Session 4: Energy Storage - Carbohydrates & Lipids

Which tissues have an absolute requirement for glucose as an energy source?

- Erythrocytes and leukocytes

- Testes

- Kidney medulla

- Lens and cornea of the eye

Stable blood glucose levels are absolutely essential for normal ____ function

Stable blood glucose levels are absolutely essential for normal brain function

What is the most severe outcome of SEVERE hypoglycaemia (~0.6mmol/L)?

Brain damage, death

How is glucose granules stored in the liver and muscle?

Glycogen

Describe the structure of glycogen

- Polymer of glucose (polysaccharide)

- Highly branched originating from dimer glycogenin

- Chains linked by α-1-4 glycosidic bonds

- Branch points = α-1-6 glycosidic bonds

What types of bonds can be found in glycogen?

The α-1-6 glycosidic bonds = form branching points

The α-1-4 glycosidic bonds = join the chains

What is glycogenin?

Glycogenin is a core protein that glycogen uses as its core and starting synthesis point.

What is glycogenesis and where does it occur?

The conversion of glucose to the storage form of glycogen

It occurs in the muscle and liver

What is the first reaction in glycogenesis?

Glucose converted to glucose-6-phosphate

Catalysed by hexokinase (most cells) or glucokinase (in liver)

What is glycogenolysis? Where does it occur?

The breakdown of glycogen into glucose-1-phosphate

It occurs in the hepatocytes and muscle cells

What is the second reaction in glycogenesis?

Glucose-6-phosphate is converted to glucose-1-phosphate

Catalysed by phosphoglucomutase

Different enzymes allow for catalysis of glycogen in glycogenolysis - what are these enzymes?

Glycogen phosphorylase = alpha-1-4 glycosidic bonds

De-branching enzyme = alpha-1-6 glycosidic bonds

What is the third reaction in glycogenesis?

Glucose-1-phosphate is converted to UDP-glucose

Catalysed by uridyl transferase

What is the fourth and final step in glycogenesis?

Glycogen (n residues) + UDP-glucose produces = glycogen (n+1 residues) + UDP

Two enzymes are involved...

Glycogen synthase = formation of α-1-4 glycosidic bonds

Branching enzyme = formation of α-1-6 glycosidic bonds

What enzyme catalyses the conversion of glucose-1-phosphate to glucose-6-phosphate in glycogenolysis?

Phosphoglucomutase

Why can't glucose-6-phosphate from glycogenolysis be broken down into free glucose in the muscle?

The muscle lacks the glucose-6-phosphatase enzymes - so the glucose-6-phosphate must enter glycolysis to produce ATP

What are the rate-limiting enzymes in glycogen synthesis (glycogenesis)?

Glycogen synthase

What are the rate-limiting enzymes in glycogen degradation (glycogenolysis)?

Glycogen phosphorylase

Hormones that regulate glycogen metabolism

Glucagon, adrenaline, insulin

Hormones that stimulate glycogen breakdown

- Glucagon

- Adrenaline

Hormones that stimulate glycogen synthesis

- Insulin

Major precursors of gluconeogenesis

1) Lactate = cori cycle via lactate dehydrogenase

2) Glycerol

3) Pyruvate

4) Glucogenic amino acids = alanine

5) Galactose

6) Fructose

Triacylglycerols are hydrophobic and therefore stored in an anhydrous form in specialised tissue known as _______.

Triacylglycerols are hydrophobic and therefore stored in an anhydrous form in specialised tissue known as white adipose tissue.

In what organ does fatty acid synthesis mainly occur?

liver

Glucose is stored in the body as...

Glycogen

Name two processes which lead to increased availability of glucose in the body

1. Glycogenolysis

2. Gluconeogenesis

Glycogen synthesis requires energy in a form of…

UTP and ATP

What are two enzymes with key regulatory roles in gluconeogenesis

Fructose 1,6-bisphosphatase

Phosphoenolpyruvate carboxykinase (PEPCK)

Name the important enzyme in glycogen metabolism which catalyses this reversible reaction…

Glucose 1-phosphate ⇔ Glucose-6-phosphate

Phosphoglucomutase

Name two rate-limiting enzymes which play key role in glycogen metabolism

Glycogen synthase

Glycogen phosphorylase

Glycogen is stored in granules in myocytes and hepatocytes. There are more granules in the liver but muscles stores more glycogen molecules.

True or false?

True

Glucose obtained from glycogenolysis is processed differently in liver and muscle because cells of one of these tissues do not have this enzyme...

Muscle does not have glucose-6-phosphatase

Glycerol is hydrophobic and fatty acid is hydrophilic

True or false?

False

Precursors for gluconeogenesis

Lactate

Glucogenic amino acids (mainly alanine)

Glycerol

Galactose and Fructose

Insulin inhibits gluconeogenesis through inhibition of the amount and/or activity of PEPCK and fructose 1,6-bisphosphatase

True or false?

True

Name enzyme playing important role in the regulation of the fatty acid synthesis

Acetyl-CoA carboxylase

The lipid which may accumulate in the liver is...

Triglyceride

Fatty acids travel complexed with ___ to muscle and other tissues

Fatty acids travel complexed with albumin to muscle and other tissues

What are the names of the hormones which influence hormone-sensitive lipase (HSL) and adipose triacylglycerol lipase (ATGL)?

Hormones that ACTIVATE HSL and ATGL (lipolysis)

- Glucagon

- Adrenaline

Hormones which INHIBIT HSL and ATGL (lipolysis)

Insulin = INHIBITS HSL and ATGL

Where does fatty acid synthesis occur?

Liver

Name of the process where fatty acids are catabolised?

Beta-oxidation

Triacylglycerols are hydrophobic and are stored in their anhydrous form in specialised tissues known as ____ tissue

Triacylglycerols are hydrophobic and are stored in their anhydrous form in specialised tissues known as white adipose tissue

What are the major precursors of gluconeogenesis?

Lactate

Glycerol

Pyruvate

Glucogenic amino acids such as alanine

Galactose

Fructose

Give an example of a disorder which arises from excess glycogen storage (excess glycogenesis)

Von Gierke disease

Glucose-6-phosphatase deficiency in liver

Give an example of a disorder which arises from insufficient glycogen degradation

McArdle disease

Glycogen phosphorylase enzyme deficiency in muscle

What are the "rate-limiting" enzymes involved in glycogen metabolism?

Glycogen synthesis = glycogen synthase

Glycogen degradation = glycogen phosphorylase

Which enzyme is lacking in muscle that leads to substrate entering into glycolysis as free glucose is not readily produced?

Glucose-6-phosphatase lacking in the muscle

Major energy sources in a 70kg man

Hypoglycaemia symptoms and plasma levels (mmol/L)

At what blood glucose plasma level (mmol/L) does hypoglycaemia lead to brain damage and death?

0.6 mmol/L

Symptoms of hypoglycaemia

Confusion, weakness, nausea, muscle cramping

Major difference between glycogen metabolism between liver and muscle

In the liver =

Glucose-6-phosphatase enzyme present

In the muscle =

LACK of glucose-6-phosphatase enzyme means that glucose-6-phosphate is not turned into free glucose. Instead, glucose-6-phosphate enters glycolysis to produce ATP instead

Compare glycogen metabolism in liver and muscle

Glucagon has ___ effect on metabolism of glycogen in the muscle

NO

Rate-limiting enzymes for glycogenesis and glycogenolysis (glycogen metabolism)?

Name two Glycogen Storage Diseases (GSDs)

Von Gierke disease

McArdle disease

Von Gierke Disease (GSD)

Deficiency in liver glucose-6-phosphatase enzyme

McArdle Disease (GSD)

Deficiency in muscle glycogen phosphorylase enzyme

There are over ___ types of GSD

15

When does gluconeogenesis occur?

During 8-10 hours of fasting (liver glycogen stores are depleted at this point via glycogenolysis) and more glucose is now required

Where does gluconeogenesis occur?

Liver and kidney cortex (cytosol)

What two key enzymes regulate gluconeogenesis?

Phosphoenolpyruvate carboxykinase (PEPCK)

Fructose 1,6-bisphosphatase

In what situations does gluconeogenesis occur?

- Starvation/fasting

- Prolonged exercise

- Stress (fight or flight)

What three hormones increase activity of enzymes (below) that regulate gluconeogenesis?

Phosphoenolpyruvate carboxykinase (PEPCK)

Fructose 1,6-bisphosphatase

- Glucagon

- Cortisol

- Adrenaline

What hormone decreases the activity of enzymes (below) that regulate gluconeogenesis?

Phosphoenolpyruvate carboxykinase (PEPCK)

Fructose 1,6-bisphosphatase

Insulin

TGs is a highly ___ energy store

efficient

Are TGs hydrophobic or hydrophilic?

hydrophobic

Triglyceride utilisation occurs during...

- Exercise

- Stress

- Starvation

- Pregnancy

The energy content of triglycerides per gram is ___ that of carbohydrate or proteins

twice

Fat mobilisation is called

Lipolysis

What enzymes regulate fat mobilisation (lipolysis) in adipose tissue?

Hormone Sensitive Lipase (HSL)

Adipose TAG Lipase (ATGL)

Hormones that stimulate LIPOLYSIS enzymes HSL + ATGL by phosphorylating them?

Glucagon

Adrenaline

leads to phosphorylation and activation of HSL/ATGL

Hormones that inhibit LIPOLYSIS enzymes HSL + ATGL by de-phosphorylating them?

Insulin

leads to de-phosphorylation and inhibition of HSL/ATGL

Free fatty acids travel complexed to ___ to muscle and other tissues where they undergo B-oxidation

albumin

Glycerol travels to ___ and is utilised in gluconeogenesis

liver

The key regulatory enzyme in fatty acid synthesis in the liver

Acetyl-CoA carboxylase

Insulin and ___ increase the activity of Acetyl-CoA carboxylase (fatty acid synthesis regulating enzyme)

Citrate

Glucagon and ___ and AMP decrease the activity of Acetyl-CoA carboxylase (fatty acid synthesis regulating enzyme)

Adrenaline

Acetyl-CoA carboxylase (key regulator) produces ___ from acetyl-CoA in fatty acid synthesis

malonyl-CoA

Fatty acid synthase complex builds fatty acids by the sequential addition of 2 carbon units provided by ___ in fatty acid synthesis

malonyl-CoA

AMPK

AMP-activated protein kinase

What is AMPK activated by?

AMP

What tissues is AMPK expressed in?

liver, sketal muscle

What does AMPK do?

1. Glucose uptake & glycolysis

2. Fatty acid oxidation

3. Decreases cholesterol synthesis

The average adult has ~30 billion fat cells weighing ___kg

15kg

White adipocytes can increase in size about ___ times during weight gain before dividing and increasing total number of fat cells

four

What enzyme can be found in small intestine that facilitates TG metabolism?

Pancreatic lipase

Lipoprotein lipase

an enzyme that sits on the outside of cells and breaks apart triglycerides (lipolysis), so that their fatty acids can be removed and taken up by the cell

Fatty acids do not easily pass the ___ barrier

blood-brain

Why is more glycogen stored in the muscles rather than liver?

In muscle =

- Glycogen stored both intra-cellularly and inter-cellularly