Color Atlas of Physiology 2003 thieme

D. Gallbladder

H2O Na+

Vagus nerve

Cl–

C bile

B bile

1

ACh

Fats

2

Fatty acids

CCK

E. Micelle-mediated “dissolution”

of cholesterol in the bile

100

Separation:

cholesterol crystals

(

mol)

80

20

pho

s

(%

L

ph

ec

40

a

60

(%

ithin

e

r

ol

mol)

Chole

st

tidylcholine

40

60

Micelle-

)

al.)

20

mediated

“dissolution”

et

Small

0

80

60

40

20

100

249

100

0

(After

Bile salts (%mol)

The liver detoxifies and excretes many mostly

lipophilic substances, which are either

generated during metabolism (e.g., bilirubin or

steroid hormones) or come from the intestinal

tract (e.g., the antibiotic chloramphenicol).

However, this requires prior biotransforma-

tion of the substances. In the first step of the

process, reactive OH, NH2 or COOH groups are

enzymatically added (e.g., by monooxy-

Digestion

genases) to the hydrophobic substances. In the

second step, the substances are conjugated

with glucuronic acid, acetate, glutathione, gly-

cine, sulfates, etc. The conjugates are now

and

water-soluble and can be

either further

processed in the kidneys and excreted in the

Nutrition10

urine, or secreted into bile by liver cells and ex-

Carriers. The canalicular membrane of hepatocytes

example, are further processed in the kidney

excreted as mercapturic acids in the urine.

contains various carriers, most of which are directly

fueled by ATP (see also p. 248). The principal carriers

are: MDR1 (multidrug resistance protein 1) for rela-

tively hydrophobic, mainly cationic metabolites,

MDR3 for phosphatidylcholine

(!p. 248), and

cMOAT (canalicular multispecific organic anion

transporter = multidrug resistance protein MRP2) for

conjugates (formed with glutathione, glucuronic

acid or sulfate) and many other organic anions.

Bilirubin sources and conjugation. Ca. 85% of

all bilirubin originates from the hemoglobin in

erythrocytes; the rest is produced by other

hemoproteins like cytochrome (!A and B).

When degraded, the globulin and iron com-

ponents (!p. 90) are cleaved from hemoglo-

bin. Via intermediate steps, biliverdin and fi-

nally bilirubin, the yellow bile pigment, are

then formed from the porphyrin residue. Each

gram of hemoglobin yields ca. 35 mg of biliru-

bin. Free unconjugated bilirubin (“indirect”

bilirubin) is poorly soluble in water, yet lipid-

soluble and toxic. It is therefore complexed

with albumin when present in the blood (2 mol

bilirubin : 1 mol albumin), but not when ab-

sorbed by hepatocytes (!A). Bilirubin is con-

jugated (catalyzed by glucuronyltransferase)

with 2 molecules of UDP-glucuronate (synthe-

250

sized from glucose, ATP and UTP) in the liver

cells yielding bilirubin diglucuronide (“direct”

The average intake of fats (butter, oil, mar-

garine, milk, meat, sausages, eggs, nuts etc.) is

roughly 60–100 g/day, but there is a wide

range of individual variation (10–250 g/day).

Most fats in the diet (90%) are neutral fats or

triacylglycerols (triglycerides). The rest are

phospholipids, cholesterol esters, and fat-

soluble vitamins (vitamins A, D, E and K). Over

95% of the lipids are normally absorbed in the

Digestion

small intestine.

Lipid digestion (!A). Lipids are poorly

soluble in water, so special mechanisms are re-

quired for their digestion in the watery en-

and

vironment of the gastrointestinal tract and for

their subsequent absorption and transport in

Nutrition

plasma (!p. 254). Although small quantities

before they can be efficiently absorbed. Opti-

of undegraded triacylglycerol can be absorbed,

dietary fats must be hydrolyzed by enzymes

10

chanical emulsification of fats (mainly in the

distal stomach, !p. 240) because emulsified

lipid droplets (1–2 µm; !B1) provide a much

larger surface (relative to the mass of fat) for

lipases.

Lipases, the fat digesting enzymes, originate

from the lingual glands, gastric fundus (chief

and mucous neck cells) and pancreas (!A and

p. 246). About 10–30% of dietary fat intake is

hydrolyzed in the stomach, while the remain-

ing 70–90% is broken down in the duodenum

and upper jejunum. Lingual and gastric lipases

have an acid pH optimum, whereas pancreatic

lipase has a pH optimum of 7–8. Lipases be-

come active at the fat/oil and water interface

(!B). Pancreatic lipase (triacylglycerol hy-

drolase) develops its lipolytic activity (max.

140 g fat/min) in the presence of colipase and

Ca2+. Pro-colipase in pancreatic juice yields

colipase after being activated by trypsin. In

most cases, the pancreatic lipases split triacyl-

glycerol (TG) at the 1st and 3rd ester bond. This

process requires the addition of water and

yields free fatty acids (FFA) and 2-monoacyl-

glycerol.

Lipid Distribution and Storage

High-density lipoproteins (HDL) exchange

certain apoproteins with chylomicrons and

Lipids in the blood are transported in lipo-

VLDL and absorb superfluous CHO from the

proteins, LPs (!A), which are molecular

extrahepatic cells and blood (!B). With their

aggregates (microemulsions) with a core of

ApoAI, they activate the plasma enzyme LCAT

very hydrophobic lipids such as triacylglycerols

(lecithin–cholesterol acyltransferase), which

(TG) and cholesterol esters (CHO-esters) sur-

is responsible for the partial esterification of

rounded by a layer of amphipathic lipids

CHO. HDL also deliver cholesterol and CHO-

(phospholipids, cholesterol). LPs also contain

esters to the liver and steroid hormone-pro-

several types of proteins, called apolipo-

ducing glands with HDL receptors (ovaries,

proteins. LPs are differentiated according to

testes, adrenal cortex).

their size, density, lipid composition, site of

synthesis, and their apolipoprotein content.

Triacylglycerol (TG)

Apolipoproteins (Apo) function as structural

Dietary TGs are broken down into free fatty

elements of LPs (e.g. ApoAII and ApoB48), lig-

acids (FFA) and 2-monoacylglycerol (MG) in the

ands (ApoB100, ApoE, etc.) for LP receptors on

gastrointestinal tract (!C and p. 252). Since

the membranes of LP target cells, and as

short-chain FFAs are water-soluble, they can

enzyme activators (e.g. ApoAI and ApoCII).

be absorbed and transported to the liver via

Chylomicrons transport lipids (mainly tri-

the portal vein. Long-chain FFAs and 2-mono-

acylglycerol, TG) from the gut to the periphery

acylglycerols are not soluble in water. They are

(via intestinal lymph and systemic circulation;

re-synthesized to TG in the mucosa cells (!C).

!D), where their ApoCII activates endothelial

(The FFAs needed for TG synthesis are carried

lipoprotein lipase (LPL), which cleaves FFA

by FFA-binding proteins from the cell mem-

from TG. The FFA are mainly absorbed by myo-

brane to their site of synthesis, i.e., the smooth

cytes and fat cells (!D). With the aid of ApoE,

endoplasmic reticulum.) Since TGs are not

the chylomicron remnants deliver the rest of

soluble in water, they are subsequently loaded

their TG, cholesterol and cholesterol ester load

onto chylomicrons, which are exocytosed into

to the hepatocytes by receptor-mediated en-

the extracellular fluid, then passed on to the

docytosis (!B, D).

intestinal lymph (thereby by-passing the

Cholesterol (CHO) and the TG imported

liver), from which they finally reach the

from the gut and newly synthesized in the liver

greater circulation (!C, D). (Plasma becomes

are exported inside VLDL (very low density

cloudy for about 20–30 minutes after a fatty

lipoproteins) from the liver to the periphery,

meal due to its chylomicron content). The liver

where they by means of their ApoCII also acti-

also synthesizes TGs, thereby taking the re-

vate LPL, resulting in the release of FFA (!D).

quired FFAs from the plasma or synthesizing

This results in the loss of ApoCII and exposure

them from glucose. Hepatic TGs are loaded

of ApoE. VLDL remnants or IDL (intermediate-

onto VLDL (see above) and subsequently

density lipoproteins) remain. Ca. 50% of the IDL

secreted into the plasma (!D). Since the ex-

returns to the liver (mainly bound by its ApoE

port capacity of this mechanism is limited, an

on LDL receptors; see below) and is re-

excess of FFA or glucose (!D) can result in the

processed and exported from the liver as VLDL

accumulation of TGs in the liver (fatty liver).

(!B).

Free fatty acids (FFAs) are high-energy sub-

The other 50% of the IDL is converted to LDL

strates used for energy metabolism (!p. 228).

(low density lipoprotein) after coming in con-

Fatty acids circulating in the blood are mainly

tact with hepatic lipase (resulting in loss of

transported in the form of TG (in lipoproteins)

ApoE and exposure of ApoB100). Two-thirds of

whereas plasma FFA are complexed with al-

the LDLs deliver their CHO and CHO-esters to

bumin. Fatty acids are removed from TGs of

the liver, the other third transfers its CHO to

chylomicrons and VLDL by lipoprotein lipase

extrahepatic tissue (!B). Binding of ApoB100

(LPL) localized on the luminal surface of the

to LDL receptors is essential for both processes

capillary endothelium of many organs (mainly

(see below).

in fat tissue and muscles) (!D). ApoCII on the

!

!

surface of TGs and VLDL activates LPL. The in-

sulin secreted after a meal induces LPL (!D),

which promotes the rapid degradation of reab-

sorbed dietary TGs. LPL is also activated by he-

parin (from endothelial tissue, mast cells, etc.),

which helps to eliminate the chylomicrons in

cloudy plasma; it therefore is called a clearance

factor. Albumin-complexed FFAs in plasma are

mainly transported to the following target

sites (!D):

Cardiac muscle, skeletal muscle, kidneys and

other organs, where they are oxidized to CO2

and H2O in the mitochondria (! oxidation) and

used as a source of energy.

Fat cells (!D), which either store the FFAs

or use them to synthesize TG. When energy re-

quirements increase or intake decreases, the

FFAs are cleaved from triacylglycerol in the fat

stimulated by epinephrine, glucagon and corti-

where they are needed (!D). Lipolysis is

The liver, where the FFAs are oxidized or

used to synthesize TG.

Cholesterol (CHO)

Cholesterol esters (CHO-esters), like TGs, are

apolar lipids. In the watery milieu of the body,

they can only be transported when incor-

porated in lipoproteins (or bound to proteins)

and can be used for metabolism only after they

have been converted to CHO, which is more

polar (!B). CHO-esters serve as stores and in

some cases the transported form of CHO. CHO-

esters are present in all lipoproteins, but are

most abundant (42%) in LDL (!A).

Cholesterol is an important constituent of

cell membranes (!p. 14). Moreover, it is a pre-

cursor for bile salts (!B and p. 248), vitamin D

(!p. 292), and steroid hormones (!p. 294ff.).

Each day ca. 0.6 g of CHO is lost in the feces (re-

duced to coprosterol) and sloughed off skin.

The bile salt loss amounts to about 0.5 g/day.

These losses (minus the dietary CHO intake)

must be compensated for by continuous re-

synthesis of CHO in the intestinal tract and

liver (!B). CHO supplied by the diet is ab-

sorbed in part as such and in part in esterified

form (!B, lower right). Before it is reabsorbed,

256

CHO-esters are split by unspecific pancreatic

carboxylesterase to CHO, which is absorbed in

Carbohydrates provide half to two-thirds of

the energy requirement (!p. 226). At least

50% of dietary carbohydrates consist of starch

(amylose and amylopectin), a polysaccharide;

other important dietary carbohydrates are

cane sugar (saccharose = sucrose) and milk

sugar (lactose). Carbohydrate digestion starts

in the mouth (!A1 and p. 236). Ptyalin, an α-

Digestion

amylase found in saliva, breaks starches down

into oligosaccharides (maltose, maltotriose, α

limit dextrins) in a neutral pH environment.

This digestive process continues in the proxi-

and

mal stomach, but is interrupted in the distal

stomach as the food is mixed with acidic gas-

Nutrition

tric juices. A pancreatic α-amylase, with a pH

continue to the final

oligosaccharide stage

duodenum. Thus, polysaccharide digestion can

10

only absorbed in the form of monosaccharides.

Thus, the enzymes maltase and isomaltase in-

tegrated in the luminal brush border mem-

brane of enterocytes break down maltose, mal-

totriose and α limit dextrins into glucose as the

final

product.

As in

the renal

tubules

(!p. 158), glucose is first actively taken up by

the Na+ symport carrier SGLT1 into mucosal

cells (!A2, p. 29 B1) before passively diffusing

into the portal circulation via GLUT2, the glu-

cose

uniport

carrier

(facilitated

diffusion;