Metabolism I: Overview

Question 1

Nutrition

Answer 1

“The scientific study of the sum of the processes concerned with the growth, maintenance and repair of the living body.”

Nutrition is the process by which we acquire the building blocks of physiological function

Question 2

Nutrients

Answer 2

Components of food which have recognisable functions in the body

Question 3

Essential Nutrients

Answer 3

: Cannot be made by the body (Eg Water!!!).
Minerals – iron, calcium, magnesium etc
Vitamins – A, B, C, D, E, K
Amino acids – Leu, Ile, Val, Lys, Met, Thr, Phe, Trp
Fatty acids – omega 3, 6

Question 4

Conditionally Essential Nutrients

Answer 4

Body unable to synthesise enough to meet demand (Eg Pathology-induced deficiency).
Amino acids – Arg, His

Question 5

Glycaemic Index (GI)

Answer 5

– how quickly a carbohydrate containing food causes an increase in blood glucose
The chemical structure of a food affects the way nutrients are handled in the body:

Example - an equal amount of carbohydrate as a solution of glucose or as porridge has different effects on blood glucose concentration and associated metabolic response

Nutrients do not exist in pure states, they often mixed within the food we eat.

This has significant impact on the availability of these nutrients, as the example here shows.

In order to measure the nutrient efficiency, the Glycaemic Index (GI) is used.

Question 6

High GI

Answer 6

(70+): Rapid rise in blood glucose levels, within 1 hour of consumption.
Eg; Corn syrup, white bread, cereals.

Question 7

Low GI

Answer 7

(Below 55): Longer, prolonged rise in blood glucose, within 2 hours of consumption.
Eg; Flax, nuts, pulses, grains.

Question 8

Fate of Carbohydrates & Proteins

Answer 8

Absorbed via the GI tract and transported to the liver via the hepatic portal vein.

Question 9

Fate of fats

Answer 9

Absorbed, packaged into chylomicrons and distributed via the lymphatic system.

Question 10

Three principle fates:

Answer 10

Energy Production
Storage
Conversion

Question 11

What are Carbohydrates?

Answer 11

A biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1.

They are either simple, made up of 1-2 sugars; or complex, made up of multiple sugars. This can be seen with:

Monosaccharide: Glucose
Disaccharide: Sucrose
Polysaccharide: Glycogen

Question 12

Carbohydrate Metabolism: Overview

Answer 12

A complex group:
Simple monosaccharides
Di- and oligosaccharides
Complex carbohydrates

Digestible carbohydrate ends up as glucose
Digestion in GI tract
Glucose, Galactose and Fructose absorbed
Converted to intermediates of glycolytic pathway in liver

Fate:
Energy (ATP),
Storage (glycogen)
Conversion (Fat storage, nucleotide precursors)
When carbohydrates are consumed, they are digested in the GI tract. Large polysaccharides are broken down into their simple sugars. These simple sugars are rapidly absorbed via the GI tract.

Once absorbed into the blood stream, these carbohydrates are transported to the liver, where they are further metabolized to follow a number of pathways:
Glucose can be directly released back into the blood stream to undertake energetic function elsewhere.
Excess glucose can be converted and stored in the liver as glycogen.
Glucose can undergo glycolysis and then:
Utilize the citric acid cycle to produce energy
Combine with Fatty Acids and Cholesterol to form TAG’s and or phospholipids as energy storage.
Become converted into nucleotide via alternate metabolism

Question 13

Carbohydrate Metabolism: Liver

Answer 13

Majority is either stored or converted
Main source of energy for liver is fat or amino acid oxidation

GLUT 2 (high Km) transporter displays a significantly high binding efficiency for glucose (Km) and therefore permit glucose uptake when levels are still very high.

Glucose is readily phosphorylated to G-6-Phosphate

Fate then depends on overall metabolic profile
Largely controlled by the counter-regulatory hormones insulin and glucagon
Insulin: storage (glycogen) and conversion/storage (FFA synthesis)
Shuttles G-6-P metabolism into Glycogen. Glycogen is essentially a storage process, and therefore to meet energic demands metabolism is shifted towards Glycolysis and the metabolism of lipids/fats.
Glucagon: breakdown (glycogen) and glucose release. Shuttles Glycogen metabolism into G-6-P, which in turn is metabolized into Glucose and released from the liver. Shifting metabolism towards increase release of Glucose.

Question 14

Describe the relationship between glucagon and insulin

Answer 14

Insulin is released in response to a rise in bloodstream glucose, and as a consequence pushes the Glucose within our meal into a storage state. This lowers the level of glucose in the bloodstream.

Glucagon is released in response to a drop in bloodstream glucose, and as a consequence pushes the release of glucose from its glycogen storage state.

Insulin and Glyogen balance off each other to provide reciprocal counter-regulatory control. This enables very fine control of Glucose metabolism and bioavailability, in a way like driving a car, where the accelerator and brake have countering action. To finely control your driving speed you need to balance the two.

The critical molecule in glucose metabolism is G-6-P as this molecule can either be converted to stored energy, in the form og Glycogen, or enabled to metabolised via Glycolysis. This metabolism produces the substrates for energy and synthesis of a range of biological molecules, including amino acids, lipids and nucleotides.

Question 15

Carbohydrate Metabolism: Muscle

Answer 15

e tissue represents the most active form of tissue in the body, after the nervous system.

Glucose is transported into muscle cells via the GLUT4 transporter. This transporter is more tightly regulated than the GLUT2, and doesn’t permit large influx of glucose, regardless of existing concentration.

Like the liver, this Glucose is readily phosphorylated to G-6-P, and then metabolized into either Glycogen, or pyruvate to enable glycolysis. This is regulated through the ratio of Insulin:Glucagon.

Unlike the liver, glycolysis is regulated by activity of cross-bridge cycling, as a result active muscle, utalising higher levels of ATP results in greater shuttling of G-6-P towards glycolysis to meet energetic demands. Therefore making the process more efficient and activity driven.

Linked to this, muscle fatigue is related to glycogen levels in the muscle. Muscles that display higher Glycogen levels are more resistant to fatigue.

Allosteric regulation of glycolysis is also achieved by ATP:AMP ratio from contractile activity
Effect on phosphfructokinase

Question 16

Fat Metabolism: Overview

Answer 16

Dietary fats are either used for:
Energy production (liver and muscle)
Storage (adipose tissue)
Conversion (cholesterol, bile acids, steroids)

Dietary fats are acquired from the diet, either through direct consumption of fats (animal fat, dairy) or through metabolism from food containing fat sources (nuts, flax).

Dietary fats are metabolized in the liver, where they are either stored in situ as liver lipids, oxidated to produce energy via the citric acid cycle, or converted int cholesterol, bile salts and steroids.

Question 17

Fat Metabolism: Absorption

Answer 17

Fatty acids from the diet enter circulation several hours after dietary glucose/amino acids

Why the ‘lag’?
Effect of insulin on adipose tissue more complex than dephosphorylation of target enzymes as for the regulation of glycogen storage.
May involve changes in gene expression

Question 18

Fat Metabolism: Transport

Answer 18

Free fatty acids are esterified into triglycerides and transported around the body in lipoproteins
Some free fatty acids transported in the blood bound to albumin
Chylomicrons
Produced in the intestines, transports dietary fat
Undergo peripheral catabolism (lose TAG —> FFAs for uptake in tissues) to chylomicron remnants (taken up by the liver)
VLDL
transports liver synthesised TAG (can include dietary fats or from de novo lipogenesis)
Undergo peripheral catabolism (delivers TAG to peripheral tissues) to LDL particles, these are taken-up by tissues (mediated by LDL receptor)

Question 19

Fat Metabolism: Lipoproteins

Answer 19

Dietary Lipids (fatty acids/TAG and cholesterol/cholesterol esters) are transported round the body as lipoproteins

Phospholipid monolayer allows tight packing of highly hydrophobic TAG

Surface proteins (apolipoproteins) vary between different lipoproteins:
B-48 unique to chylomicrons
B-100 LDL and HDL
Lipids are either insoluble or sparingly soluble in water which creates problems of transport and delivery. These are solved by the creation of lipoproteins - complex aggregates of lipids and protein.

The overall structure of each lipoprotein is broadly similar; they do, however, differ greatly in relative size and density.

Characteristically they comprise a monolayer of phospholipid enclosing hydrophobic material. The protein parts of the complex are bound to the lipoprotein surface, they are known as apoproteins (sometimes they are called the apolipoproteins) and they dictate the ultimate fate of the lipoprotein.

Question 20

Triacylglycerol:Cholesterol ratio determines

Answer 20

functional consequence of LDL vs HDL lipoproteins.

Question 21

HDL

Answer 21

passes through the blood stream unopposed.

Question 22

LDL

Answer 22

passes through the blood stream with tendency to stick to arteries, causing blockages.

Question 23

Fat Metabolism: Liver

Answer 23

Some fats are stored in the liver (especially when chronically elevated and following liver damage)
The principle role of the liver in processing fats is fatty acid synthesis (for storage in adipose) oxidation (for energy) or ketogenesis (conversion) to provide ketones for the brain during ‘starved’ conditions

Regulated by
Compartmentation (synthesis in cytosol vs oxidation in mitochondria)
Insulin:glucagon (fat synthesis vs. fat oxidation)
Allosteric regulation (Malonyl coA regulates transport across mitochondrial membrane)
During lipogenesis (largely from excess glucose), the livers energy demand is met by amino acid oxidation

The patterns of control of fat metabolism in liver are very similar to those of carbohydrate metabolism. Once again there is counter-regulation by insulin and glucagon/adrenaline. Points to note are:
the key role of malonyl-Co A, it blocks movement of acyl-CoA into mitochondria, the key step that separates fatty acid synthesis from fatty acid breakdown
amino acid oxidation provides energy during lipogenesis
without insulin the negative effect of malonyl- CoA on transport of acyl-CoA into mitochondria is lost and so is control of ketone body synthesis. This is the metabolic explanation for the high risk of ketoacidosis in uncontrolled diabetes due to absence of insulin (Type 1 Diabetes).

Question 24

Fat Metabolism: Adipose Tissue

Answer 24

As with carbohydrate metabolism there is some tissue specificity of lipid metabolism. However, the general features are particularly clear in adipose tissue (Frayn 3.9). Points to note are:
The key roles of the two different lipases:
LPL - lipoprotein lipase, an endothelial wall enzyme, which is activated/elevated in response to insulin and clears circulating triglyceride from plasma to the tissues. It is called ‘Clearing Factor’ Lipase in the older literature.
HSL - hormone sensitive lipase, an enzyme found within adipose cells which is suppressed in response to insulin and activated - via phosphorylation - by adrenaline
Insulin regulation of LPL and HSL is rather slow and appears to involve changes in gene expression. The slow responses appear to cater for the lag of approximately three hours between the post-prandial rise in insulin and the appearance of chylomicrons in the circulation.

Question 25

Fat Metabolism: Adipose Tissue Regulation

Answer 25

Insulin activates/elevates an enzyme on the endothelial cell layer around adipose tissue involved in fat uptake:
Lipoprotein Lipase (LPL): Hydrolyses TAGs (to FFAs) from lipoproteins allowing uptake into adipose tissue
Insulin promotes glucose uptake into adipose via GLUT4
Glucose metabolised to glycerol-3-P which is used to re-esterify the FFAs; so stored as TAG

Insulin suppresses an enzyme within adipose tissue involved in fat breakdown
Hormone-Sensitive Lipase (HSL): hydrolyses stored triglycerides to free fatty acids and glycerol which enter circulation and distribute (bound to albumin) to liver and muscle for energy
Adrenaline directly activates HSL, increasing FFA release (“fight or flight”)

Question 26

Amino Acid Metabolism: Overview

Answer 26

Important: There is no ‘store’ of amino acids
Conversion to substrate for fat synthesis or glycogen (indirect storage)
Energy in liver (especially during lipogenesis)

Conversion to a large number of different things
Protein synthesis/turnover
Hormones, nucleotides, etc.
Carbon ‘skeletons’ enter pathways of glucose and fat metabolism
NH3 excreted

Question 27

Amino Acid Metabolism: Liver

Answer 27

Amino acids can be used to derive carbon skeletons (a-keto acid) that enter other metabolic pathways
Removal of the amino group and transfer to another substrate: Transamination
Alanine + alpha keto-glutarate = Pyruvate + glutamate
Eventually used to synthesise urea (removal of waste nitrogen and excretion)
Amino acids classified as ‘essential’ or ‘non-essential’
Low protein diet reduces waste nitrogen as the liver will use carbon skeletons from carbohydrate to synthesis non-essential amino acids