PHM142 Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
CELLULAR ARCHITECTURE AND
PHYSIOLOGY OF THE LIVER
PHM 142
November 10, 2015
Ivan Nayve, (Calvin) Ho Lau, Adrienne Pham, Mathew Luen
OUTLINE
• Anatomy and Histology
• Hepatic Vascular System
• Liver Physiology
• Carbohydrate Metabolism
• Alcohol Detoxification
2
THE LIVER
•Heaviest gland in the body
(~3lb)
•Performs over 500 metabolic
functions
•Located inferior to the
diaphragm in the upper right
region of the abdomen
3
ANATOMY OF THE LIVER
Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9th edition. McGraw Hill, New York.
4
CELL TYPES
•80% hepatocytes
•Major functional cell of the liver
•Specialized epithelial cells with a
wide range of functions
•Single cell layer form hepatic laminae
Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328.
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CELL TYPES
•20% nonparenchymal cells
•Sinusoidal endothelial cells
• Small fenestrations for diffusion
• Endocytosis and secretion
• Kupffer cells
• Macrophages with endocytotic function
• Immune defense
• Pit cells
• Large granular lymphocytes
• Antiviral liver defense
• Stellate (Ito) cells
• Main source of ECM components
• Vitamin A storage
Bouwens et al. (1992) Liver cell heterogeneity: functions of non-parenchymal cells. Enzyme. 46: 155-168.
6
THE HEPATIC PORTAL CIRCULATION
•Directs blood from small intestine, stomach, pancreas and spleen to the liver
•
75% of blood entering liver is
nutrient rich venous blood
Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328.
Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9th edition. McGraw Hill, New York.
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THE HEPATIC PORTAL CIRCULATION
•25% of blood enters liver as
oxygenated arterial blood
Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328.
Tortora et al. (2009) Principles of anatomy and physiology, 12th edition. John Wiley & Sons Inc., New Jersey.
8
FUNCTIONS
1.
Bile production – ↑ pH, emulsify fat
7.
Metabolism of drugs (first-pass effect)
2.
Storage – carbohydrates, vitamins, fat,
copper, iron
8.
Activation of Vitamin D
9.
Embryonic haematopoiesis
3.
Carbohydrate Metabolism
4.
Detoxification – ammonia, alcohol
5.
Phagocytosis – Kuppfer cells – worn out
RBC’s, bacteria
6.
Synthesis of proteins (albumin, fibrinogen,
lipoproteins)
Vanputte et al. Seeley’s Anatomy and Physiology, 9th edition. McGraw Hill, New York, 2011.
10. Excretion of bilirubin
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CARBOHYDRATE METABOLISM
• Glycogen Synthesis
•Blood glucose taken up by
hepatocytes and converted to
glycogen for storage
•Liver expresses Glycogen Synthase,
an enzyme required for glycogen
synthesis
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GLYCOGENOLYSIS AND GLUCONEOGENESIS
• Glycogenolysis
GLYCOGEN
• Glycogen is broken down to form
glucose which can be released into
the blood
GLUCOSE
• Gluconeogensis
• De novo synthesis of glucose
from non-carbohydrate sources
such as amino acids, lactate, and
glycerol
AMINO ACIDS,
LACTATE, GLYCEROL
11
GLYCOGENOLYSIS AND GLUCONEOGENESIS
12
ALCOHOL METABOLISM IN HEPATOCYTE
•Hepatocyte is the major site of
alcohol metabolism
1. Ethanol is oxidized to
acetaldehyde by alcohol
dehydrogenase (ADH)
This reaction is catalyzed by
NAD+/NADH
90% of alcohol present in the liver is
oxidized through this reaction
Modified from: Bullock, C. (1990), The biochemistry of alcohol metabolism — A brief review. Biochemical
Education,
13
18: 62–66.
The same conversion can also be performed by the Microsomal Ethanol-Oxidizing System (MEOS)
– this accounts for the remaining 10%
•It involves cytochrome P450 oxidase enzymes – in particular the CYP2E1 enzyme
•Ethanol is oxidized to acetaldehyde while O2 is reduced to form H2O and NADPH is used as a
hydrogen donor, forming NADP+
•This reaction requires hydrolysis of ATP
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2. Acetaldehyde is oxidized to
acetate by aldehyde
dehydrogenase (ALDH)
This reaction is catalyzed by
NAD+/NADH (NAD+ acts as a
cofactor)
This occurs in the mitochondria
and the resulting acetate is
released into the bloodstream
to be further oxidized into CO2
and water in the peripheral
tissues
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SUMMARY
• Liver composed of 80% hepatocytes (main functional unit)
• 20% are non-parenchymal cells:
Cell Type
Function
Sinusoidal Endothelial cells
Endocytosis and secretions
Kupffer cells
Phagocytosis
Pit cells
Antiviral defense
Ito cells
Vitamin A storage
• Blood delivery to the liver is through the portal vein (nutrient-rich) and the hepatic artery
(oxygen-rich) and mixes in the liver sinusoids
• Carbohydrate metabolism in the liver includes glycogen synthesis, glycogenolysis and
gluconeogenesis
• Ethanol is first oxidized to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is further
oxidized into acetate by aldehyde dehydrogenase. Acetate will enter the bloodstream and
be oxidized and removed in the form of H2O and CO2.
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REFERENCES
• Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47:
281-328.
• Bouwens et al. (1992) Liver cell heterogeneity: functions of non-parenchymal cells. Enzyme.
46: 155-168.
• Bullock, C. (1990) The biochemistry of alcohol metabolism — A brief review. Biochemical
Education, 18: 62–66.
• Postic et al. (2004) Role of the liver in the control of carbohydrate and lipid homeostasis.
• Tortora et al. (2009) Principles of anatomy and physiology, 12th edition. John Wiley & Sons
Inc., New Jersey.
• Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9th edition. McGraw Hill, New York.
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