Read First - Central Role of the Liver

8/2/2019 Read First - Central Role of the Liver

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Key Points

Metabolic interrelationship among

macronutrients

The central role of the liver in metabolism


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Metabolic interrelationship among the

macronutrients

Each of the macronutrients (carbohydrate, lipid

and protein) can provide human cells with

energy, as well as being involved in both anabolic

and catabolic reactions in human cells

Anabolic reactions: require energy

Catabolic reactions: produce energy (e.g.

Infection, trauma which results in rapid loss ofmuscle due to break down of body stores for

energy)


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macronutrients

The metabolic interrelationship amongcarbohydrates, lipids and proteins in the humanbody is well established

For example: Excess dietary carbohydrate is fattening excess

glucose is known to slow down lipolysis andcontribute to the synthesis of triglycerides for storage(glucose is converted to fat via acetyl CoA)

Important amino acids can be synthesised fromglucose and fatty acids

Muscle protein is used for energy in catabolic states


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macronutrientsNote that some

reactions are

reversible (indicated

by a return arrow)

or irreversible

(indicated by asingle arrow)

Also note that the

glycerol from

triglycerides can

enter glycolysis astriose phosphate

through a number

of conversion steps

(not shown)


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macronutrients

Glycogenesis occurs in the liver and muscle

during fed-state

Glycogenolysis occurs during fasting state

Gluconeogenesis occurs during starvation

(essential to maintain optimal BGL to provide

brain and RBCs)


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macronutrients

-oxidation (break down of fatty acids toacetyl CoA for ATP production)

Takes 2 carbons from the FFA at a time producing

acetyl CoA (through a number of steps) Acetyl CoA can not be used to make glucose as it

lacks sufficient carbons

Excess accumulation of Acetyl CoA leads to the

saturation of the TCA cycle This results in shunting of accumulated Acetyl CoA

to produce ketones


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The Central role of the liver in

metabolism

The liver plays a key role of processor and

distributor in metabolism, furnishing by way

of the bloodstream a proper combination of

nutrients to the organs and tissues.


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metabolism

Carbohydrate Metabolism

Dietary glucose is phosphorylated by glucokinase (and

hexokinase to a lesser extent) in the liver to glucose-6-

phosphate (this occurs to trap it in the cell) Other dietary monosacccharides (e.g. Fructose,

galactose) are also phosphorylated and rearranged to

glucose-6-phosphate into the liver

Catabolism of glucose-6-phosphate can result ATP

production from the hepatocytes via the aerobic

pathways (TCA cycle and oxidative phosphorylation)


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metabolism

Carbohydrate Metabolism

There are several anabolic routes taken by

glucose-6-phosphate, including:

Glycogenesis (formation of glycogen)

Lipogenesis (formation of fatty acids and triglycerides

via acetyl CoA)

Cholesterogenesis (formation of cholesterol via acetyl

CoA)

Nucleotide synthesis (pentose phosphate pathway)


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metabolism


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metabolism

Amino Acid Metabolism

The liver is the most active organ in amino acid

metabolism in both the fed and fasting states

The liver is the site for the synthesis of important

structural and plasma proteins (e.g. Albumin,

clotting factors)

Amino acids are also converted in the liver intonon-protein compounds which require nitrogen

(e.g. Nucleotides, hormones and porphyrins)


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metabolism


Catabolism of amino acids can take place in the liver

where they are transaminated (removal of NH3) and

degraded to acetyl CoA and other TCA intermediates The urea cycle in the liver removes the NH3 (and its

excreted as a waste product)

Acetyl CoA and TCA intermediates are used as follows:

Oxidised for ATP production

Glycogenesis

Lipogenesis


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metabolism


During fasting, amino acids from muscle protein

breakdown to provide the chief substrate for

gluconeogenesis (making new glucose)

The carbon of the amino acids from muscle

protein is delivered to the liver via the alanine-

glucose cycle

Alanine is an amino acid which is very easily

formed when a NH3 is transferred to pyruvate


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metabolism

The Alanine-glucose cycle


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metabolism

The Alanine-glucose cycle

This is very important in the maintenance of BGLs

during fasting

When these stores are depleted it is a key stage in

changing from the fasting state to the starvation

state (brain becomes reliant on ketones for energy

and substrates available for gluconeogenesis are

depleted)


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metabolism

Fatty Acid Metabolism

Most of the dietary fatty acids are removed fromchylomicrons and stored in adipose tissue

The liver is the major site of fatty acid synthesis. Excess

glucose and amino acids are used to make fatty acids They fatty acids made in the liver can be assembled into

liver triglycerides, with much of the triglycerides thenbeing transported via the VLDLs to the adipose tissue forstorage

Chylomicrons: lipoproteins carrying exogenous lipids Other lipoproteins (VLDL, LDL, IDL, HDL): lipoproteins

carrying endogenous lipids

(HDL= good cholesterol; others = bad cholesterol)


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metabolism

Fatty acid metabolism

The metabolic pathway called -oxidation is very

important in the liver. It breaks down (oxidises)

fatty acids into the 2-carbon compound Acetyl-CoA

Acetyl-CoA is used by the liver for

ATP production Cholesterogenesis

Ketogenesis


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metabolism

Ketones

Important as an overflow pathway for excess

Acetyl CoA

Ketones are used as an energy source during the

starvation phase

Ketogenesis most important function is getting

rid of excess Acetyl-CoA


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metabolism

Formation of ketone bodies (ketogenesis)

The ketone bodies include: acetoacetate, -hydroxybutyrate and acetone

Ketogenesis is an overflow pathway in the liver that deals

with excess Acetyl-CoA. It also provides the liver with away of distributing fuel to other tissues

Other tissues (e.g. Heart, kidneys) convert the ketonesback to acetyl-CoA for energy production through the TCAcycle

Brain can use ketones for energy only during starvation

Ketosis (high blood ketone levels occurs in starvation) thiscan result in keto-acidosis


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References

Gropper SS, Smith JL, Groff JL. Advanced

Nutrition and Human Metabolism. 5th Edition.

Wadsworth Cengage Learning, California

Read First - Central Role of the Liver

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