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

VIII. Ketogenesis and Ketosis
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possibly increased incidence of atherosclerosis was
observed in the latter.
C. Feline Fasting Hyperlipidemias
Not surprisingly, some of the same diseases that are associated
with hyperlipidemia in dogs are associated with
hyperlipidemia in domestic cats, including diabetes and
nephrotic syndrome ( Jones, 1995 ; McCullagh, 1978 ;
Watson and Barrie, 1993 ). Some cats, however, have a
well-characterized familial hyperlipidemia because of lipoprotein
lipase deficiency ( Brooks, 1989 ; Jones, 1993, 1995 ;
Jones et al ., 1983 ; Watson et al ., 1992b ; Whitney, 1992 ).
There is lipemia with hyperchylomicronemia and increases
in plasma levels of cholesterol and triacylglycerol ( Jones,
1993, 1995 ; Whitney, 1992 ). The high plasma levels of lipids
lead to deposition in tissues (xanthoma formation) in
the skin, nerve sheaths, and other locations ( Jones, 1993 ;
Whitney, 1992 ). Pressure on spinal or other nerves from
xanthomas or subsequent granulomas may lead to peripheral
neuropathy ( Jones et al ., 1986 ). The disease appears
to be autosomal recessive, and homozygotes apparently
manufacture a defective lipoprotein lipase and do not have
a defective or missing apolipoprotein C-II activator ( Peritz
et al ., 1990 ; Watson et al ., 1992b ).
D. Equine Fasting Hyperlipidemia
The phenomenon of equine hyperlipidemia was reported in
horses with maxillary myositis ( Hadlow, 1962 ) and equine
infectious anemia ( Gainer et al ., 1966 ). It is likely that the
hyperlipidemia described in these early reports was due to
anorexia, and it has been shown that fasting alone causes
hyperlipidemia in horses and that pregnancy, lactation, and
obesity accentuate the effect ( Eriksen and Simesen, 1970 ;
Schotman and Kroneman, 1969 ; Schotman and Wagenaar,
1969 ; Schotman and Wensing, 1977 ). Total plasma triacylglycerol
may increase from a normal fed value of less
than 500 mg/l to more than 2000 mg/l ( Morris et al ., 1972 ;
Naylor et al ., 1980 ) and, in severe cases, may exceed
10,000 mg/l ( Freestone et al ., 1991 ; Naylor et al ., 1980 ;
Schotman and Wensing, 1977 ). Although most horses are
susceptible to this effect of calorie deprivation, it is harmless
for the majority, and only becomes pathological for a
few. Ponies and females are more susceptible to the pathological
syndrome, which can be fatal ( Hughes et al ., 2004 ).
Survival rates are inversely proportional to plasma triacylglycerol
concentrations ( Schotman and Wagenaar, 1969 ),
and severe fatty liver and increased plasma levels of liver
enzymes have been reported ( Schotman and Wagenaar,
1969 ). Like in other mammals, fasting increases plasma
levels of LCFA in horses and ponies ( Baetz and Pearson,
1972 ; Naylor et al ., 1980 ; Watson et al ., 1992a ), and the
hyperlipidemia in horses and ponies is due to increased
VLDL levels ( Bauer, 1983 ; Morris et al ., 1972 ; Watson
et al ., 1992a ). Presumably, horse liver is removing LCFA
from plasma and reesterifying them into triacylglycerol,
which are released to the plasma as VLDL. It appears that
the liver of fasting horses has a high capacity for reesterification
of LCFA into triacylglycerol, which is exported
as VLDL. Horses do have increased plasma ketone levels
when fasting ( Rose and Sampson, 1982 ), so some of
the LCFA removed from plasma by liver are converted to
ketones, but additional LCFA are reesterified to glycerol
and are recycled to the plasma as triacylglycerol in VLDL.
The mechanism of fasting equine lipemia is uncertain;
it could be increased secretion or decreased uptake
of VLDL or a combination thereof. In one study, fasting
horses were injected with Triton WR 1339, a compound
shown to inhibit lipoprotein lipase in rats, and the rate of
increase in plasma triacylglycerol levels was observed
( Morris et al ., 1972 ) and compared with the preinjection
level of triacylglycerol. The authors claimed that the rate
of increase was not related to the level of triacylglycerol
concentration. However, only four horses were used, which
may not have been enough given the high variation in fasting
triacylglycerol levels observed among them. On close
examination of the data, it is apparent that three horses
showed a perfect rank correlation of fasting triacylglycerol
level and rate of triacylglycerol increase after Triton injection,
with the fourth being a considerable outlier to the
trend. In addition, the dose of Triton was such that all the
horses developed anemia because of intravascular hemolysis.
Thus, elucidation of the mechanism of fasting equine
lipemia will have to await additional kinetic or enzyme
studies.
There are reports of apparent therapeutic success with
intravenous glucose and oral carbohydrates ( Dunkel and
McKenzie, 2003 ; Durham, 2006 ; Hallebeek and Beynen,
2001; Mogg and Palmer, 1995 ; Watson and Love, 1994 ).
This therapy makes sense in that increasing plasma glucose
levels should lead to increased insulin and decreased
glucagon levels, which should inhibit lipolysis in adipose
which is generating plasma LCFA used for triglyceride
synthesis. In addition, the hormonal changes may stimulate
lipoprotein lipase activity. Although supplemental insulin
has been used with carbohydrate therapy, its efficacy and
safety have not been adequately evaluated, and one report
indicates that hyperlipemic horse have hyperinsulinemia as
well ( Oikawa et al ., 2006 ).
VIII. KETOGENESIS AND KETOSIS
A. Introduction
The ketones or ketone bodies, which are composed of
acetoacetic acid, 3-hydroxybutyric acid (also known as