binding globulin (CBG, also called transcortin; see p. 1021)

Growth hormone–binding protein (low-affinity form; see p. 994)



Insulin-like growth factor 1–binding proteins (see p. 996)

Retinol-binding protein (RBP; see p. 970)

Sex hormone–binding globulin (SHBG; see p. 1099)

Thyroxine-binding globulin (TBG; see pp. 1008–1009)

Transferrin (see p. 941)

Transthyretin (see pp. 1008–1009)

Vitamin D–binding protein (see p. 1064)


Angiotensinogen (see p. 1028)


Apo A-I

Apo A-II

Apo A-IV

Apo B-100

Apo C-II

Apo D

Apo E

TABLE 46-4

Major Classes of Lipoproteins







Density (g/cm3)






Diameter (nm)






Mass (kDa)






% Protein (surface)






% Phospholipid (surface)






% Free cholesterol (surface)






% Triacylglycerols (core)






% Cholesteryl esters (core)






Major apolipoproteins

A-I, A-II, B-48, C-I, C-II, C-III, E (1%–2%)

B-100, C-I, C-II, C-III, E

B-100, C-III, E


A-I, A-II, C-I, C-II, C-III, D, E

Adapted from Voet D, Voet JG: Biochemistry, 2nd ed. New York, John Wiley & Sons, 1995, p 317.


Synthesis of Plasma Proteins by the Liver

Contributed by Fred Suchy

The synthesis of the hepatic proteins for secretion into the blood plasma occurs via the secretory pathway (see pp. 34–35). The synthesis begins in the rough endoplasmic reticulum (RER). Nearly all proteins secreted by the liver are glycosylated. N-linked glycosylation occurs in the RER (see p. 32), and further remodeling occurs in the Golgi (see pp. 37–38). O-linked glycosylation also occurs in the Golgi (see pp. 38–39). The ER can also conjugate proteins with lipid.

Amino-Acid Uptake

A major role of the liver is to take up and metabolize dietary amino acids that are absorbed by the gastrointestinal tract (see p. 923) and are transported to the liver in portal blood. These amino acids are taken up by both Na+-dependent and Na+-independent transporters that are identical to some of the amino-acid transporters in the kidney, small intestine, and other tissues (see Table 36-1). An unusual feature of the liver is that, with few exceptions, the same amino-acid transporter may be located on both the basolateral and apical membranes. For example, Na+-dependent glutamate uptake by the excitatory amino-acid transporters SLC1A1 (EAAT3) and SLC1A2 (EAAT2) occurs primarily at the apical membrane, but dexamethasone (corticosteroid) treatment can induce their expression at the basolateral membrane. In general, hepatic amino-acid transporters are highly regulated at the transcriptional and post-translational levels. imageN46-13


Glutamate Transporters

Contributed by Emile Boulpaep, Walter Boron

The high-affinity glutamate transporters are classified as members of the SLC1 gene family (see Table 5-4).

Gene Name

Transporter Names




EAAT2 or GLT-1

For a detailed discussion of the family members, consult the review by Kanai and Hediger. listed below


Kanai Y, Hediger MA. The glutamate/neutral amino acid transporter family SLC1: Molecular, physiological and pharmacological aspects. Pflugers Arch. 2004;447:467–479.

Amino-Acid Metabolism

Under physiological conditions, total and individual plasma concentrations of amino acids are tightly regulated. The liver controls the availability of amino acids in the systemic blood, activating ureagenesis after a high-protein meal and repressing it during fasting or low protein intake. Unlike glucose, which can be stored, amino acids must either be used immediately (e.g., for the synthesis of proteins) or broken down. The breakdown of α-amino acids occurs by deamination to α-keto acids and image (Fig. 46-14). The α-keto acids (“carbon skeleton”), depending on the structure of the parent amino acid, are metabolized to pyruvate, various intermediates of the citric acid cycle (see Fig. 58-11), acetyl coenzyme A (acetyl CoA), or acetoacetyl CoA. The liver detoxifies ~95% of the image through a series of reactions known as the urea cycle (see Fig. 46-14); the liver can also use image—together with glutamate—to generate glutamine. imageN46-14 Individual deficiencies in each of the enzymes involved in the urea cycle have been described and result in life-threatening hyperammonemia. The urea generated by the urea cycle exits the hepatocyte via a urea channel, which is, in fact, AQP9. The urea then enters the blood and is ultimately excreted by the kidneys (see pp. 770–772). The glutamine synthesized by the liver also enters the blood. Some of this glutamine is metabolized by the kidney to yield glutamate and image, which is exported in the urine (see pp. 829–831).


FIGURE 46-14 Amino-acid metabolism and urea formation in hepatocytes. When a hepatocyte takes up an α-amino acid, it either must use it immediately in protein synthesis or deaminate it. The deamination reaction transfers the amino group of the α-amino acid to α-ketoglutarate, yielding glutamate and the corresponding α-keto acid. Depending on the backbone of the α-keto acid, it may be metabolized into acetoacetyl CoA, acetyl CoA, pyruvate, or a variety of citric acid cycle intermediates. The image that results from the regeneration of the α-ketoglutarate is consumed in the urea cycle. The other amino group of the urea is derived from the amino group of aspartate. The CO moiety of urea is derived from CO2. The liver then exports the urea, which exits the hepatocyte via AQP9. NAD+, oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; Pi, inorganic phosphate; UT-B, urea transporter B. imageN46-19


Hepatic Detoxification of image by Formation of Glutamine

Contributed by Emile Boulpaep, Walter Boron

Each day, as part of protein catabolism, the liver detoxifies ~940 mmol of amino groups that are derived from the breakdown of amino acids. The liver detoxifies image by converting it to urea (95% of the total) and glutamine (the remaining 5%). Both products leave the liver and reach the kidney, which disposes of them—directly or indirectly—in the urine.

As indicated in Figure 39-6, the liver consumes ~40 mmol of these amino groups in the reaction

image (NE 46-1)

Glutamine is the most prevalent amino acid in the body. The liver detoxifies the remainder via the urea cycle.

The enzyme required for the conversion in Equation NE 46-1 is glutamine synthetase (see p. 290). In the liver, this enzyme is restricted to the last one or two hepatocytes contiguous with the hepatic venule (zone III; see Fig. 46-3). This strict localization is thought to play an important role in glutamine metabolism. The uptake of an individual amino acid into the hepatocyte may represent the rate-limiting step in its own metabolism and may therefore be an important target for regulation. This type of regulation of uptake occurs for alanine, a critical substrate of gluconeogenesis, and also for glutamine.



Contributed by Alisha Bouzaher

NADH and NAD+ are, respectively, the reduced and oxidized forms of nicotinamide adenine dinucleotide (NAD) and their close analogs are NADPH and NADP+, the reduced and oxidized forms of nicotinamide adenine dinucleotide phosphate (NADP). The coenzymes NADH and NADPH each consist of two nucleotides joined at their phosphate groups by a phosphoanhydride bond. NADPH is structurally distinguishable from NADH by the additional phosphate group residing on the ribose ring of the nucleotide, which allows enzymes to preferentially interact with either molecule.

Total concentrations of NAD+/NADH (10−5M) are higher in the cell by ~10-fold compared to NADP+/NADPH (10−6M). Ratios of the oxidized and reduced forms of these coenzymes offer perspective into the metabolic activity of the cell. The high NAD+/NADH ratio favors the transfer of a hydride from a substrate to NAD+ to form NADH, the reduced form of the molecule and oxidizing agent. Therefore, NAD+ is highly prevalent within catabolic reaction pathways where reducing equivalents (carbohydrate, fats, and proteins) transfer protons and electrons to NAD+. NADH acts as an energy carrier, transferring electrons from one reaction to another. Conversely, the NADP+/NADPH ratio is low, favoring the transfer of a hydride to a substrate oxidizing NADPH to NADP+. Thus, NADPH is utilized as a reducing agent within anabolic reactions, particularly the biosynthesis of fatty acids.


Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 6th ed. WH Freeman: New York; 2012.

Wikipedia. s.v. Nicotinamide adenine dinucleotide. [Last modified May 8, 2015] [Accessed May 15, 2015].

The liver is also the main site for the synthesis and secretion of glutathione. GSH is critical for detoxification (in conjugation reactions in the liver) and for protection against oxidative stress in multiple organs. Thus, erythrocytes that have low levels of GSH are more prone to hemolysis. Because >90% of the GSH in the circulation is synthesized in the liver, GSH efflux across the basolateral membrane from the hepatocyte to the sinusoid is important. Bidirectional transport of glutathione across the basolateral membrane may occur in part by one of the OATPs as well as MRP4 by cotransport with bile acids. In addition, MRP2 exports some conjugated GSH across the canalicular membrane into bile, as stated above, and an unidentified transporter can similarly export smaller amounts of unconjugated GSH.

The liver obtains dietary triacylglycerols and cholesterol by taking up remnant chylomicrons via receptor-mediated endocytosis

As discussed beginning on pages 929–933, enterocytes in the small intestine process fatty acids consumed as dietary triacylglycerols and secrete them into the lymph primarily in the form of extremely large proteolipid aggregates called chylomicrons (Fig. 46-15). These chylomicrons—made up of triacylglycerols, phospholipids, cholesterol, and several apolipoproteins (see Table 46-4)—are synthesized in the intestine and pass from the lymph to the blood via the thoracic duct. As discussed on page 1182, lipoprotein lipase (LPL) on the walls of the capillary endothelium in adipose tissue and muscle then partially digests the triacylglycerols in these chylomicrons. The results of this digestion are glycerol, fatty acids, and smaller or “remnant” chylomicrons, which are triacylglycerol depleted and thus enriched in cholesterol. The glycerol and fatty acids generated by LPL enter adipocytes and muscle cells. The cholesterol-rich remnant chylomicrons, conversely, remain in the blood and make their way to the liver, where they enter hepatocytes by basolateral receptor–mediated endocytosis (see p. 42) involving multiple endocytic receptors, primarily the cell-surface heparan sulfate proteoglycan syndecan-1, other heparan sulfate proteoglycans, and low-density lipoprotein–related receptors. The binding of apolipoprotein E on the surface of chylomicron remnants promotes efficient clearance of apolipoprotein E–containing lipoprotein remnants. After entry, the chylomicron remnants undergo degradation in lysosomes. Thus, chylomicrons transport dietary triacylglycerols to adipose tissue and muscle, whereas their remnants transport dietary triglycerides and cholesterol to hepatocytes.


FIGURE 46-15 Cholesterol metabolism. FA, fatty acid; PL, phospholipid; TG, triacylglycerol.

The hepatocyte can also take up across its basolateral membrane the long-chain fatty acids (LCFAs)imageN46-15 liberated by LPL but not used by other tissues. Although LCFAs can diffuse rapidly across artificial phospholipid bilayers, it is clear that LCFA integral or membrane-associated proteins can mediate LCFA uptake by a wide variety of mammalian cells. In the liver, three proteins participate in fatty-acid uptake:

1. Fatty-acid translocase (FAT or CD36; see p. 930). FAT is an 88-kDa membrane protein that takes up modified forms of low-density lipoproteins (LDLs) and fatty acids from circulation. The basal expression of FAT in hepatocytes is low but is induced significantly by a high-fat diet or by the activation of nuclear receptors (see Table 3-6), including SXR, peroxisome proliferator–activated receptor-γ (PPARγ), and LXR. FAT is also expressed in Kupffer cells and hepatic stellate cells.

2. Fatty-acid transport protein 5 (FATP5 or SLC27A5). FATP5 is exclusively expressed in the liver, where it localizes to the basolateral plasma membrane and accounts for ~50% of fatty-acid uptake by hepatocytes.

3. Liver-type fatty acid–binding protein 1 (FABP1). FABP1 is a cytosolic protein.


Fatty Acids

Chain Length

Contributed by Emile Boulpaep, Walter Boron



Number of Carbon Atoms

Short-chain fatty acid



Medium-chain fatty acid



Long-chain fatty acid



Very-long-chain fatty acid



To derive energy from the neutral fats in the remnant chylomicrons, hepatocytes must first split the triacylglycerols into glycerol and fatty acids. The fatty acids thus derived from remnant chylomicrons, as well as those that enter the hepatocyte directly, mainly undergo β-oxidation in mitochondria (see pp. 1183–1185). imageN46-16


α- and ω-Oxidation of Fatty Acids

Contributed by Fred Suchy

α-oxidation occurs in peroxisomes and is used for branched fatty acids that cannot directly undergo β-oxidation. In the case of very-long-chains fatty acids, imageN46-15 these must first be reduced in length by peroxisomes.

ω-oxidation occurs in the SER of the liver for detoxification and assumes great importance when β-oxidation is defective.

The acetyl CoA derived from β-oxidation can enter the citric acid cycle (see p. 1185), where it is oxidized to produce large amounts of energy. The acetyl CoA that is not used by the liver is converted by the condensation of two molecules of acetyl CoA to yield acetoacetic acid. The liver is the only organ that produces acetoacetate for metabolism by muscle, brain, and kidney, but it does not use this substrate for its own energy needs. In fasting states or in poorly controlled diabetes, in which the supply of acetyl CoA is in excess, the acetyl CoA is diverted to produce acetoacetate, which in turn can yield β-hydroxybutyrate and acetone. Together, acetoacetate, β-hydroxybutyrate, and acetone are referred to as ketone bodies. Another fate of fatty acids in the liver is that they can be re-esterified to glycerol, with the formation of triacylglycerols that can either be stored or exported as very-low-density lipoproteins (VLDLs) and released into the circulation for use by peripheral tissues.

Cholesterol, synthesized primarily in the liver, is an important component of cell membranes and serves as a precursor for bile acids and steroid hormones

The body's major pools of cholesterol include the cholesterol and cholesterol derivatives in bile, cholesterol in membranes, cholesterol carried as lipoproteins in blood (see Table 46-4), and cholesterol-rich tissues. Cholesterol is present in membranes and bile mainly as free cholesterol. In plasma and in some tissues, cholesterol is esterified with LCFAs. The major sources of cholesterol are dietary uptake of cholesterol and de novo synthesis of cholesterol by various cells (Table 46-5). The major fates of cholesterol are secretion into bile, excretion in the feces when intestinal cells are sloughed, sloughing of skin, and synthesis of steroid hormones. However, in mammals, the most important route for the elimination of cholesterol is the hepatic conversion of cholesterol into bile acids. In the steady state, the liver must excrete an amount of sterol (as cholesterol and bile acids) that equals the amount of cholesterol that is synthesized in the various organs and absorbed from the diet.

TABLE 46-5

Sources and Fates of Cholesterol in Humans


FLOW (g/day for a 70-kg human)

Intestinal absorption




Biliary secretion


Cholesterol consumed in synthesis of bile acids


Cholesterol secreted in VLDLs by the liver


Modified from Cooper AD, Ellsworth JL: Lipoprotein metabolism. In Zakim D, Boyer TD (eds): Hepatology. Philadelphia, WB Saunders, 1996.

The liver is the major organ for controlling cholesterol metabolism (see Fig. 46-15). The liver obtains cholesterol from three major sources: (1) The intestine packages dietary cholesterol as chylomicrons, which travel via the lymph to blood vessels in adipocytes and muscle, where LPL hydrolyzes triacylglycerols to fatty acids and glycerol. The resultant cholesterol-enriched remnant chylomicrons are then delivered as cholesterol to the liver. (2) The liver synthesizes cholesterol de novo. (3) The liver takes up cholesterol in the guise of LDL. In contrast, the liver exports cholesterol in two major ways: (1) The liver uses cholesterol to synthesize bile acids and also includes cholesterol and cholesteryl esters in the bile. (2) The liver also exports cholesterol to the blood in the form of VLDLs.

Synthesis of Cholesterol

The de novo synthesis of cholesterol occurs in many extrahepatic tissues, as well as in the intestine and liver. The synthesis of cholesterol proceeds from acetyl CoA in a multistep process that takes place in the SER and cytosol (Fig. 46-16). The hepatic synthesis of cholesterol is inhibited by dietary cholesterol and by fasting and is increased with bile drainage (fistula) and bile duct obstruction. The rate-limiting step in cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate by HMG-CoA reductase, the level of which is decreased—in typical negative-feedback fashion—by cholesterol levels in the cell (Box 46-4). The most potent cholesterol-lowering agents that are clinically available today—the “statins”—are inhibitors of HMG-CoA reductase. imageN46-17


FIGURE 46-16 Cholesterol synthesis. The liver synthesizes cholesterol de novo from acetyl CoA in a multistep process that occurs in the SER and cytosol.

Box 46-4

Control of Cholesterol Synthesis

A series of 29 enzymatic reactions (Diwan, 1998–2008) converts acetyl CoA to cholesterol (see Fig. 46-16). Biosynthetic pathways, as well as uptake pathways for precursors, are under tight negative-feedback control. HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, is a 97-kDa enzyme intrinsic to the ER. The protein is anchored in the ER by a 339–amino-acid domain that spans the membrane eight times and is required for activity of the protein. In the short term, decreased intracellular levels of ATP—via AMP kinase (AMPK; see pp. 1220–1222)—lead to phosphorylation of HMG-CoA reductase, which reduces the activity of the enzyme and thereby presumably preserves energy stores in the cell.

Far more important is the long-term control of the amount of HMG-CoA reductase, which can increase as much as 200-fold. The amount of HMG-CoA reductase protein increases after cells are depleted of mevalonate or when the demand for mevalonate-derived metabolites rises. HMG-CoA reductase activity is upregulated by a combination of enhanced gene transcription, increased mRNA translation, and increased stability of the enzyme. These changes are reversed by the addition of the sterol cholesterol or of mevalonate to the cells. The transmembrane domain of HMG-CoA reductase may serve as a receptor for the regulatory effects of sterols.

The repression by sterols of the genes encoding HMG-CoA reductase—as well as HMG-CoA synthase and the LDL receptor—is mediated by specific transcription factors and specific sequence elements within the 5′ upstream region to which the transcription factors bind. The transcription factors, which belong to a family known as sterol regulatory element–binding proteins (SREBPs; see pp. 87–88), are central to feedback control of cholesterol homeostasis. These SREBPs are membrane-bound basic helix-loop-helix transcriptional activators (see p. 83) that control genes involved in the synthesis and receptor-mediated uptake of cholesterol and fatty acids. SREBP-1 is most abundant in the liver, whereas SREBP-2 is expressed ubiquitously. However, it is SREBP-2 that regulates most genes that encode enzymes of cholesterol biosynthesis.


Diwan JJ. Cholesterol synthesis. 1998–2008. [Accessed September 2014].


Treatment of Hyperlipidemia

Contributed by Fred Suchy

Several approaches are available to treat hyperlipidemia in patients. These approaches include the following:

1. Bile acid sequestrants, which enhance the excretion of sterols in the feces.

2. Nicotinic acid (e.g., niacin), which decreases the production of VLDL cholesterol.

3. Fibric-acid derivatives (e.g., clofibrate), which decrease the production of VLDL cholesterol.

4. HMG-CoA reductase inhibitors (i.e., the “statins”), which decrease cholesterol synthesis.

HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, is a 97-kDa enzyme intrinsic to the ER. The protein is anchored in the ER by a 339–amino-acid domain that spans the membrane eight times and is required for activity of the protein. In the short term, decreased levels of [ATP]i lead to a phosphorylation of HMG-CoA reductase, which reduces the activity of the enzyme and thereby presumably preserves energy stores in the cell.

Far more important than the short-term regulation of HMG-CoA reductase is the long-term control of the amount of the enzyme, which can increase as much as 200-fold. The amount of HMG-CoA reductase protein increases after cells are depleted of mevalonate or when the demand for mevalonate-derived metabolites is increased. HMG-CoA reductase activity is upregulated by a combination of enhanced gene transcription, increased mRNA translation, and increased stability of the enzyme. These changes are reversed by the addition of cholesterol or mevalonate to the cells. The transmembrane domain of HMG-CoA reductase may serve as a receptor for the post-translational regulatory effects of sterols.

Sterol repression of HMG-CoA reductase gene expression—as well as the expression of LDL and HMG-CoA synthase genes—is mediated by specific transcription factors (i.e., proteins) that bind to specific DNA sequence elements within the 5′ upstream region of target genes. The DNA-binding proteins are called sterol regulatory element–binding proteins (SREBPs; see pp. 87–88); they are membrane-bound basic helix-loop-helix transcriptional activators (see p. 83 and Fig. 4-9C). The DNA to which these transcription factors bind are called sterol regulatory elements (such as SRE-1). The binding of SREBPs to SREs controls genes involved in the synthesis and receptor-mediated uptake of cholesterol and fatty acids.

The liver is the central organ for cholesterol homeostasis and for the synthesis and degradation of LDL

The liver is the hub of an exogenous loop in which the liver takes up dietary cholesterol as remnant chylomicrons and exports cholesterol and cholesterol metabolites into bile. The liver is also the hub of an of endogenous loop in which the liver exports cholesterol and other lipids as VLDLs and takes them up from the blood as LDLs. Table 46-4 summarizes the properties of these lipoproteins, as well as of two others: the intermediate-density lipoproteins (IDLs) and the high-density lipoproteins (HDLs). As we move from left to right in Table 46-4, the size of the particles decreases, the density increases (because the fractional mass of protein increases), the fractional amount of triacylglycerols decreases, and the fractional amount of phospholipids increases.

Regardless of the source of the cholesterol, the liver can package cholesterol along with other lipids and apolipoproteins as VLDLs—the liver's transit system for exporting endogenous triacylglycerols, phospholipids, cholesterol, and cholesteryl esters. The VLDLs are large—and therefore less dense—when the availability of triacylglycerols is high (e.g., obesity, diabetes), but they are small when triacylglycerol availability is low. VLDLs enter the bloodstream from the liver (see Fig. 46-15) and eventually make their way to the blood vessels of adipose tissue and muscle, where the same LPL that degrades chylomicrons degrades the VLDLs on the luminal surface of blood vessel endothelial cells. In the process, fatty acids are released to the tissues. Thus, VLDLs act as lipid shuttles that transport endogenous triacylglycerols to adipose tissue for storage as fat or to muscle for immediate use. As a result of the LPL activity, the large, buoyant VLDLs rapidly shrink to become the smaller IDLs and the even smaller LDLs. The half-life of VLDLs is less than an hour. In plasma, only minute amounts of IDLs are present.

Both the liver and extrahepatic tissue can take up LDLs—and to a lesser extent, IDLs—by the process of receptor-mediated endocytosis (see p. 42). LDLs are the major carriers of cholesterol in plasma. The half-life of LDLs is 2 to 3 days. Of course, uptake of LDL by the liver is a major pathway of cholesterol input to the liver. The liver degrades ~40% to 60% of LDLs, and no other tissue takes up more than ~10%. LDL uptake by other tissues provides a mechanism for the delivery of cholesterol that can be used for the synthesis of cell membranes and steroid hormones or for storage as cholesteryl ester droplets.

The other major player in cholesterol metabolism is HDL, which is composed of cholesterol, phospholipids, triacylglycerols, and apolipoproteins (see Table 46-4). The two major apolipoproteins of HDLs, A-I and A-II, are made by the intestines as part of chylomicrons, as well as by the liver. As LPL digests VLDLs on endothelial cells, some excess surface material (i.e., cholesterol and phospholipids) of these rapidly shrinking particles is transferred to the HDLs. In peripheral cells such as macrophages, the cholesterol transporter ABCA1 facilitates the efflux of cholesterol, which then combines with lipid-poor HDLs. An enzyme that is associated with HDL, lecithin–cholesterol acyltransferase (LCAT)—synthesized in the liver, then takes an acyl group from lecithin and esterifies it to cholesterol to produce a cholesterol ester (CE).

When the CE-enriched HDL (HDL-CE) reaches the liver, it binds to scavenger receptor class B type 1 (SR-B1),imageN46-18 which mediates selective uptake of HDL-CE. The cholesterol moiety is targeted for biliary excretion. This pathway may also process LDL-CE and free cholesterol. In contrast to uptake by the LDL receptor, the selective uptake of CE by SR-B1 does not involve endocytosis. Instead, a poorly defined mechanism first moves CE to a reversible plasma-membrane pool and then to an irreversible pool within the cell.


Scavenger Receptor Class B Type 1

Contributed by Emile Boulpaep, Walter Boron

The scavenger receptors can bind a very broad range of polyanionic ligands. SR-B1 does not just bind but also transports cholesterol-enriched HDL and LDL into the cell.


Krieger M. Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. J Clin Invest. 2001;108:793–797.

Rhainds D, Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking: Defining the rules for lipid traders. Int J Biochem Cell Biol. 2004;36:39–77.

Not only does SR-B1 mediate the hepatic uptake of HDL-CE, but cholesteryl ester transfer protein (CETP) in blood plasma can mediate the transfer of CE from HDL-CE to VLDLs, IDLs, and LDLs—all of which contain apolipoprotein B-100. These less-dense lipoproteins can now move to the liver for uptake by the LDL receptor. The HDL-mediated removal of cholesterol from peripheral tissues via both SR-B1 and CETP for transport to the liver and excretion in bile is known as reverse cholesterol transport. This process is thought to protect against atherosclerosis.

The liver is the prime site for metabolism and storage of the fat-soluble vitamins A, D, E, and K

We discuss the intestinal uptake of the fat-soluble vitamins on page 933.

Vitamin A

Vitamin A (retinol and its derivatives)—like dietary vitamin D, as well as vitamins E and K—is absorbed from the intestine and is then transported in newly synthesized chylomicrons or VLDLs. After some peripheral hydrolysis of its triacylglycerol, the remnant chylomicrons are taken up by the liver. In the hepatocyte, retinyl esters may be hydrolyzed to release free retinol, which can then be transported into the sinusoids bound to retinol-binding protein (RBP) and prealbumin. Alternatively, retinyl esters may be stored in the hepatocyte or transported as RBP-bound retinol to stellate (Ito) cells, the storage site of >80% of hepatic vitamin A under normal conditions. Retinol may also undergo oxidation to retinal and conversion to retinoic acid, which plays a key role in phototransduction (see p. 367). Retinoic acid is conjugated to glucuronide and is secreted into bile, where it undergoes enterohepatic circulation and excretion. Liver disease resulting in cholestasis may lead to a secondary vitamin A deficiency by interfering with absorption in the intestine (lack of the bile needed for digestion/absorption of vitamin A) or by impairing delivery to target tissues because of reduced hepatic synthesis of RBP.

Vitamin D

Skin cells—under the influence of ultraviolet light—synthesize vitamin D3 (see p. 1064). Dietary vitamin D can come from either animal sources (D3) or plant sources (D2). In either case, the first step in activation of vitamin D is the 25-hydroxylation of vitamin D, catalyzed by a hepatic cytochrome P-450 enzyme. This hydroxylation is followed by 1-hydroxylation in the kidney to yield a product (1,25-dihydroxyvitamin D) with full biological activity. Termination of the activity of 1,25-dihydroxyvitamin D also occurs in the liver by hydroxylation at carbon 24, mediated by another cytochrome P-450 enzyme.

Vitamin E

The fat-soluble vitamin E is absorbed from the intestine primarily in the form of α- and γ-tocopherol. It is incorporated into chylomicrons and VLDLs with other products of dietary lipid digestion. As noted above, these particles reach the systemic circulation via the lymphatics and undergo some triacylglycerol hydrolysis. In the process, some vitamin E is transferred to other tissues. The α- and γ-tocopherol remaining in the remnant chylomicrons is transported into the liver, which is the major site of discrimination between the two forms. The α-tocopherol is secreted again as a component of hepatically derived VLDL and perhaps HDL. The γ-tocopherol appears to be metabolized or excreted by the liver. A hepatic tocopherol-binding protein may play a role in this discriminatory process.

Vitamin K

Vitamin K is a fat-soluble vitamin produced by intestinal bacteria. This vitamin is essential for the γ-carboxylation—by the ER enzyme γ-glutamyl carboxylase—of certain glutamate residues in coagulation factors II, VII, IX, and X as well as anticoagulants protein C and protein S (see Table 18-4) and certain other proteins. Intestinal absorption and handling of vitamin K—which is present in two forms, K1 and K2—are similar to those of the other fat-soluble vitamins, A, D, and E. Common causes of vitamin K deficiency, which can lead to a serious bleeding disorder, include extrahepatic or intrahepatic cholestasis, fat malabsorption, biliary fistulas, and dietary deficiency, particularly in association with antibiotic therapy.

The liver stores copper and iron


The trace element copper is essential for the function of cuproenzymes such as cytochrome C oxidase and superoxide dismutase (see p. 1238). Approximately half the copper in the diet (recommended dietary allowance, 1.5 to 3 mg/day) is absorbed in the jejunum and reaches the liver in the portal blood, mostly bound to albumin. A small fraction is also bound to amino acids, especially histidine.

High-affinity copper import across the hepatocyte basolateral membrane is mediated by the copper transport protein CTR1 (SLC31A1). Copper then binds to members of a family of intracellular metallochaperones that direct the metal to the appropriate pathway for incorporation into cuproenzymes or for biliary excretion. It is unknown how hepatocytes distribute copper to the different intracellular routes. The copper chaperone Atox1 ferries the copper through the cytosol to the Wilson disease P-type ATPase ATP7B (Box 46-5; see also p. 118), which is located predominantly in the trans-Golgi network and late endosomes. Intracellular copper levels modulate the activity, post-translational modification, and intracellular localization of ATP7B. Once inside the vesicular lumen, copper can couple with apo-ceruloplasmin (apo-Cp) to form holo-ceruloplasmin holo-Cp, which the hepatocyte secretes across the sinusoidal membrane into the blood. Alternatively, the hepatocyte can secrete the copper—perhaps with hepatic copper-binding proteins such as COMMD1 (copper metabolism MURR1 domain)—across the canalicular membrane into the bile. More than 80% of the copper absorbed each day is excreted in bile, for a total of 1.2 to 2.4 mg/day. The small intestine cannot reabsorb the secreted Cu-protein complexes. Processes that impair the biliary excretion of copper result in the accumulation of copper, initially in the lysosomal fraction of hepatocytes, with subsequent elevation of plasma copper levels.

Box 46-5

Wilson Disease

Wilson disease is inherited as an autosomal recessive illness caused by a mutation in ATP7B, the pump responsible for copper accumulation in the trans-Golgi network. The impaired biliary excretion of copper causes a buildup of copper in cells, which produces toxic effects in the liver, brain, kidney, cornea, and other tissues. The disease is rare, but it must be considered in the differential diagnosis of anyone younger than 30 years with evidence of significant liver disease. Patients most often have neuropsychiatric complications, including ataxia, tremors, increased salivation, and behavioral changes. Slit-lamp examination of the cornea reveals the diagnostic Kayser-Fleischer rings at the limbus of the cornea.

Because of the lack of functional ATP7B, the apoceruloplasmin in the trans-Golgi network cannot bind copper to form ceruloplasmin. As a result, the hepatocytes secrete apoceruloplasmin, which lacks the ferroxidase activity of ceruloplasmin. Moreover, the serum concentrations of ceruloplasmin are low. Indeed, the best way to confirm the diagnosis of Wilson disease is the detection of a low serum ceruloplasmin level and elevated urinary copper excretion. A few affected patients have normal ceruloplasmin levels, and the diagnosis must then be sought through liver biopsy. The disease can be treated by chelating the excess copper with penicillamine.

Ceruloplasmin, an α2-globulin synthesized by the liver, binds 95% of copper present in the systemic circulation. Ceruloplasmin has ferroxidase activity but has no critical role in the membrane transport or metabolism of copper.


Dietary iron is absorbed by the duodenal mucosa and then transported through the blood bound to transferrin (see p. 941), a protein synthesized in the liver. The liver also takes up, secretes, and stores iron. Entry of iron into hepatocytes is mediated through specific cell-surface transferrin receptors (see p. 42). Within the cell, a small pool of soluble iron is maintained for intracellular enzymatic reactions, primarily for those involved in electron transport. However, iron is also toxic to the cell. Hence, most intracellular iron is complexed to ferritin (see p. 941). The toxicity of iron is clearly evident when normal storage mechanisms become overwhelmed, as occurs in hemochromatosis (see Box 45-6), an autosomal recessive disease in which regulation of iron absorption is uncoupled from total-body storage levels.

Hepatocytes also play a critical role in iron homeostasis by synthesizing hepcidin (see p. 941), which lowers plasma iron levels by downregulating the iron-efflux pump FPN1 (see p. 941) in the intestine and macrophages, thereby blocking the release of iron into the circulation. The consequent iron retention in duodenal enterocytes effectively blocks dietary iron absorption and leads to iron retention in reticuloendothelial macrophages. The expression of the HAMP gene, which encodes hepcidin, increases with iron loading and inflammatory cytokines, and decreases with anemia and hypoxia (consistent with enhanced erythropoiesis; see pp. 440–442).




Length (m)



Area of apical plasma membrane (m2)









Crypts or glands






Nutrient absorption



Active Na+ absorption



Active K+ secretion