Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

102
Chapter | 4 Lipids and Ketones
D. Catabolism of Ketones
1 . Reduction and Oxidation
Reduction is a possibility for acetoacetate, and, of
course, the reduction product is 3-hydroxybutyrate. 3-
Hydroxybutyrate is a metabolic cul de sac because it can be
metabolized only by being reconverted to acetoacetate. In
comparison to acetoacetate, 3-hydroxybutyrate should be
viewed as a means by which the liver can export reducing
power (hydrogen) to the peripheral tissues for combustion
and energy generation there.
Both acetoacetate and 3-hydroxybutyrate can be
reduced by being converted to LCFA. This fate is more
likely to occur in mammary gland than in adipose tissue.
Plasma 3-hydroxybutyrate has been shown to be a milk fat
precursor in cows ( Palmquist et al ., 1969 ), goats ( Linzell
et al ., 1967 ), and rabbits ( Jones and Parker, 1978 ). A substantial
portion of 3-hydroxybutyrate used for milk fat synthesis
in ruminants is incorporated as a four-carbon unit
( Kinsella, 1970 ; Palmquist et al ., 1969 ).
Ultimately, the fate of most 3-hydroxybutyrate and
acetoacetate is oxidation in the peripheral tissues. Once
3-hydroxybutyrate has been oxidized to acetoacetate, the
acetoacetate is converted to acetoacetyl-CoA by the following
reaction:
acetoacetate succinyl-CoA ←⎯⎯→acetoacetyl-CoA
succinate
This reaction is catalyzed by 3-ketoacid CoA-transferase,
and viewed from the point of converting succinyl-CoA
to succinate, it effectively bypasses the succinyl-CoA synthetase
reaction of the citric acid cycle. Because the reaction
catalyzed by succinyl-CoA synthetase produces one
GTP from GDP, the 3-ketoacid CoA-transferase reaction
effectively consumes 1 mole of ATP. The reaction also
pushes succinyl-CoA toward oxaloacetate in the citric acid
cycle, and oxaloacetate will be needed to form citrate from
the acetyl-CoA derived from the acetoacetyl-CoA.
3-Ketoacid CoA-transferase is found in spleen, skeletal
muscle, brain, adipose, heart, lung, and kidney of
rodents and sheep although the activities are very low in
sheep heart and brain ( Williamson et al ., 1971 ). In general,
though, the highest activities are in the heart and kidney.
Activity of 3-ketoacid CoA-transferase is absent in liver
( Williamson et al ., 1971 ). The absence of the enzyme from
liver is logical because if there were a need for NADH for
combustion in the liver, it could be obtained directly from
acetyl-CoA in the citric acid cycle rather than shunting the
acetyl-CoA units into ketones and back again.
Acetyl-CoA is produced from acetoacetyl-CoA via the
acetoacetyl-CoA thiolase reaction, which was discussed
under ketogenesis. All tissues have thiolase, and it is in
greatest activity in heart, liver, and kidney ( Williamson
et al ., 1971 ). Heart and brain of sheep have significantly
less thiolase than in rodents. The activities of 2-ketoacid
CoA-transferase and acetoacetyl-CoA thiolase are relatively
stable in fasting, fed state, high-fat diet, and diabetes
except that in rodents, thiolase increases upon feeding
a high-fat diet ( Williamson et al ., 1971 ). In general, it
appears that the ketone utilizing capacity of the body is
relatively constant, and ketone availability controls ketone
oxidation.
For many years, acetone was viewed as a metabolic
dead end, a substance destined to be excreted in the urine
or exhaled in the breath. Although much acetone does
indeed wind up in the breath and urine, evidence has accumulated
that indicates that some acetone is metabolized
( Kalapos et al ., 1994 ; Luick et al ., 1967 ; Owen et al .,
1982 ; Vander Jagt et al ., 1992 ). Furthermore, evidence for
the catabolic pathway for acetone metabolism indicates
that it is metabolized to pyruvate, apparently via hydroxyacetone
and pyruvaldehyde ( Vander Jagt et al ., 1992 ).
Thus, by this mechanism, it is possible that small amounts
of fat can be converted to glucose.
Labeling patterns of milk glutamate carbons following
injection of 2- 14 C-acetone into cows, indicated that acetone
was metabolized via pyruvate ( Black et al ., 1972 ; Luick
et al ., 1967 ). Labeling patterns of glucose in humans
injected with radiolabeled acetone also indicate metabolism
via pyruvate ( Owen et al ., 1981 ). In rats, however,
labeling patterns of glucose following radiolabeled acetone
injection indicate that acetone can be metabolized via pyruvate
and acetate, but that the latter pathway predominates
( Kosugi et al ., 1986 ). Thus, there appear to be real species
differences in acetone metabolism. In humans, at least,
the fraction of acetone that is metabolized versus excreted
varies inversely with acetone concentration ( Owen et al .,
1982 ), so it appears that the catabolizing pathways for acetone
are not capable of handling large quantities.
2 . Renal Metabolism and Excretion
The kidney cannot synthesize ketones to any appreciable
extent ( Lynen et al ., 1958 ; Weidman and Krebs, 1969 ) but
is a voracious consumer of ketones as an energy source in
ruminants ( Kaufman and Bergman, 1971, 1974 ) and nonruminants
( Baverel et al ., 1982 ; Weidman and Krebs, 1969 ).
It is interesting though that in fasting sheep, the kidney
removes from the plasma and catabolizes both acetoacetate
and 3-hydroxybutyrate ( Kaufman and Bergman, 1974 ),
whereas in fasting humans, there is substantial removal of
3-hydroxybutyrate and a slight production of acetoacetate
( Owen et al ., 1969 ).
Ketones are freely filterable in the glomerulus. There
appears to be in humans and dogs, at least, a direct or
indirect energy-consuming tubular transport system for
acetoacetate and 3-hydroxybutyrate, which approaches
saturation at relatively low plasma concentrations of
ketones such as encountered in the fed state or a one day