Download 4. Liver and Gall Bladder

AHS 2013 Digestion and Metabolism
Sarah Harney
4. Liver and Gall Bladder,
Fuel Metabolism
• Functions of the Liver and Gallbladder
• Cholesterol synthesis and metabolism
• How are nutrients utilised? Differences
between absorptive and post-absorptive
states
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4. Liver and Gall Bladder
Functions of the Liver
•
Metabolic regulation/normalisation
– Glucose, fat, protein
•
Blood protein regulation
– Production and removal of waste
products
•
Hormonal function
– Production and removal
•
Bile secretion
•
Synthesis and modification of hormones
•
Plasma protein synthesis
•
Cholesterol metabolism
•
Metabolism of many drugs
Reading: Stanfield pp 577-580
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AHS 2013 Digestion and Metabolism
Sarah Harney
Blood flow to/from the liver
• The liver receives blood from 2 sources:
- the hepatic artery
-the hepatic portal vein
• Blood from the GI tract is carried via the
hepatic portal vein to the liver
• Nutrients and other substances absorbed
in the small intestine are processed or
detoxified by the liver before the blood flow
is returned to the heart (via the hepatic
vein)
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Anatomy of the Liver
• The liver is organized into functional units known as lobules
3 vessels at each
corner of the lobule:
Branches of the
hepatic portal vein
and hepatic artery + a
bile duct
Blood flows from both
veins and arteries into
expanded capillaries
called sinusoids
Bile is secreted into bile
canaliculi which drain into
the bile ducts
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AHS 2013 Digestion and Metabolism
Sarah Harney
Blood flow though liver lobules
• Flow of nutrients from
hepatic portal vein
• Concentration
gradient of nutrients
from hepatic portal
vein to central vein
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Role of the Liver in Metabolic Regulation
Metabolic processing of all major nutrient groups
(carbohydrates, proteins, lipids):
• Glucose converted to glycogen for storage (glycogenesis)
• Amino acids converted to fats
• Amino acids converted to glucose
(gluconeogenesis)
• Amino acid catabolism to urea
• Free fatty acids converted to triglycerides and cholesterol
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AHS 2013 Digestion and Metabolism
Sarah Harney
Plasma Proteins
Plasma proteins are synthesized by the liver
Albumins
• Most abundant plasma proteins
• Transport lipophilic molecules e.g. steroid + thyroid hormones
Globulins
• and globulins
• -globulins – bind hydrophobic substances for transport in the blood
• - and -globulins – blood clotting factors
( -globulins i.e. antibodies are produced by lympohocytes
and not by the liver)
Fibrinogen
• Soluble precursor of fibrin, forms blood clots
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Plasma Proteins — deficiencies
Albumins
• Reduced plasma osmolarity, leading to oedema (esp.
abdominal)
and Globulins
• clotting, increased bleeding time
Fibrinogen
• Impaired clotting
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AHS 2013 Digestion and Metabolism
Sarah Harney
Liver and Hormones
• Synthesises Insulin-like Growth Factor (IGF-I)
– in response to Growth Hormone (GH, produced by
pituitary)
– Stimulates soft tissue and bone growth
• Metabolism of hormones
– Degradation and removal of hormones from
circulation
– Detoxification and removal of many drugs
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Bile
• Continuous secretion
by liver, 250 ml-1l per
day
• Required for
emulsification of fat,
enables fat digestion
by lipases
• The sphincter of
Oddi regulates entry
of bile into
duodenum
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AHS 2013 Digestion and Metabolism
Sarah Harney
Gallbladder
• The gallbladder stores bile
• 95 % of bile salts secreted are
reabsorbed and recycled
• Bile is concentrated in the gall
bladder
• Cholesterol can precipitate
out of bile to form gallstones
• Gallbladder removal
(cholecystectomy) can be
performed to treat gallstones
without seriously affecting
digestion or absorption
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Enterohepatic circulation of Bile Salts
• ~ 95 % of bile salts are
reabsorbed by terminal ileum
• Transported back to liver via
heptic portal vein- enterohepatic
circulation
• Bile salts are recycled multiple
times during a meal
• Total pool of bile salts = 3-4 g
•Bile salts released during a meal
= 3-15 g
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AHS 2013 Digestion and Metabolism
Sarah Harney
Bilirubin, the waste product of red blood cell
breakdown, is excreted in bile
• Yellow pigment, gives bile characteristic colour
• Red blood cells removed from blood by
macrophages in liver and other tissues
• Bilirubin is the breakdown product of the
haem part of haemoglobin protein
• Liver cells remove bilirubin from blood and excrete it into
bile
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Bilirubin accumulation causes Jaundice
Bilirubin accumulation may result from:
• Excessive breakdown of red blood cells (prehepatic)
• Liver disease resulting in inefficient excretion of
bilirubin (hepatic)
• Bile duct obstruction (post-hepatic)
Hyperbilirubinaemia
Bilirubin accumulation in tissues - Jaundice
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AHS 2013 Digestion and Metabolism
Sarah Harney
Cholesterol — structure
• Cholesterol
– 3 x 6-Carbon rings + 1x 5-Carbon ring
– Basic structure for steroid hormones
– Essential component of all plasma membranes
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Cholesterol — roles
• Most produced in liver
– inverse ratio to intake i.e. Increases dietary intake reduces
synthesis and reduced intake increases synthesis by the
liver
• Facilitates transport between liver and other organs
• Enters cells via LDL receptors
– Regulation by down-regulation of LDLr and intracellular
production
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AHS 2013 Digestion and Metabolism
Sarah Harney
Steroid hormones
• Based on cholesterol
• Fat-soluble
• Pass through cell membrane
• Typically receptors are cytosolic i.e.
intracellular
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Cholesterol and Lipoproteins
• Cholesterol is synthesized by the liver
• Cholesterol synthesis is inversely regulated by dietary intake i.e.
increased dietary intake reduces synthesis and reduced intake
increases synthesis by the liver
• Cholesterol is transported in the plasma as lipoproteins –
complexes containing cholesterol, phospholipids, triglycerides and
apoproteins (co-factors for various enzymes)
Lipoproteins have a
hydrophilic outer shell and a
hydrophobic inner core
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AHS 2013 Digestion and Metabolism
Sarah Harney
Cholesterol and Lipoproteins
• Lipoproteins are classified depending on their density
VLDLs Very low density lipoproteins, high concentration of lipid
LDLs Low density lipoproteins
HDLs High density lipoproteins, high concentration of protein
• High plasma cholesterol levels are a major risk factor for heart
disease
Normal levels 200 mg/dl (mg per 100 ml, or ~ 5 mM)
High levels
> 240 mg/dl (> ~ 6 mM)
• A high ratio of HDL to LDL reduces the risk for atherosclerosis,
hence, HDL is ‘good cholesterol’
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Cholesterol and Atherosclerosis
• Atherosclerois (hardening of the arteries) is caused by
deposition of a fatty, cholesterol-rich plaque inside
arteries
• Narrowing of the arteries results in increased blood
pressure and can lead to complete occlusion, resulting in
heart attack or stroke (depending on what arteries are
affected)
• Statins (e. g. Lipitor, Zocor) inhibit cholesterol synthesis
and are used to reduce plasma cholesterol
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AHS 2013 Digestion and Metabolism
Sarah Harney
Cholesterol — excretion
• Produced by hepatocytes (liver)
• Excreted via Bile
• HDLs take up and transport cholesterol from cells around
the body and transport it to the liver for degradation and
excretion
• Supersaturation may lead to gall stones
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Fuel Metabolism – Carbohydrate,
Protein, Fat
• Excess nutrients are converted to stored fuel sources
• Excess glucose is stored as glycogen, in liver and skeletal
muscle – once maximal storage capacity (~ 500 g) is full,
excess glucose is converted to fatty acids and triglycerides
• Excess amino acids are converted to glucose and fatty
acids
• Excess fatty acids are assembled as triglycerides
All nutrients surplus to requirements
are converted to fatty acids and stored
as triglycerides in adipose tissue
Reading: Stanfield pp 608-612
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AHS 2013 Digestion and Metabolism
Sarah Harney
Roles of different tissues in metabolism
Liver – maintains blood glucose levels by glycogen
storage/breakdown and gluconeogensis
Adipose tissue – main energy storage site, regulates fatty acid
levels in blood
Muscle – main site for amino acid storage, major energy user
Brain – only uses glucose but cannot store glycogen, relies on
blood glucose being maintained
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Fuel Metabolism
Process
Liver
Blood
Glycogenesis
Glucose
Glycogen
Blood glucose
Glycogenolysis
Glycogen
Glucose
Blood glucose
Gluconeogenesis
Amino acids
Glucose
Blood glucose
Protein Synthesis
Amino acids
Protein
Blood amino acids
Protein breakdown
(proteolysis)
Protein
Amino acids
Blood amino acids
Fat synthesis
(lipogenesis)
Fatty acids
Triglycerides
Blood fatty acids
Fat breakdown
(lipolysis)
Triglycerides
Fatty acids
Blood fatty acids
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AHS 2013 Digestion and Metabolism
Sarah Harney
Fuel Metabolism – Anabolism and Catabolism
Anabolism - Synthesis of large macromolecules from smaller
molecular subunits
(Energy-requiring)
Catabolism – Breakdown of large, energy-rich macromolecules
(Energy-yielding)
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Absorptive and Postabsorptive States
Absorptive State (Fed)
• Nutrients absorbed for
~3-4 hrs after eating
• Energy input > Energy output
• Energy is stored in
macromolecules
(anabolism)
Postabsorptive State (Fasting)
• Time between meals, no
nutrients being absorbed
• Energy output > Energy input
• Energy stores are utilized
(catabolism)
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AHS 2013 Digestion and Metabolism
Sarah Harney
Feeding & Fasting — Carbohydrate
Absorptive State (Fed)
• Glucose is the major
energy source
Postabsorptive State (Fasting)
• Glycogen depletion
• Glycogen synthesis + storage
• Glucose sparing to conserve
glucose for the brain
• Excess glucose converted to fat
• Gluconeogenesis
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Feeding & Fasting — Protein
Absorptive State (Fed)
Postabsorptive State (Fasting)
• Protein synthesis
• Protein catabolism
• Excess converted and stored
as triglycerides
• Amino acids used for
gluconeogenesis
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AHS 2013 Digestion and Metabolism
Sarah Harney
Feeding & Fasting — Fat
Absorptive State (Fed)
• Triglyceride synthesis and
storage
Postabsorptive State (Fasting)
• Triglyceride catabolism
• Fatty acids used as energy
source for non-glucosedependent tissues
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Absorptive Metabolism
Absorption of small nutrients
Blood
Glucose
Most body cells
Liver + muscle
CO2 + H2O
+ Energy
Glycogen
Fatty Acids
Liver + adipose tissue
Glycerol
Fatty acids
Amino acids
Liver
Fatty acids
Muscle etc.
Protein
Triglycerides
Stanfield, Fig. 21.3
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AHS 2013 Digestion and Metabolism
Sarah Harney
Postabsorptive Metabolism
Stored Macromolecules
Adipose tissue
Muscle + oth cells
Proteins
Triglycerides
Amino acids
Liver
Muscle
Glycogen
Glycogen
Fatty
Fatty acids
acids Glycerol
Liver
Lactate, pyruvate
Glucose
Ketones
Blood
Amino acids
Fatty acids
Ketones
Glucose
Non-nervous tissue
Nervous tissue
CO2 + NH3 + H2O + Energy
CO2 + H2O + Energy
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Stanfield, Fig. 21.4
Appendix
Summary of nutrient metabolism in different tissues
From: http://www.nature.com/scitable/topicpage/dynamic-adaptation-of-nutrient-utilization-in-humans-14232807
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