Download Proseminar 3: Questions and Answers

Student Questions and Answers December 3, 2002
Q 1. What could be the reason why the blood-brain barrier also exists for long chain fatty
acids? Why should or could neurons not metabolise them? (Additional question by another
student) Can ganglia take up and utilise fatty acids from the blood?
Answer: FK: In fact, free fatty acids are taken up by the brain (so-called lipid-mediated
transport), but this is not sufficient for complete energy supply. So the question is, why
there is no specific carrier or receptor to pass the two membranes of capillary endothelial
cells, as they exist for e.g. glucose, amino acids, choline, purine bases, nucleosides,
hormones, and so on. The absence of such a carrier for free fatty acids certainly does not
mean that massive uptake and β-oxidation of fatty acids could do any harm to neurons,
so this might appear to be a major flaw of animal evolution. However, a carrier could be
hardly so specific not to transport also other lipophilic substances, including toxic ones,
and therefore it turned out to be better to avoid it.
The blood brain barrier should also exist around ganglia belonging to the CNS (like
basal ganglia), whereas ganglia of the peripheral nervous system should be able to utilise
fatty acids as energy source.
Q 2. Does the heart muscle use fatty acids more excessively than glucose because of their
higher energy contents (it has to do the hardest work of all muscles)?
Answer: FK: Cardiac muscle in many ways is similar to striated skeletal muscles, but
has also several unique features. It has a much richer supply of mitochondria than
skeletal muscle, has little glycogen and a very limited anaerobic capacity. The heart can
use a variety of substrates to oxidatively regenerate ATP depending upon availability. In
the postabsorptive state, the heart utilises fatty acids (60-70%) and carbohydrates
(~30%). After a high carbohydrate meal the heart can adapt to utilise carbohydrates
(glucose) almost exclusively. Lactate can be used in place of glucose, and becomes
important during exercise. The heart can also utilise amino acids and ketones instead of
fatty acids. Ketone bodies are always consumed to some degree, which can be rather
high under certain conditions (diabetic ketoacidosis).
Q 3. What happens to HDL in the liver?
Answer: FK: After uptake (via the apoB,E-receptor, which is the “classical” LDL
receptor, or via SR-BI, the scavenger receptor BI), the particle is targeted to lysosomes
for degradation. Some of its components (cholesterol esters, triglycerides) may be
packed into VLDL and re-enter circulation, while part of its cholesterol load will be
oxidised to bile acids.
Q 4. Is it the foam cells that cause heart attacks by closing the capillaries, or is it just LDL?
Answer: FK: Atherosclerosis, the leading cause of heart attacks and stroke, affects large
and medium-sized arteries (occlusion of capillaries probably is a very frequent incident
and only affects a small number of cells). It is a disease of the arterial intima leading to the
formation of fibrous (atheromatous) plaques and to stenosis/ occlusion of the lumen. It
involves deposits of fatty substances, cholesterol , cellular waste products, calcium and
fibrin, as well as the proliferation of smooth muscle cells. The aetiology of atherosclerosis
is a very complex and still heavily disputed matter. In many, but not all hypothesis
lipoproteins play an important role. Excess LDL in the circulation can be trapped within
the artery wall, accumulate there, and eventually they become oxidised. These "modified"
lipoproteins are rapidly taken up by smooth muscle cells, they act pro-inflammatory, and
attract monocytes, finally giving rise to the formation of foam cells. Each of these
processes disturbs the critical balance of interactions between cells (endothelial cells,
smooth muscle cells, blood cells, blood platelets) and proteins (cytokines, blood clotting
factors), leading to on-going damage to the endothelial wall and, eventually, to clot
formation.
Q 5. How is cholesterol finally degraded (it could not be circulating in the body for ever)?
Answer: FK: There is no degradation, but cholesterol is metabolised to steroids
(quantitatively insignificant) and bile acids. Most of the bile acids and salts secreted into
the intestine (>90%) are re-absorbed and cycled back to the liver (enterohepatic circle),
but 5 to 10% are excreted, virtually the only way to get rid of the carbon backbone of
cholesterol!
Q 6. Why is there only a protein storage in muscle cells (that should not be used up), if it is
essential for survival in times of starvation?
Answer: FK: There may be several reasons: a) Both synthesis and degradation of amino
acids and proteins are much more “expensive” than gluconeogenesis/glycolysis or fatty
acid synthesis/degradation; b) unlike the other systems proteins are formed from 20
different building blocks, so you need many more enzymes for formation and degradation,
what makes it slower and more difficult to regulate; c) amino acid degradation gives rise
to different products, some of them are harmful and have to be removed; d) all proteins
contain a lot of solvent, so they energy stored per unit volume is even less favourable than
with glycogen/starch; e) major parts of proteins are not directly accessible from the
surface, so the degradation would be much slower than that of e.g. the highly branched
glycogen;
Q 7. Is β-hydroxybutyrate also synthesised and used in times of surplus (when the body will
store energy)?
Answer: FK: To a limited degree ketone bodies are formed even in times of sufficient
supply with glucose (“normal” plasma levels for all 3 compounds together are below 0.6
mM, values above 1 mM are an indication of an abnormal metabolic situation, and >1.5
mM ketoacidosis will be observed; in untreated severe diabetes up to 5 mM can occur).
Q 8. Directly after starvation, how long does it take to rebuild the used up muscle protein &
glycogen stores?
Answer: FK: The glycogen stores usually are re-filled within 1 or 2 days. Muscle
protein can only be formed as component of muscle cells, and thus takes much longer
(weeks rather than days).
Q 9. Isn´t the presence of certain ketone bodies (i.e. acetone, acetoacetate) harmful for the
body in times of starvation?
Answer: FK: (see also above, Q 7) Acetoacetate and β-hydroxybutyrate are moderately
strong acids. If present in concentrations above 1.5 to 2 mM, their acidity can no longer
be buffered by the buffer systems present in blood, and thus metabolic acidosis (pH <
7.37) will develop. This state will lead to hyperventilation (to breath out more CO2),
and, most significantly, to hyperkaliaemia. The latter condition can lead to cardiac
arrhythmia, shock and even coma. Severe acidosis with pH <6.8 cannot be survived
without emergency treatment.
Q 10. Can you give details about how the biosynthesis of ketone bodies is activated?
Answer: FK: Ketogenesis is indirectly controlled by insulin and glucagon. In fasting
conditions insulin is low and glucagon is high; in the liver, glycolysis will be downregulated, and gluconeogenesis is turned on; at the same time lipolysis in the adipose
tissue is triggered, so free fatty acids are massively released. The situation in the liver
cells then simply reflects substrate-level regulation (i.e. control by substrate
availability): The 2 possible fates of free fatty acids in the liver are: synthesis of TAG or
β-oxidation. Under conditions of gluconeogenesis, glycerol-3-phosphate is not available
for TAG-synthesis; additionally, free fatty acids inhibit acetyl CoA carboxylase and
thus directly promote fatty acid β-oxidation (malonyl-CoA strongly inhibits carnitine
acyltransferase I). At the same time gluconeogenesis is turned on in the liver, so the
TCA-cycle will come to a stop due to oxaloacetate depletion. Acetyl-CoA will
accumulate and HMG-CoA will be formed at high rates.
Q 11. Have animals with long starvation periods (e.g. lions) adopted other strategies to
overcome these starvation periods? Do they only sacrifice muscle proteins for
gluconeogenesis? They need a huge amount of glucose when hunting the next prey and not
every hunt is successful. The brain doesn´t need that much glucose and they can recycle
lactate to glucose, still it is a dangerous situation.
Answer: FK: I think there is no principal difference between the situation in man and
different animals during starvation. Animals may benefit from their significantly lower
relative brain mass, therefore the level of gluconeogenesis they have to maintain may be
also considerably lower than in man. This could mean less heavy loss of skeletal
muscles. Additionally, many species can better adapt to starvation than we can, mainly
by reducing the over-all metabolic rate, shrinking of various organs, and so on.
Q 12. Is the biosynthesis of proinsulin regulated or are always sufficient amounts available?
Answer: FK: The synthesis of proinsulin in the ß-cell is regulated at the translational
level. By a still unknown mechanism the translation of preproinsulin mRNA is up to 30fold increased by high glucose levels. This enables the ß-cell to rapidly replenish insulin
stores depleted by glucose-induced insulin release.
Q 13. What fraction of the total muscle protein can be degraded without being harmful?
Answer: FK: I really can´t tell, but if you consider the massive weight losses
experienced after long-standing malnutrition that can be survived, obviously a major
fraction of “normal” muscle body mass can be spent without immediate danger of life.