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

104
Chapter | 4 Lipids and Ketones
pancreatic islet cells will release less insulin and more glucagon,
so that plasma insulin concentrations will decrease and
plasma glucagon concentrations will increase. These hormonal
changes will increase cAMP concentrations in adipose
cells, which leads to the activation of hormone-sensitive
lipase.
Through the action of hormone-sensitive lipase, triacylglycerols
are hydrolyzed with release of LCFA and glycerol.
LCFA are utilized directly by tissues for energy but
are also taken up by the liver in proportion to their plasma
concentration. During fasting, hepatic concentrations of
malonyl-CoA and methylmalonyl-CoA are relatively low,
so carnitine acyltransferase I activity is relatively high,
and LCFA-CoA are quickly converted to LCFA-carnitine,
which is translocated into the mitochondrion ( McGarry
et al ., 1977 ). Once in the mitochondrion LCFA-carnitine is
converted to LCFA-CoA again.
Following β-oxidation of ketones, some acetyl-CoA is
combusted in the citric acid cycle. However, during fasting,
gluconeogenesis is quite active in the liver, and much of
the mitochondrial oxaloacetate is used for that purpose and
is unavailable for citrate formation with acetyl-CoA; consequently,
large quantities of acetyl-CoA are shunted into
ketogenesis.
Acetoacetate and 3-hydroxybutyrate can be utilized by
most extrahepatic tissues. Because peripheral tissues can
also use LCFA, the utility of hepatic production of ketones
from LCFA was not clear originally. However, many tissues
have as great or greater capacity for utilizing plasma
ketones as for utilizing plasma LCFA. Among these tissues
are heart and kidney ( Hall, 1961 ; Little et al ., 1970 ; Owen
et al ., 1969 ; Williamson and Krebs, 1961 ). In some species,
such as the rat ( Hawkins et al ., 1971 ) and human ( Owen
et al ., 1967 ), ketones constitute a major energy source for
the brain during fasting. In some other species though, it
appears that the brain prefers glucose and utilizes only
small quantities of ketones in the fed or fasted state in the
sheep ( Jones et al ., 1975 ; Lindsay and Setchell, 1976 ; Pell
and Bergman, 1983 ), the dog ( Wiener et al ., 1971 ), and the
pig ( Tildon and Sevdalian, 1972 ). Resting skeletal muscle
utilizes ketones preferentially as a fuel during short-term
starvation ( Owen and Reichard, 1971 ); however, LCFA
are preferred during long-term starvation ( Owen and
Reichard, 1971 ) or exercise ( Hagenfeldt and Wahren,
1968a, 1968b ).
Ketones are quite soluble, require no protein carrier,
and diffuse (in their un-ionized form) or are transported
rapidly through biological membranes including the bloodbrain
barrier ( Hawkins et al ., 1971 ; Persson et al ., 1972 ).
The liver has an advantage over other tissues regarding
uptake of LCFA from plasma albumin because of its
unique sinusoidal vascular system. Therefore, the liver can
be regarded as a machine that can rapidly remove LCFA
from plasma and convert them to a form, the ketones, that
other tissues can utilize rapidly.
Because they must be bound to albumin if they are to
be nontoxic, the maximum safe plasma concentration of
LCFA is fixed by the albumin concentration. Furthermore,
in prolonged fasting, albumin concentration decreases,
which lessens the number of LCFA carriers. Generally,
LCFA concentrations do not rise above 2 mmol/l in fasting,
whereas ketone concentrations can increase to 3 to
4 mmol/l or more. Thus, ketones can have a greater concentration
gradient to allow their entry into the cell.
Although the acid nature of ketones has received much
attention in the clinical literature, less well recognized is
the toxic potential of LCFA. If LCFA are released into
the plasma in excess of hepatic uptake, albumin-binding
capacity will be exceeded ( Spector and Fletcher, 1978 ).
Unbound fatty acids may damage endothelial cells, perhaps
because of detergent action, oxidation of unsaturated
LCFA, or changes in cell metabolism ( Ramasamy et al .,
1991 ). Such damage to endothelial cells has been proposed
as a mechanism in the development of atherosclerotic
plaque ( Zilversmit, 1973 ). There is some evidence in
humans and guinea pigs that high levels of LCFA within
the heart may predispose it to arrhythmias (Cowen and
Vaughn-Williams, 1977; Oliver et al ., 1968 ). The possible
role of LCFA in causing some cases of pancreatitis was
discussed earlier.
Ketogenesis in fasting should be viewed as an evolved
mechanism with specific survival value for peripheral tissues
and not a burden that the liver is placing on the rest of
the body. It is important to remember that fasting animals
should be expected to have a degree of ketonemia, ketonuria,
and ketolactia. Thus, any disease condition which causes
anorexia will usually be accompanied by increased ketone
levels in body fluids that have no significance other than the
fact that the animal has a subnormal caloric intake.
G. Diabetic Ketosis
Although diabetes mellitus is covered in more depth elsewhere
in this book, no discussion of ketones would be
complete without a mention of this disease. Diabetes is diagnosed
more frequently in dogs and cats than other domestic
species, and the ketoacidosis that occurs can be fatally
severe and was discussed under acid-base balance above.
In experimental diabetes in dogs, plasma total ketone
concentrations are 3.2 mmol/l as compared with 0.1 mmol/l
in healthy dogs ( Balasse et al ., 1985 ). Diabetes is accompanied
by hyperglycemia, whereas most other ketotic
syndromes occurring in domestic animals are usually
accompanied by normoglycemia or hypoglycemia. The
ketonemia in diabetes is due to increased lipolysis in
adipose plus accelerated hepatic gluconeogenesis, both
brought about by a lack of insulin. Thus, there are abundant
plasma LCFA as ketogenic substrates and metabolic
conditions in the liver that favor ketone synthesis.