Seven Flashcards
List some functions of the liver.
The liver serves multiple critical functions for the body. The liver is intimately involved in blood conditioning (I prefer this work over filtration) and detoxification, glucose homeostasis, protein synthesis, lipid/cholesterol metabolism, bile acid synthesis/bile formation, vitamin absorption, and hormone metabolism just to name a few of its many jobs.
Describe the hemodynamics of the liver. Where does its blood come from? Where does it go?
The liver receives its blood flow from two sources. The majority (75-80%) comes from the portal vein. The portal vein forms from the confluence of the splenic vein and
the mesenteric veins that drain the intestines. The remaining 20 to 25% of blood flow to the liver is from the hepatic artery (a branch of the celiac artery). Whereas the vascular
resistances in the intestine and the spleen primarily determine portal vein blood flow, the
intrahepatic vascular resistance determines hepatic arterial blood flow. Hepatic arterial
blood flow typically changes reciprocally with portal blood flow in an attempt to
maintain a constant total liver perfusion and oxygen supply. The liver is a bit pressed for
oxygen since the organ is metabolically very active, and the majority of the blood flow to
the liver is from venous sources in which oxygen tension is less than arterial sources.
The hepatic artery is therefore an important (although not always essential) source of oxygen to the liver. The hepatic artery is also important as a source of oxygen to the
biliary tree in the area of the porta hepatis.
Altogether, the blood flow to the liver is about 1500 to 1800 ml/min; that’s about
one fourth of the cardiac output to you and me. Once in the liver, the blood percolates
though the parenchyma of the organ and finally is returned to the systemic circulation
through the right and left hepatic veins that drain into the inferior vena cava. The
pressure gradient between the portal veins and hepatic veins is remarkably low, about 5
mm Hg. The diagram below outlines the splanchnic circulation and portal flow.
List 5 cells of the liver and describe their function.
HEPATOCYTES. Hepatocytes are the workhorses of the liver; they are responsible for
much of the liver’s metabolic abilities that will be discussed in this lecture. They account
for 60% of the cells in the liver.
ENDOTHELIAL CELLS. Endothelial cells line the sinusoids. They are self-
proliferating cells that account for 10% of the cells in the liver. While these cells perform
a barrier function between blood and hepatocytes, open fenestrations form a “sieve plate”
that allows nutrients, waste products, hormones, and other substances in blood to come
into contact with hepatocytes. Cellular receptors mediate uptake of selected proteins.
Endothelial cells also produce nitrous oxide and other effector molecules that contribute
to the mediation of hepatic blood flow.
STELLATE CELLS (Ito cells). These are fat-storing cells that are also responsible for
the synthesis of extracellular matrix. These cells respond to vasoactive substances and
thereby provide the cellular machinery that regulates sinusoidal blood flow. In the event
of severe or persistent liver injury these cells can become dangerously activated; the cells
actually transform into myofibroblasts that cause fibrogenesis in the liver. This can then
lead to irreversible liver damage.
KUPFFER CELLS. These are the resident macrophages of the liver. They can be self-
proliferating but also can be recruited from extrahepatic sources. They are located
predominantly in the periportal region (towards the sinusoidal inflow) and their main
function is phagocytosis of particulate matter (cellular debris, parasites, viruses, bacteria)
and receptor-mediated endocytosis of unwanted molecules (e.g., immune complexes,
bacterial endotoxins). Like stellate cells, activated Kupffer cells can contribute to liver
injury.
CHOLANGIOCYTES. These are columnar epithelial cells that line the bile ducts.
Describe the role of the liver as the glucostat. Define glycolysis. Define gluconeogenesis. What are the substrates for it in the liver? Where do they come from? Define oxidative phosphorylation. Define glycogenolysis.
Brain cells, erythrocytes, myocytes, and cells of the renal cortices are “picky eaters”. They vastly prefer and require glucose as their primary energy source. The liver plays the central role as a “glucostat”. It removes glucose, if it is in excess, via glycogen synthesis, glycolysis, and lipogenesis and liberates glucose if needed via glycogenolysis and gluconeogenesis. Glucose moves into and out of the liver cell by way of the Glut-2 transporter. Some glucose, fructose, and galactose metabolism takes place in the liver, but not much. For the most part, glucose cycles to muscle and other body tissues where lactate, pyruvate, and alanine are generated by glycolysis. These trioses are then returned to the liver and converted into carbohydrate via gluconeogenesis. In summary, glucose
homeostasis is maintained in the hepatocyte by interdependent cyclic pathways that serve as branch points for the metabolism of simple sugars. More on this later…
A few terms need to be defined here. Glycolysis is the pathway by which glucose
is phosphorylated and broken down anaerobically to make ATP. This pathway plays a
minor role in the liver. Oxidative phosphorylation is the utilization of pyruvate (formed
from glycolysis) to make ATP. Gluconeogenesis is the production of glucose from lactate, pyruvate, and amino acids cycled to the liver from muscles via a pathway
commonly referred to as the “hexose shunt”. Glycogenolysis is the release of glucose
stores from glycogen.
Describe the daily rhythm of liver metabolism in a fed state, short term and long term fasting state.
During a typical carbohydrate rich meal, glucose is absorbed at a rate of more
than 40 g/h. Over half of this is taken up by the liver and converted to glycogen, or
converted to fatty acids; only a small amount is oxidized in the liver. During a short term
fast, the liver releases glucose at a rate sufficient to cover the body’s glucose needs (about
- 5 g/h), two thirds of which is derived from glycogenolysis and the remainder from
gluconeogenesis. After about 24 hours of fasting, glycogen stores become depleted. In
this case, cerebral metabolism adapts and glucose requirements fall to 2 g/h, whereas
ketone bodies (from fatty acids) are more heavily utilized as an energy fuel. Also, if
starvation continues, the liver enters a catabolic mode by which muscle can be broken
down, with amino acids (especially alanine and glutamine) delivered to the liver for use
as substrates in gluconeogenesis.
What are plasma lipoproteins made up of? What do the apoproteins do? List the 5 lipoproteins. What other enzymes does the liver synthesize that are important to FA metabolism?
The liver has a pivotal role in lipoprotein metabolism. Plasma lipoproteins are
complex particles with a surface made up of cholesterol, phospholipids, and specific
apoproteins. These particles have a central hydrophobic core of cholesterol esters and
triglycerides (3 fatty acids attached to one lonely glycerin base). Different lipoprotein
classes differ in the relative amount of their apoproteins and are directed with specific
functions. The apoproteins are not only essential structural (solubilizing/emulsifying)
components of lipoprotein particles, but also act as recognition sites for receptor
mediated endocytosis of lipoproteins and as activators of enzymes involved in lipid
metabolism. In addition to the synthesis and secretion of lipoproteins, the liver also
secretes lipid-metabolizing enzymes, such as lecithin:cholesterol acyltransferase (LCAT)
and hepatic triglyceride lipase.
There are 5 major lipoproteins. They are HDL (high density lipoproteins), IDL
(intermediate density lipoproteins), LDL (low density lipoproteins), VLDL (would you
believe very low density lipoproteins), and CM (chylomicrons-translates kind of into
‘small blobs of fat’).
Describe chylomicrons including their life cycle, what they consist of, which apoproteins they have, etc.
Chylomicrons are the largest particles. They consist largely (more than 90%) of
triglycerides and are secreted by the intestinal mucosa into the intestinal lymph, from
where they enter the systemic circulation. They support exogenous, dietary triglycerides
and cholesterol and are processed in the capillaries of skeletal muscle and adipose tissue.
Here, chylomicrons bind to the endothelial surface and their triglycerides are digested by
membrane bound lipoprotein lipase, an enzyme that is activated by apoprotein C-II, a
constituent of chylomicrons. The hydrolytic products (fatty acids and monoglycerides)
are taken up by adipocytes and skeletal muscle cells where they are deposited as fat or
oxidized as fuel. The remaining lipoprotein particles (conveniently called chylomicron
remnants), are rich in cholesterol, apo B-48, and apo-E. The liver takes up these
remnants via the chylomicron remnant receptor. Thus, dietary triglycerides are delivered
to muscle and fat, whereas dietary cholesterol is targeted to the liver.
Describe the life cycle of VLDL, IDL, and LDL. What are they composed of? Which apoproteins do they contain?
During carbohydrate-rich feeding, the liver converts carbohydrates into fatty acids that after esterification are released into the bloodstream in the form of apo-E, apo C-II, and apo B-100 rich VLDL. VLDL is processed in the skeletal muscle and adipose tissue
in a similar way to chylomicrons. Their remnants are termed IDL and contain apoB-100
and apo-E. IDL are taken up in part by the liver via the LDL receptor or undergo further
processing in plasma (loss of apo-E) to yield cholesterol rich LDL. LDL functions to
supply extrahepatic tissues with cholesterol, where uptake occurs via LDL-receptor
mediated endocytosis. Like many peripheral tissues, the liver parenchyma expresses the
LDL receptor. Cholesterol is retaken by the liver and used for bile acid synthesis or
excreted as it is into bile. Kupffer cells also serve as a scavenger to remove especially
high concentrations of cholesterol.
What does HDL do/contain? What are they converted to? What happens with excess LDLs, especially if the liver has deficient LDL receptors? How do statins work?
HDL is formed from unesterified cholesterol that is released during cellular
turnover. Esterification of cholesterol in HDL occurs by the action of LCAT, an enzyme
synthesized and released by the liver into circulation. These cholesterylesters are then
found as IDL and may eventually appear in LDL (as shown in the figure below). Apo B-
100 is recognized by the LDL receptor; when LDL binds to its receptor it triggers LDL
internalization. In the event of LDL receptor deficiency or deficit, LDL uptake occurs
via scavenger cells and cholesterol esters are deposited in macrophages. Over time this
leads to the formation of foam cells, xanthomas, and atherosclerotic plaques.
The LDL receptor density on the hepatocyte cell membranes is regulated by the
hepatocellular cholesterol content; low cellular cholesterol upregulates the receptor and
simultaneously activates HMG-CoA reductase, the rate-controlling enzyme in cholesterol
synthesis. Inhibition of this enzyme further increases LDL receptor density and helps
with serum cholesterol reduction (this is the mechanism of action of the most commonly
prescribed cholesterol lowering medicines—WOW! This stuff really does matter!).
Which proteins are synth and secreted in the liver? Which types of proteins are they? What are some exceptions? Due to this protein synth, what happens in acute liver failure? Describe the process of liver protein synth. What things decrease liver protein synth? Increase?
Except for immunoglobulins, most circulating plasma proteins are synthesized in
the liver. They are produced by hepatocytes, except for von Willebrand factor, which is
produced by endothelial cells. Except for albumin and C-reactive protein, all proteins
secreted by the liver are glycoproteins. A list of the most important secreted hepatic
proteins is on the next page:
The half-lives of plasma proteins are highly variable and range from hours
(clotting factors) up to 20 days (albumin). Accordingly, acute liver failure is often first
manifest as a blood coagulation defect. The capacity of the liver to synthesize albumin is
high. Under normal conditions about 12 gm of albumin are produced and exported from
the liver every day. This can increase up to 4 fold in the setting of albumin losses.
Hepatocytes are constitutively protein-secreting cells. They continuously
synthesize and secrete proteins; there are no stores of newly synthesized proteins that can
be released upon demand. Thus, the hepatocellular protein secretory rate is primarily
influenced by alterations in the rate of protein synthesis (controlled at transcriptional and
translational levels). More rapidly secreted proteins (e.g. albumin) are transported from
endoplasmic reticulum for Golgi apparatus quickly. On the other hand, more slowly
secreted proteins (e.g. fibrinogen and transferrin) move through the cellular protein
synthesis and secretion machinery more slowly.
Protein synthesis in the liver decreases upon amino acid deprivation (starvation)
and decreases under the influence of glucagon. These conditions simultaneously
stimulate proteolysis and RNA breakdown, whereas RNA synthesis is inhibited.
Conversely, high amino acids concentrations, and insulin stimulate protein synthesis and
inhibit proteolysis. Thyroid and growth hormone also stimulate hepatic synthesis of
plasma proteins.
When does the liver release amino acids? How does this occur? When is this release inhibited? Which amino acids have the highest rate of extraction? Which AAs does the liver not degrade? Where are they degraded? Describe what happens with AAs in the liver and muscle in starvation. Where does the ammonia in the portal system and liver come from? What does the liver do with it?
The liver acts as a metabolic buffer in the control of plasma amino acid
concentrations. In the setting of lower amino acid levels, the liver releases amino acids.
The amino acids are derived from hepatic proteolysis and this process is stimulated by glucagon, and amino acid deprivation; this same process is inhibited by plentiful amino
acids and insulin. Conversely, in the setting of the postprandial absorptive state, amino
acids are delivered to the liver in high concentrations and are efficiently extracted to be
metabolized by this magnificent organ.
The highest rate of amino acid extraction is observed for the gluconeogenic amino acids alanine, serine, and threonine. In addition, the liver degrades most amino acids.
Exceptions are the branched chain amino acids, leucine, valine, and isoleucine—these are
only used for protein synthesis in the liver and are not catabolized (these are broken down
primarily in the skeletal muscle).
In starvation, the muscle becomes a major site of amino acid release. A glucose-
alanine cycle between the liver and muscle exists in this situation; alanine released from
the muscle is taken up by the liver and used for gluconeogenesis; glucose is delivered to
the muscle and enters the glycolytic pathway. The pyruvate generated from glycolysis in
the muscle is transaminated to alanine that flows back to the liver. Look how the words
the muscle line up four times in a row—except for the fourth I didn’t plan that!
The portal venous blood contains high amounts of ammonia that is generated by
the action of intestinal bacteria on amino acids, especially glutamine. Ammonia is also
produced in the liver during the catabolism of amino acids. Ammonia is detoxified in the
liver by both the liver specific pathway of urea synthesis and by glutamine synthesis.
What role does the liver have with hormones? Give specific examples.
Many peptide hormones are substantially cleared during a single liver passage.
These same hormones when present can markedly impact on the control of hepatocyte
function. Because of these interactions, hormone gradients along the liver acinus
contribute to the expression and maintenance of zonal hepatocyte heterogeneity.
On the flip side, the liver is also the site of hormone transformation from inactive
to active forms. Examples of this are vitamin D and thyroid hormone. In the liver,
vitamin D is hydroxylated in position 25 (with hydroxylation at position 1 performed in
the kidney). These hydroxylation reactions are required for the conversion of vitamin D
to its active form (1,25-dihydroxycholecalciferol). The liver is the site of 70% of total- body T4 (prohormone) to T3 conversion via deiodination. The liver secretes T3 and this
is responsible for most thyroid hormone effect.
The figure below tabulates the hepatic role in the processing of several hormones
and mediators.
The inability to metabolize many of these hormones/neurotransmitters may be in
large part responsible for portal hypertensive encephalopathy—cerebral dysfunction that
results as a consequence of liver disease.
What are the two ways in which the liver can detoxify substances leading to excretion?
Many potentially harmful endo- and xenobiotics are hydrophobic and therefore
lipid soluble. Still these lipid soluble molecules are small and are easily filtered by the
renal glomeruli. Once in the renal tubules, lipid soluble molecules readily cross cell
membranes and are reabsorbed (so not efficiently excreted in the tinkle). These
molecules can often be taken up by the liver, for detoxification and excretion.
Detoxification consists of either (i) transformation of the molecule into a water-soluble
one that can be excreted by the kidney (via filtration or tubular secretion), or (ii)
modification and then secretion into bile that is able to accommodate more hydrophobic
molecules.
Describe phase I and phase II reactions. How do these occur with acetaminophen?
There are two reaction types that are most important. They are simple names
phase I reactions and would you believe phase II reactions. Phase I reactions are
mediated by a family of oxidative enzymes collectively referred to as the cytochrome P-
450 system. Phase I reactions can both toxify or detoxify a drug or other substance. As a
rule, phase I reactions are rate limiting steps in the metabolism of a drug. They are often
affected by other drugs, age, and genetic variations. Phase II reactions are conjugation
reactions through which a metabolite or xenobiotic is conjugated to a solubilizing
molecule such as glucoronide, glutathione, or a sulfate (just to name a few of the more
important conjugates). Conjugation reactions are among the most powerful reactions
known in biology. Phase II reactions are fast, well preserved (even in liver failure), and
provided that enough conjugate is around work every time.
An example of such molecular processing is the role of the liver in “clearance” (or
“riddance”) of a favorite student drug, acetaminophen (Tylenol by trademark). Most
acetaminophen is conjugated by a phase II reaction to glucuronic acid or sulfate—the
resulting conjugate is excreted in the urine. The remainder goes through a phase I reaction mediated mostly by cytochrome P-450 2E1; the result is a toxic molecule
(NAPQI). Usually, NAPQI is quickly detoxified by conjugation (phase II again) to
glutathione (labeled GSH in the diagram below).
What are the components of bile?
Bile is among the most important of the liver’s products. It’s a golden-green fluid
that is produced in the liver and transported into the intestine; in health, it resembles fresh
motor oil. The principal contents of bile are bile acids, phospholipids (including
lecithin), cholesterol, and bile pigments. Bile also contains water, electrolytes (especially
the cation sodium, and the anions chloride and bicarbonate), some proteins and some
metabolites.
Describe how the structure of bile acids leads to their function. What is their life cycle like?
Bile acids are the major organic constituents of bile and account for 50 percent of
the solid components of bile. Let’s keep things simple, bile acids are carboxylic acids
with a cyclopentanoperhydrophenathrene nucleus and a branched side chain of three to
nine carbon atoms that ends in a carboxyl group. Now, I know what you thinking – HO
HUM! Bernstein, stop being so chemically simplistic! But forgive me as I state more of
the obvious about this chemistry. This structure makes bile acids amphipathic in the
sense that they have a hydrophobic nucleus and a hydrophilic end. The chemical
properties of bile are further defined by their concentration in bile. At low concentration,
bile acids do not interact with one another. But if you crowd bile acids together and
achieve a critical micellar concentration, the hydrophobic regions interact with one
another and the hydrophilic regions interact with one another to form micelles. Micelles
can transport water insoluble fats in the hydrophobic core and can remain water soluble
because of a hydophilic shell. An example of a micelle is shown on the top of the next
page.
Bile acids are the metabolites of cholesterol. Primary bile acids (cholic and
chendeoxycholic acids) are synthesized exclusively in the liver and undergo
enterohepatic circulation that will be described below—briefly though most bile acids in
the intestine are reabsorbed in the terminal ileum, transported back to the liver via and
portal circulation, and recycled. Primary bile acids are metabolized by intestinal bacteria
to form secondary bile acids (deoxycholic acid and lithocholic acid). Bile acids are
conjugated in the liver (forming bile salts) to decrease toxicity and to facilitate excretion.
Describe phospholipids and their interaction with bile acids.
Phospholipids are the second most abundant organic compounds in bile.
Phospholipids are also amphipathic with a hydrophobic fatty acid chain and a hydrophilic
phosphatidylcholine grouping; alone they are not water-soluble. In an aqueous
environment, phospholipids will form crystals. Fortunately, bile salts are potent
solubizers of phospholipids. Micelles then form that contain phospholipids and bile acids; this combination is remarkably capable of solubilizing other lipids and especially
cholesterol.
Describe the free cholesterol in bile. How can it lead to cholesterol crystals or gall stones?
A relatively small amount of free cholesterol is present in bile; it accounts for
only four percent of the total solids in bile. The presence of cholesterol in bile is
important for two reasons. First, bile cholesterol can be excreted and therefore it
regulates body stores of cholesterol. In bile, most cholesterol is nonesterified and is
therefore water insoluble. In the presence of appropriate concentrations of bile salts and
phospholipids, cholesterol is kept safe in the interior or soluble micelles. In setting of
excess bile cholesterol relative to concentration of bile salts and phospholipids,
cholesterol crystals and gallstones can form.
Describe bilirubin in bile. Describe its complete life cycle.
Bilirubin is the last of the important organic solids in bile. Bilirubin is the most
significant of a group of bile pigments. These pigments account for only 2 percent of the
solids in bile. They are chemically related to porphyrins like hemoglobin, from which
they are derived. Bilirubin alone is insoluble in water; fortunately, in the body bilirubin
is almost always conjugated to glucoronic acid and thereby rendered soluble. Bilirubin
and the other bile pigments are powerfully colored; in fact, stercobilinogen is responsible
to the brown color of feces (a.k.a. stool, doodie, or ?*!^). Bilirubin metabolism is
illustrated in the diagram below.
Hemoglobin—>bilirubin—>into liver, glucoronidated—>into intestine—->can be excreted, converted to bilirubin again, converted to urobilinogen, to kidney, excreted.
Describe the life cycle of bile (synth, secretion, transport, modifications at the different steps of transport,
To review biliary functional anatomy, bile starts off as the secretion of
hepatocytes into microscopically small bile canalicula (see page 3). Canalicular bile is
the primary secretion product of the hepatocytes. Bile’s ionic composition is modified by
the epithelial cells (cholangiocytes) in the bile ductules.
The bile flows into progressively larger ducts and then into two ducts, simply
termed the right and left hepatic ducts (the name of the duct correlates with the particular
hepatic lobe from which it drains). Along the way, the bile is further modified by the
secretory and absorptive functions of the cholangiocytes.
On the canalicular level, osmotic filtration is the major determinant of bile
formation. In this regard, osmotically active solutes are transported from the hepatocytes
to the biliary canalicula and are concentrated there by energy dependent transport processes. Some of filtration is bile salt dependent and some functions independently of
the transport of bile salts. Water then flows into the canalicula to dissipate osmotic
gradients and this promotes forward flow of the fluid. These general principles are
shown in the diagrams below.
Describe the extrahepatic flow of bile including the function of the gallbladder. How is this process regulated?
Returning to a more macroscopic level, the right and left hepatic ducts merge
outside the liver to form a common hepatic duct. The common duct, termed the common
hepatic duct proximal to the cystic duct takeoff and termed the common bile duct below
that landmark drains into the intestine through a muscular sphincter, the sphincter of Oddi
(named after that dog that Garfield always picks on). If the sphincter is closed, some bile
will be stored and concentrated in the gallbladder. It is a vestigial organ from our
caveman days when we didn’t eat but every three or four days. Then we would kill a
wooly mammoth or the like and gorge ourselves 15,000 calories at a time…much of it
pure fat. Fortunately, we stored enough bile stored in the gallbladder to help with fat
emulsification. Now that we have Schnuck’s, we really don’t need gallbladders; they’re
probably more trouble than they’re worth. Discharge of bile from the gallbladder into the
duodenum by a short “endocrine reflex”; it is mediated by cholecystokinin (CCK).
Released by secretory cells of the duodenum, in response to fat, CCK causes contraction
of gallbladder smooth muscle.
What is the function of bile?
The function of bile resides not only in the excretion of xenobiotics and
endobiotics (such as aged proteins, bilirubin, cholesterol, and porphyrins) but also serves
digestive functions. This digestive function largely is based upon the detergent effect of
bile to emulsify/solubilize fats, and providing the ingredients to for micelles for fat
absorption.
Describe enterohepatic circulation as it pertains to bile. What happens when it’s not functioning as it should?
Once bile is excreted into the intestine it performs many of its digestive functions.
About 95% of the bile salts are then reabsorbed in the ileum and returned to the
hepatocytes via the portal circulation. The bile acid pool recirculates 5 to 15 times per
day (twice a meal). In the setting of ileal dysfunction, diarrhea can result from the irritant
activity bile acids delivered into the colon. Alternatively, reduced reabsorption of bile
acids by the ileum can deplete bile stores and cause fat malabsorption. The following
figure illustrated the enterohepatic circulation.
