Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 432	Biochemistry	Spring 2002
Lecture Notes:: 18 February	© R. Paselk 2002
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Metabolic Integration

Begin with a review of the Stages of Catabolism. Recall the major branch point at pyruvate and the decision point when making acetyl-CoA which is now commited to energy production or lipid biosynthesis. Note also the entry of glucose by facilitated diffusion, which is then committed to the cell by phosphorylation by Hexokinase - the net effect is an active transport, since G-6-P cannot escape the cell.

"Carbohydrate Stress" and Fasting

As an exercise in the integration of metabolic systems we can look at how the body responds to "carbohydrate stress," the situation occuring when blood glucose levels fall below the normal homeostatic level of about 5 mM. This commonly occurs during a fasting state.

Before following the development of a fasting state and its metabolic consequences, let's set some baselines by noting the potential available fuel in humans as represented by a 'typical' male, as shown in Table 1, below:

Next let's look at the normal and fasting fuel usage of various tissues in Table 2:

Tissue Fed  Fasting  used released used released Liver Glucose (stored as glycogen), Amino acids, Fatty acids Fats, Glucose Amino acids, Lactate, Fatty acids, Glycerol Glucose, Ketone bodies  Kidney  Glucose   Amino acids, Lactate, Fatty acids, Glycerol   Glucose  Intestine  Glucose, Aspartate & Glutamate, Asparagine & Glutamine Fatty acids, Amino acids other than asx & glx, Carbohydrates       Adipose  Glucose     Fatty acids, glycerol   Muscle  Glucose (some stored as glycogen), Branched chain amino acids  Lactate, Alanine & Glutamine  Fatty acids, Ketone bodies, Branched chain amino acids,  Amino acids other than branched chain, Lactate  Brain  Glucose  -  Glucose & Ketone bodies  -

For humans the brain uses about 20% of resting energy, regardless of whether its user is "vegging out" or studying like crazy. In the fed state the brain uses about 4 g/hr while the anerobic tissues (e.g. red blood cells) use about 1.5 g/hr. This is a particular problem because the brain is quite restricted in what fuels it can use, while the anerobic tissues are restricted to glucose alone.

Now we can look at what occurs in fasting. In Table 3, below, is some data on the varying concentrations of key fuels and insulin, the major metabolic regulatory hormone. Notice that glucose concentrations fall for a few days, but then stabilize at about 3.5 mM. Given that an average liver has about 100 g of glycogen, and that glucose usage in the fed state is about 9-10 g/hr an average man would run out of glucose in only ten hours if some other fuel source did not become available after feeding. In fact liver glycoigen lasts for about 24 hours. So what's going on?

Looking at fasting from 24 hours to 24 days or so, we see

• After 24 hours the liver glycogen is depleted, so glucose is supplied by a high level of gluconeogenesis from lactate (from anerobic tissues, about 39g of glucose/day, resting), glycerol (from fats in adipose, about 19g of glucose/day, resting), and amino acids (from muscle, about 60g of glucose/day after one day, resting). Since the brain needs about 100g of glucose equivalents/d and it only has the glucose from amino acids and glycerol available, the remainder must come from ketone bodies. Other tissues, such as muscle can use fatty acidsand ketone bodies, and in fact "prefer" these fuels.
• As the fast progresses the brain shifts more to ketone bodies. Thus the brain uses only16g of glucose/day after several weeks, with ketone bodies providing the remaining energy. This is critical, as a continued high use of gluconeogenesi from muscle amino acids would quickly deplete muscle to less than 50% of its initial mass and mammals generally cannot survive at less than 50% of normal muscle mass (muscle has about enough protein to provide 17 days of glucose, assuming 50 g/day).

So how are these changes initiated and controlled?

Glucose/Fatty acid contol cycle (muscle): During carbohydrate stress (liver glycogen stores are depleted, so serum [glucose] falls) the utilization of glucose by muscle falls as fatty acids are metabolized.

• Low [glucose] causes a drop in insulin, which normally inhibits fatty acid release from adipose.
• Free fatty acids are released from the adipose tissue.
• Free fatty acids are used in peripheral tissues and:
  • The acetyl-CoA/CoA-SH ratio rises as fatty acids are broken down, activating Pyruvate DH Kinase, which in turn phosphorylates Pyr DH Complex to the inactive form.
  • Fatty acid and Ketone body oxidation in the mitochondria of results in an increase in [citrate], which is transported to the cytosol by the Pyruvate-Malate Cycle.
  • Citrate potentiates the effects of ATP on PFK, reducing its activity, and in turn causing a consequent increase in [G-6-P].
  • The high [G-6-P] in turn inhibits Hexokinase, blocking further glucose use by the muscle.

Glucose/Ketone body/Fatty acid control cycle (peripheral tissues, i.e. brain, kidney, intestine): When at rest the non-muscle peripheral tissues generally consume more glucose than muscle. So how do they respond to carbohydrate stress?

• Ketone bodies controlk gulcose utilization in a manner similar to fatty acids:
  • PFK activity is decreased by increased [citrate].
  • The resultant increase in [G-6-P] inhibites Hexokinase, blockng further use of glucose.
  • The metabolism of Ketone bodies results in a rise in the acetyl-CoA/CoA-SH ratio, activating Pyruvate DH Kinase, which in turn phosphorylates Pyr DH Complex to the inactive form.
• A high concentration of 3-hydroxybutyrate effects blood fatty acid concentrations in a number of ways:
  • It reduces the rate of adipose tissue lipolysis
  • It increases the sensitivity of adipose tissue to insulin, which decreases lipolysis (appears to be quantitatively most important.
  • It stimulates insulin secretion by the pancrease.

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Last modified 20 February 2002