|Lecture Notes:: 7 December||
General discusion of fat metabolism, exercise, and fasting.
Fatty acids can be used as the major fuel for tissues such as muscle, but they cannot cross the blood-brain barrier, and thus cannot be used by the central nervous system (CNS). This becomes a major problem during starvation (fasting), particularly for organisms such as ourselves in which CNS metabolism constitute a major portion of the resting basal metabolic rate. These organism must provide glucose to the CNS to provide for metabolic needs, and thus during the initial fasting period must break down substantial amounts of muscle tissue (protein) to provide the amino acid precursors of gluconeogenesis. Obviously the organism could not survive long under such a regime. What is needed is an alternate fuel source based on fat rather than muscle. The so-called ketone bodies serve this function:
Note that only two of the ketone bodies are in fact ketones, and that acetone is an "unintentional" breakdown product resulting from the instability of acetoacetate at body temperature. Acetone is not available as fuel to any significant extent, and is thus a waste product.
CNS tissues can use ketone bodies any time, the problem is the normally very low concentrations (< 0.3 mM) compared to glucose (about 4 mM). Since the KM's for both are similar, the CNS doesn't begin to use ketone bodies in preference to glucose until their concentration exceed's the concentration of glucose in the serum.
The system becomes saturated at about 7 mM. The limiting factor in using ketone bodies then becomes the ability of the liver to synthesis them, which requires the induction of the enzymes required for acetoacetate biosynthesis. Normal glucose concentrations inhibit ketone body synthesis, thus the ketone bodies will only begin to be synthesized in high concentrations as serum glucose concentrations fall. As an example, ketone bodies might start at about 0.1 mM after an overnight fast, rise to 3 mM after a 3 day fast, and go to 7-8 mM with prolonged fasting (>24 days).
Ketogenesis occurs in the mitochondrial matrix in liver mitochondria. Fatty acids are first broken down to acetyl CoA via beta-oxidation (providing energy for liver metabolism from the reducing equivalents generated). The acetyl CoA is then used in ketogenesis:
Depending on the status of the liver, acetoacetate can now be reduced to give D-b-hydroxybutyrate, which delivers more reducing equivalents, and thus ATP equivalents, to the peripheral tissues at the expense of the liver:
The ketone bodies are water soluble and are transported across the inner mitochondrial membrane as well as across the blood-brain barrier and cell membranes. Thus they can be used as a fuel source by a variety of tissues including the CNS. They are preferred substrates for aerobic muscle and heart, thus sparing glucose when they are available.
In the peripheral tissues the ketones must be reconverted to acetyl CoA in the mitochondria:
The energy provided to the peripheral tissues from acetoacetate and for b-hydroxybutyrate are shown below:
Note the P/O ratios for the ketone bodies: Acetoacetate = 19 ATP / 8 O = 2.38; Butyrate = 21.5 ATP / 9 O = 2.39 which are higher than we calculated for palmitate (2.3), but again lower than for glucose (2.67).
These reactions can be thought of as giving the liver overall control of fat metabolism. Lower vertebrates store fat in the liver. In a sense adipose tissue can be thought of then as "extended liver" tissue metabolically. Note that the liver can adjust the amount of reducing equivalents, and thus ATP equivalents, it sends to the peripheral tissues by adjusting the amounts of acetoacetate vs. b-hydroxybutyrate it exports. Thus the percentage of the free energy distributed between the tissues is shown below:
One might think that since an unsaturated fatty acid is created during b-oxidation that unsaturated fatty acids should be handled easily by this system. However two problems occur due to the high level of specificity of the enzymes involved:
Two new enzymes are required to handle these situations, as shown in Figure 19.12 on p 574: Enoyl-CoA isomerase (isomerizes a cis-3,4-double bond to a trans-2,3-double bond), and 2,4-Dienoyl-CoA reductase (reduces the cis-4,5-double bond in the trans-2,3-cis-4,5-dienoyl-CoA derivative formed during b-oxidation). The resulting products are then broken down by the b-oxidation enzymes.
Chemically fatty acid biosynthesis is a review of of b-oxidation and pyruvate carboxylation. Want to reverse the reactions of b-oxidation. But b-oxidation is highly favorable as is, and want synthesis to also be favorable - obviously some variations in the pathways are needed.
Two reactions enable the synthesis pathway: