Download Regulation of Hepatic Triacylglycerol Synthesis and Lipoprotein

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ClinicalScience (1981) 61,129-133
EDITORIAL REVIEW
Regulation of hepatic triacylglycerol synthesis and lipoprotein
metabolism by glucocorticoids
D . N. B R I N D L E Y
Department of Biochemistry, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UX.
The excessive synthesis and storage of triacylglycerol (triglyceride) has a number of clinical
implications. It is obviously the main symptom of
obesity where excess lipid is stored in adipose
tissue. Abnormal accumulations of triacylglycerols can also be manifested as a fatty liver,
e.g. as a'result of the ingestion or inhalation of
toxic compounds and damage to the liver. These
conditions are often associated with an increase
in the rate of triacylglycerol synthesis in the liver
and are aggravated if the ability to secrete the
triacylglycerol in very-low-density lipoproteins
(VLDL) is impaired. If the increased synthesis of
triacylglycerol results in a greater secretion of
VLDL, then this implies that the flux of
cholesterol into low-density lipoprotein (LDL)
should also be increased. This is because cholesterol is secreted as part of the VLDL particle to
facilitate the transport of triacylglycerol. When
the triacylglycerol is removed from the VLDL by
the action of lipoprotein lipase (EC 3.1.1.34), the
cholesterol appears in the circulation in lowdensity lipoproteins. It therefore seems important
to understand how the body controls triacylglycerol metabolism and to identify the mechanisms by which the synthesis of triacylglycerols in
the liver becomes raised.
At present this knowledge is incomplete, but it
has become evident from animal work that the
availability of glucocorticoids is an important
factor 11, 21. Although the control of glucocorticoid metabolism in experimental animals is
probably different from that in man, nevertheless
their effects on metabolism are likely to be
Key words: atherosclerosis, diabetes, diet, ethanol,
fatty liver, fructose, glucocorticoids, insulin, lipid
metabolism, lipoprotein lipase, lipoproteins, obesity,
L-a-phosphatidate phosphohydrolase, sorbitol, stress,
'triglycerides.
Abbreviations: LDL, low-density lipoproteins;
VLDL, very-low-density lipoproteins.
9
similar. High concentrations of circulating cortisol are associated with excessive fat deposition
in Cushing's syndrome and in obesity in experimental animals 131. Most human obesity is not
associated with gross elevations of serum cortisol
concentrations, but obesity may involve an
increased sensitivity to glucocorticoid action [31.
These hormones facilitate the action of insulin in
stimulating the synthesis of fatty acids [4,5].
Their effects on the synthesis of triacylglycerols
in liver seem to be more direct and the available
evidence indicates that they stimulate the synthesis of the enzyme phosphatidate phosphohydrolase [ 1, 21. The 'microsomal and soluble
phosphatidate phosphohydrolase (Fig. 1) have a
regulatory function, particularly in enabling the
liver to synthesize increased quantities of triacylglycerol. This enzymic adaptation therefore
partly explains why injections of corticotropin or
glucocorticoids stimulate hepatic triacylglycerol
synthesis [2, 61 and produce a fatty liver [7, 81
Glucocorticoids also promote the secretion of
VLDL [9, 101.
The influence of glucocorticoids on the activity
of phosphatidate phosphohydrolase is particularly apparent in stress conditions. This
activity can increase in starvation [ l 1, 121, mildly
ketotic diabetes [ 131, severely ketotic diabetes
[ 141, hypoxia [ 151, after surgical stress including
subtotal hepatectomy [ 121, and after hydrazine
injection [16, 171. It may seem paradoxical that
the capacity of the liver to synthesize triacylglycerols should increase in conditions where the
concentrations of circulating glucagon, catecholamines and glucocorticoids increase relative to
insulin. The liver receives a large supply of fatty
acids from adipose tissue and decreases its own
synthesis of these acids. The latter event is
accompanied by a decreased concentration of
malonyl-coenzyme A (CoA), a key intermediate
in this process, which also inhibits Poxidation
0143-S221/81/OS0129-OS$Ol.S0/1 @ 1981 The Biochemical Society and the Medical Research Society
D. N.Brindley
130
ADIPOSE TISSUE
LIVER
VLDL
VLDL
Ketones
J
+ Pdhway increased
---+Pathway decreased
FIG. 1. Fatty acid metabolism in severe ketotic diabetes or severe stress. The direction of fatty
acid metabolism in severe diabetes or stress where the concentration of insulin to glucagon,
catecholamines, corticotropin and glucocorticoids is very low is shown. The enzyme activities that
are referred to are indicated by: (1) glycerophosphate acyltransferase (EC 2.3.1.15); (2) carnitine
palmitoyltransferase (EC 2.3.1.21); (3) phosphatidate L-a-phosphohydrolase (EC 3.1.3.4); (4)
lipoprotein lipase (EC 3.1.1.34).
[ 181 through its action on carnitine palmitoyltransferase. Lack of insulin has also been
reported to decrease the activity of glycerophosphate acyltransferase, particularly that in the
mitochondria1 fraction [ 191. These changes promote the partitioning of fatty acids into poxidation and ketogenesis rather than into esterification (Fig. 1). However, the supply of fatty
acids to the liver often exceeds its need for energy
production via ,&oxidation, and the excess acids
and their acyl-CoA esters are potentially toxic.
Their conversion into triacylglycerols enables
them to be stored temporarily in a safe form and
allows CoA to be regenerated. This explains why
these stress conditions are often accompanied by
a fatty liver.
The liver can also secrete this triacylglycerol
provided that lipoprotein synthesis is not
inhibited as it may be in some toxic conditions.
This VLDL secretion can increase in ketotic
diabetes [20] and, since insulin is required for the
activity of lipoprotein lipase in adipose tissue,
triacylglycerol clearance is decreased and a
hypertriglyceridaemia results (Fig. 1). The action
of insulin in increasing lipoprotein lipase activity
in adipose tissue can be potentiated by gluco-
corticoids [2 11. By contrast, the lipoprotein lipase
activity in heart appears to be maintained
primarily by glucocorticoids and insulin may
promote this action [22]. This ability of the heart
to oxidize and esterify fatty acids is also high in
keototic diabetes 1231. In this condition the liver
is supplying energy to the heart in the form of
triacylglycerols and ketones, and to the brain as
glucose and ketones. In this instance the control
of hepatic phosphatidate phosphohydrolase by
glucocorticoids appears to resemble their control
of some enzymes of gluconeogenesis.
The diurnal peak of corticosterone in rats
occurs about 4 h before the maximum food
intake 1241. This peak is probably responsible for
the increased synthesis of phosphatidate phosphohydrolase, so that its activity is greatest when
the liver increases its synthesis of fatty acids.
Nutrients such as glycerol, sorbitol, fructose and
ethanol stimulate hepatic triacylglycerol synthesis. When these are given as acute loads to
rats, they provoke a much larger glucocorticoid
response than does the equivalent load of glucose
and they do not increase insulin concentrations
[251. The effect of the former nutrients again
increases phosphatidate phosphohydrolase ac-
Glucocorticoids and lipid metabolism
tivity a few hours later [261. This stimulation by
ethanol and the accompanying increase in the
synthesis and accumulation of triacylglycerols in
the liver can be largely prevented if the rats are
adrenalectomized and then given sodium chloride
solution (150 mmol/l) to drink [25]. Alternatively,
chronic administration of the hypolipidaemic
drug, benfluorex, also diminishes the ethanolinduced increase in corticosterone, the increase in
phosphohydrolase activity and the stimulation of
triacylglycerol synthesis [27,281.
When rats were fed diets enriched with fat, the
duration of the corticosterone response to feeding
the fructose load was prolonged (111; D. N.
Brindley, J. Cooling, H. P. Glenny, S. L. Burditt
& I. S. McKechnie, unpublished work). This may
partly explain why high-fat diets exaggerate the
effects of sucrose 129, 301, sorbitol 1311 and
ethanol [32-341 in stimulating hepatic triacylglycerol synthesis and in promoting a hypertriglyceridaemia. It has also been reported that
feeding high-fat diets to rats increases their stress
reactions to cold [351, and the production of
corticosterone in response to Nembutal narcosis
and to corticotropin injection [36]. This increased
sensitivity to stress, and the high glucocorticoid
concentrations that can result, could contribute
to the hyperglycaemia and insulin resistance that
has been observed in rats fed a high proportion of
dietary fat L37-411. This condition is likely to be
accompanied by a decreased number of insulinbinding sites on adipocytes and hepatocytes 142,
431. A decreased number of insulin-binding sites
is also seen in the hepatocytes of rats with a
pituitary tumour that secretes somatotropin, prolactin and corticotropin and this is accompanied
by insulin resistance [441. Rats fed high-fat rather
than high-carbohydrate diets have high lipoprotein lipase activities in their cardiac and
skeletal muscles, whereas the activity in adipose
tissue is low ([451; N. Lawson & D. N. Brindley,
unpublished work). This alteration can also be
understood in terms of the greater production of
corticosteroids and the insulin insensitivity that
can accompany fat feeding.
The discussion so far has been concerned with
the effects of glucocorticoids on triacylglycerol
and lipoprotein metabolism particularly in
relation to the effects of insulin. Glucocorticoids
stimulate triacylglycerol synthesis, VLDL secretion and therefore the flux of cholesterol into
LDL. They may also aggravate insulin insensitivity. These actions could contribute to their
observed effects in producing hypertriglyceridaemia and hypercholesterolaemia [46-481.
Glucocorticoid concentrations in the blood are
likely to be high in stress, diabetes, after smoking
131
[49-5 11 and after consuming diets rich in sucrose
b21, fat 11, 361 and low in ascorbate [53-551.
Furthermore there are likely to be interactions
amongst these conditions. High concentrations of
glucocorticoids have been reported to cause
damage to vascular endothelial cells and to the
intima [56, 571, to retard cell growth 1581, to
decrease platelet and whole-blood clotting times
[59, 601 and they can induce hypertension [611.
There also appears to be a close correlation
between moderate and severe atherosclerosis in
human beings and high concentrations of circulating glucocorticoids [621.
Taken together these observations provide one
possible link between many of the acknowledged
risk factors associated with an increased incidence of atherosclerosis and changes in hormonal balance. This article has attempted to
review how increases in the availability of
glucocorticoids could modify the direction and
rate of triacylglycerol synthesis and lipoprotein
metabolism. It is hoped that this information may
contribute to a better understanding of the
biochemical changes that occur in complex
metabolic diseases such as fatty liver, obesity,
diabetes and atherosclerosis.
Conclusions
Glucocorticoids increase the activity and concentration of L-cc-phosphatidate phosphohydrolase
(EC 3.1.3.4) in the liver. This enzyme has an
important regulatory function and this change
facilitates the increased synthesis, accumulation
and secretion of triacylglycerols by the liver. The
increased production of very-low-density lipoprotein also means that the ultimate flux of
cholesterol into low-density lipoproteins is
increased.
If insulin concentrations are low, or if there is
insulin insensitivity, then the clearance of circulating triacylglycerol by adipose tissue decreases
and a hypertriglyceridaemia may result.
The clearance of triacylglycerols by the heart
can increase in relative terms, since its lipoprotein lipase activity is maintained by glucocorticoids rather than by insulin.
Changes in glucocorticoid status may be
significant in determining the effects on metabolism of stress, diabetes, smoking and the
consumption of diets deficient in ascorbate or
rich in sucrose, sorbitol, ethanol and fat.
It is proposed that changes in glucocorticoid
status that could occur in these conditions could
contribute to the development of fatty livers,
132
D.N . Brindley
maturity onset diabetes, obesity and atherosclerosis.
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