1 Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts 02118; and 2 Endocrine-Metabolism Division, Department of Medicine and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755
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ABSTRACT |
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Malonyl-CoA is an allosteric inhibitor of carnitine
palmitoyltransferase (CPT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are
oxidized. In rat skeletal muscle, the formation of malonyl-CoA is
regulated acutely (in minutes) by changes in the activity of the
-isoform of acetyl-CoA carboxylase
(ACC
). This can occur by at
least two mechanisms: one involving cytosolic citrate, an allosteric
activator of ACC
and a
precursor of its substrate cytosolic acetyl-CoA, and the other
involving changes in ACC
phosphorylation. Increases in cytosolic citrate leading to an increase
in the concentration of malonyl-CoA occur when muscle is presented with
insulin and glucose, or when it is made inactive by denervation, in
keeping with a diminished need for fatty acid oxidation in these
situations. Conversely, during exercise, when the need of the muscle
cell for fatty acid oxidation is increased, decreases in the ATP/AMP
and/or creatine phosphate-to-creatine ratios activate an
isoform of an AMP-activated protein kinase (AMPK), which phosphorylates
ACC
and inhibits both its basal activity and activation by citrate. The central role of cytosolic citrate links this malonyl-CoA regulatory mechanism to the
glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme.
Lancet 1: 785-789, 1963) and to a
mechanism by which glucose might autoregulate its own use. A similar
citrate-mediated malonyl-CoA regulatory mechanism appears to exist in
other tissues, including the pancreatic
-cell, the heart, and
probably the central nervous system. It is our hypothesis that by
altering the cytosolic concentrations of LCFA-CoA and diacylglycerol,
and secondarily the activity of one or more protein kinase C isoforms,
changes in malonyl-CoA provide a link between fuel metabolism and
signal transduction in these cells. It is also our hypothesis that
dysregulation of the malonyl-CoA regulatory mechanism, if it leads to
sustained increases in the concentrations of malonyl-CoA and cytosolic
LCFA-CoA, could play a key role in the pathogenesis of insulin
resistance in muscle. That it may contribute to abnormalities
associated with the insulin resistance syndrome in other tissues and
the development of obesity has also been suggested. Studies are clearly
needed to test these hypotheses and to explore the notion that exercise
and some pharmacological agents that increase insulin sensitivity act
via effects on malonyl-CoA and/or cytosolic LCFA-CoA.
acetyl-CoA carboxylase; AMP-activated protein kinase; cytosolic citrate; glucose-fatty acid cycle; exercise; obesity; protein kinase C
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ARTICLE |
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The Malonyl-CoA Fuel-Sensing and Signaling Mechanism
In the liver, malonyl-CoA is both an intermediate in the de novo synthesis of fatty acids (135) and an allosteric inhibitor of carnitine palmitoyltransferase I (CPT I), the enzyme that regulates the rate at which long-chain fatty acyl(LCFA)-CoAs enter the mitochondria where they are oxidized (72). In contrast, in tissues such as skeletal and cardiac muscle, in which the synthesis of fatty acids de novo is minimal (6), regulation of CPT I is presumably its dominant role. The early studies of McGarry et al. (70) demonstrated that the concentration of malonyl-CoA in skeletal muscle is diminished by 80% after 48 h of starvation, in keeping with the increased need for fatty acid oxidation in the fasting state. More recently, it has become apparent that malonyl-CoA levels in muscle can also be acutely (in minutes) regulated. Thus we have found that the concentration of malonyl-CoA increases two- to sixfold within 20 min when a rat soleus muscle is incubated with glucose and insulin (Fig. 1) and within 6 h when it is made inactive as a result of denervation [i.e., in situations in which the need for fatty acid oxidation is decreased (115)]. Conversely, during exercise (139) or electrically induced contractions (29, 115), or when a muscle is incubated in a medium devoid of glucose (115) (i.e., in situations in which the need for fatty acid oxidation to generate ATP is increased), malonyl-CoA levels are diminished within seconds to minutes. This rapid response of malonyl-CoA to changes in the fuel supply or energy expenditure of the muscle cell has been referred to as the malonyl-CoA fuel-sensing and signaling mechanism (Fig. 2). In this review, we will explore how this mechanism operates and examine its relationship to other fuel-sensing mechanisms, such as those mediated by AMP-activated protein kinase (AMPK) (48) and the glucose-fatty acid cycle (96, 97). We will also examine the notion that malonyl-CoA can serve as a link between fuel metabolism and signal transduction in muscle and other tissues and that disturbances in this linkage contribute to the pathophysiology of insulin resistance and obesity. That changes in malonyl-CoA can play a pivotal role in the regulation of insulin secretion by glucose and possibly other insulin secretagogues has been reviewed elsewhere (84, 94, 152) and will be discussed briefly in Link to cellular signaling.
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Acetyl-CoA Carboxylase: Isoforms
A major factor in the regulation of malonyl-CoA levels in muscle and other tissues is acetyl-CoA carboxylase (ACC), a cytosolic enzyme that catalyzes the carboxylation of cytosolic acetyl-CoA to form malonyl-CoA (Fig. 3). Two principal isoforms of ACC have been identified, a 265-kDa protein now referred to as ACC
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Recent studies indicate that
ACC and
ACC
are the products of
distinct genes and that they have different affinities for their
substrate, cytosolic acetyl-CoA (Table 1). However, excluding a
200-amino acid sequence unique to the
NH2 terminus of
ACC
, the two isoforms show
~75% amino acid identity, and they have their functional domains in
homologous regions. Because of its predominant location in skeletal and
cardiac muscle, it has been proposed that
ACC
is involved in the
regulation of fatty acid oxidation rather than fatty acid biosynthesis
(1, 11, 45, 64, 138). It has also been suggested that the
NH2-terminal sequence of
ACC
could be responsible for
anchoring it to the mitochondrial outer membrane so as to control more
closely the concentration of malonyl-CoA in the vicinity of CPT I (45). These notions remain to be proven, however.
Until the past 2-3 yr, most of our knowledge of ACC regulation was
of the ACC isoform in liver. A
large body of work had shown that its activity is modulated acutely (in
minutes to hours) by changes in the phosphorylation state of specific
serine residues by an AMP-activated protein kinase, cAMP-dependent
protein kinase, and/or phosphatases (25, 44, 48, 57, 81, 146) (see also ACC
Regulation During Exercise and Recovery) and chronically (in hours to days) by changes in enzyme abundance due to
alterations in gene expression at the level of transcription and mRNA
stability (47, 57, 58). In keeping with these observations, hepatic ACC
activity has been shown to decrease during starvation and to increase
rapidly with refeeding (79, 81, 146), initially because of changes in
phosphorylation state and later from changes in abundance. In general,
insulin and glucose increase the activity of
ACC
by diminishing its
phosphorylation and by inducing its synthesis, and glucagon and
catecholamines have the opposite effects (47, 57, 58, 147). Other
potential regulators of ACC in liver include citrate, which is both the
major precursor of the cytosolic acetyl-CoA from which malonyl-CoA is
synthesized and an allosteric activator of ACC (2, 58) and LCFA-CoA and malonyl-CoA itself, both of which are allosteric inhibitors (1, 2, 47).
In vitro, citrate counters the inhibition of ACC caused by malonyl-CoA
and LCFA-CoA (2, 42). The physiological relevance of these effects of
citrate is uncertain, however, because its concentration in liver does
not appear to change markedly with nutritional state (124). The role of
LCFA-CoA in regulating ACC
activity in liver, in vivo, has also been questioned (2, 42, 135).
ACC isolated from muscle, like
ACC
from other tissues, is
allosterically activated by citrate and inhibited by palmitoyl-CoA (LCFA-CoA) and malonyl-CoA (131). On the other hand, in contrast to
ACC
in liver, it shows little
if any change in assayable activity (11, 26, 138, 141) or abundance as
a result of starvation or refeeding despite substantial changes in
malonyl-CoA concentration (72, 141). This has caused a number of groups to reexamine how ACC in muscle is regulated in response to nutritional and hormonal perturbations. It also initiated studies of ACC regulation during exercise and other states in which fatty acid oxidation is altered.
Cytosolic Citrate: A Signal of the Fuel Status of the Muscle Cell
and a Regulator of ACC
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Increases in the apparent concentration of cytosolic citrate, analogous
to those in skeletal muscle, have been observed in heart (41, 113),
brain (107), and the pancreatic -cell (94) in response to changes in
their fuel and hormonal milieu. They appear to require the presence of
glucose at normal or high physiological concentrations (41, 66, 102,
113) and may be enhanced when ketone bodies or free fatty acids are
also provided (41, 66, 107). An hypothetical scheme that takes into
account these observations, as well as the relevance of malate, to
explain how cytosolic citrate is regulated in skeletal muscle is
presented in Fig. 5. Key events, as
proposed by many others (20, 97, 113), include:
1) increases in the concentrations
of oxaloacetate and acetyl-CoA in the mitochondria, 2) the condensation of this
acetyl-CoA and oxaloacetate to form citrate, and
3) the efflux of citrate into the
cytosol, via the citrate transporter, in exchange for malate and
possibly other anions. Malate functions in this scheme as the
antiporter for citrate efflux from the mitochondria. In addition,
oxaloacetate, generated in the cytosol by aspartate transamination and
the ATP-citrate lyase reaction, is converted to malate to enter the
mitochondria, where it repletes and expands the pool of tricarboxylic
acid cycle intermediates (anaplerosis). Glucose is a major player in
these events. It can provide acetyl-CoA for citrate synthesis; it is the principal source of pyruvate, required for the pyruvate carboxylase reaction in the mitochondria (134) and for the deamination of aspartate
and glutamate (not shown) in the cytosol; and its metabolism in the
glycolytic pathway results in the generation of the cytosolic NADH
needed for the conversion of cytosolic oxaloacetate to malate (66, 106,
113) (Fig. 5). Similar lines of thinking have been put forth to explain
how glucose increases the concentration of citrate in the pancreatic
-cell (94, 102) and the heart (41, 113). Ketone bodies can
potentiate the effects of glucose in these settings by serving as a
source of mitochondrial acetyl-CoA; indeed, in the presence of glucose
they increase the concentration of acetyl-CoA in rat skeletal muscle to
levels well above those produced by glucose alone (104), even though
they concurrently inhibit pyruvate dehydrogenase (46). Because
acetyl-CoA is an activator of pyruvate carboxylase (148), the increase
in acetyl-CoA generation caused by ketone bodies (104) could also
increase oxaloacetate formation in the mitochondria.
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In muscle, the question of whether citrate functions principally as an
allosteric activator of ACC or a provider of the cytosolic acetyl-CoA
from which malonyl-CoA is synthesized is still unresolved. On the one
hand, we have found that incubation of muscle with hydroxycitrate, an
inhibitor of ATP-citrate lyase (Fig. 3), markedly depresses the
increase in malonyl-CoA caused by insulin and glucose, suggesting that
citrate is the major source of cytosolic acetyl-CoA (116). On the other
hand, studies with immunopurified
ACC suggest that the observed
changes in whole cell citrate, if they are reflected in cytosol, will
cause at least a 1.5- to 2-fold increase in ACC activity (134).
Furthermore, this may be an underestimate, because the magnitude of
ACC
activation by citrate is
probably blunted by its phosphorylation during tissue processing (131, 134).
Cytosolic Citrate Links the Malonyl-CoA Fuel-Sensing and Signaling Mechanism to the Glucose-Fatty Acid Cycle
The apparently central role of cytosolic citrate in the malonyl-CoA fuel-sensing and signaling mechanism links it to the glucose-fatty acid cycle concept proposed by Randle and co-workers (96-98) on the basis of studies in heart muscle. According to the glucose-fatty acid cycle concept, increases in fatty acid or ketone body oxidation elevate the concentrations of acetyl-CoA and NADH in mitochondria, leading to inhibition of glucose metabolism at pyruvate dehydrogenase and, in the presence of glucose, to increases in the mitochondrial and subsequently the cytosolic concentration of citrate (46, 66, 97). The increase in cytosolic citrate in turn restrains glycolysis at the level of phosphofructokinase. This further diminishes the use of glucose as a fuel, although it may actually increase glucose incorporation into glycogen (66, 97).The common involvement of cytosolic citrate in both the malonyl-CoA fuel-sensing system and the glucose-fatty acid cycle has led us to hypothesize that an increase in its concentration is not a unique feature of the glucose-fatty acid cycle, but rather a more general signal to the muscle cell that it has an excess of fuel for its immediate needs (116). According to the hypothesis proposed, the precise effect of such an increase in citrate will depend on the fuel(s) present in excess. When it is primarily glucose (e.g., in muscles incubated with high concentrations of glucose and insulin or in organisms infused with insulin and glucose), the increase in citrate restrains both fatty acid oxidation (via malonyl-CoA) (see also Ref. 6) and the further use of glucose itself as a fuel (Fig. 6). In other words, a glucose autoregulatory mechanism (106) accompanies the regulation of fatty acid oxidation by malonyl-CoA. In contrast, when muscle is presented with an excess of free fatty acid (FFA) (in the presence of glucose), we believe the putative glucose autoregulatory mechanism remains and may even be enhanced, but that inhibition of fatty acid oxidation by glucose will not be as marked. This is because the increase in cytosolic LCFA-CoA that accompanies an excess of FFA both allosterically inhibits ACC, thereby diminishing malonyl-CoA formation (131) (Fig. 3), and competes with malonyl-CoA for binding on CPT I (73). In keeping with this notion, perfusion of a rat heart with FFAs and glucose, although it causes an increase in citrate (97), is associated with a decrease rather than an increase in the concentration of malonyl-CoA (6). To our knowledge, a similar study has not been carried out in skeletal muscle.
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An interesting, but somewhat more complex, picture is observed when the
fuels in excess are ketone bodies. Thus we have shown that, in the
presence of glucose, the ketone bodies acetoacetate and
-hydroxybutyrate markedly inhibit the oxidation of fatty acids (10,
105), as well as glucose (10, 46, 66, 104, 105), in rat skeletal muscle
in vivo and in an isolated perfused hindquarter preparation.
Furthermore, in incubated rat soleus muscle, acetoacetate causes the
same inhibition of phosphofructokinase and stimulation of glycogen
synthesis (66) that it does in heart, and it increases the
concentrations of citrate, malate, and malonyl-CoA (66, 116) to an even
greater extent than does glucose alone. In contrast, in the absence of
glucose, or when the concentration of glucose is low, acetoacetate
produces no increase in citrate or malate, and it causes only a small
increase in malonyl-CoA (116), which could be accounted for by
cytosolic acetyl-CoA generation from acetylcarnitine (Fig. 3). These
findings suggest that acetoacetate by itself has little effect on the
cytosolic concentrations of citrate and malonyl-CoA, but that it
potentiates the effects of glucose on these metabolites. Put another
way, acetoacetate appears to allow the glucose autoregulatory and
malonyl-CoA fuel-sensing mechanisms to come into play at a lower
glycolytic rate. Whether the ketone bodies inhibit fatty acid oxidation
effectively when glucose availability is low is not known. That they
may not do so is suggested by the observation that acetoacetate does
not replace fatty acids as the major fuel of muscle in the isolated hindquarter preparation of a rat with diabetic ketoacidosis unless insulin, as well as glucose, is added to the perfusion medium (104).
Operation of the Malonyl-CoA Fuel-Sensing and Signaling Mechanism in Muscle In Vivo
As will be discussed later, the activity of an AMPK is increased when ACCOne condition in which changes in malonyl-CoA in muscle are unexplained
is the starved-fed transition. In rats starved for 48 h, we have
observed 1.5- to 2-fold increases in the concentration of malonyl-CoA
in various muscles after 3-24 h of refeeding, but modest increases
in the concentrations of citrate or malate, if any, or in the activity
of ACC (26). Possibly, during
refeeding, the activity of ACC
is increased allosterically by a decrease in the concentration of a
negative effector such as LCFA-CoA (26, 117); however, this remains to
be proven.
The existence of a malonyl-CoA fuel-sensing and signaling mechanism in humans is suggested by the observation of Bavenholm et al. (9) that the concentrations of malonyl-CoA, citrate, and malate increase concurrently in human leg muscle during a euglycemic-hyperinsulinemic clamp. In addition, whole body oxidation and presumably muscle fatty acid oxidation were markedly diminished in the subjects they evaluated. In an earlier study, Sidossis et al. (123) reported that decreases in oleate oxidation in humans undergoing a euglycemic-hyperinsulinemic clamp are accompanied by decreases in the concentration of long-chain fatty acylcarnitine in muscle, suggesting inhibition of CPT I. They attributed this to an increase in the concentration of malonyl-CoA, although malonyl-CoA itself was not measured. In toto, these reports suggest both that malonyl-CoA levels are regulated in human muscle and that, as in the rat, they play a role in the regulation of fatty acid oxidation.
Unanswered Questions About Malonyl-CoA in Skeletal Muscle
Does it regulate CPT I? Implicit in the malonyl-CoA fuel-sensing and signaling concept is the notion that changes in the concentration of malonyl-CoA in skeletal muscle regulate CPT I activity and, secondarily, fatty acid oxidation. Such a mechanism has been clearly demonstrated in liver (69, 151), where the whole cell concentration of malonyl-CoA is in the range at which it competitively inhibits purified CPT I and where alterations in malonyl-CoA concentration, in vivo, correlate closely with changes in CPT I activity and fatty acid oxidation (69, 151). Changes in the concentration of malonyl-CoA for the most part also correlate closely with changes in fatty acid oxidation in skeletal muscle. Thus, in the rat, malonyl-CoA levels are low in starvation (26, 76, 141) and during exercise (139), and they are high in the fed state (26, 141). Likewise, they are diminished and fatty acid oxidation is increased in muscles incubated with 5-aminoimidazole-4-carboxamide ribonucleoside [AICAR, an AMP analog that activates 5'-AMPK and secondarily diminishes ACC activity (74, 142)]. Still further evidence for an association is a remarkably close correlation (r = 0.95) between increases in whole body respiratory quotient and malonyl-CoA levels in muscle of 48-h-starved rats throughout the first 24 h of refeeding (26). Furthermore, these increases in malonyl-CoA were accompanied by decreases in the concentration of long-chain fatty acylcarnitine in muscle, suggesting inhibition of CPT I (26).
Despite these findings and similar observations in heart (6, 112), some questions persist about the relationship between malonyl-CoA concentration and fatty acid oxidation in skeletal muscle. One of these relates to the fact that CPT I is a different protein in skeletal muscle and liver and that the muscle isoform is more sensitive to inhibition by malonyl-CoA by two orders of magnitude (IC50 0.03 vs. 2.7 mM) (70). Because the concentration of malonyl-CoA measured in intact rat muscle is 1-4 nmol/g and in human muscle, 0.1-0.3 nmol/g (9, 89), only a small fraction of this malonyl-CoA must be accessible to CPT I for fatty acid oxidation not to be suppressed at all times (72). As recently suggested by McGarry and Brown (69) "this paradox might be explained if the cytosol contains a binding protein that sequesters malonyl CoA when the tissue has a need for fatty acid oxidation" or if "a significant fraction of the malonyl CoA... measured in heart and skeletal muscle is present within the mitochondria (possibly produced there by the action of propionyl CoA carboxylase on acetyl CoA). In the latter event, it would not be accessible to CPT I, which is located in the outer mitochondrial membrane." Whatever the explanation, it is likely that the effective concentration of malonyl-CoA that interacts with CPT I in muscle is both lower than that measured in whole tissue and subject to greater variation. If so, an intriguing possibility is that the regulation of such a "microenvironment" of CPT I is related to the unique NH2-terminal region of ACCAre there other intracellular determinants of fatty acid oxidation?
Changes in the concentration of malonyl-CoA are almost certainly not
the sole intracellular determinant of the rate at which muscle oxidizes
fatty acids. One circumstance in which malonyl-CoA does not appear to
play a pivotal role is during intermediate periods of starvation, when
ketone bodies are the major fuel of the muscle cell (105). Ketone body
utilization accounts for at least 60-80% of the
O2 consumed by muscle in humans
after 3-7 days (38, 90) and in the rat after 48 h of starvation
(104), despite high plasma FFA levels. In the rat, this occurs even
though the concentration of malonyl-CoA in muscle is low (26, 76, 141).
Presumably acetoacetate and -hydroxybutyrate are inhibiting fatty
acid oxidation in this situation by a mechanism not involving malonyl-CoA (e.g., by competition for CoA in the mitochondria). The
possibility that compartmentation of malonyl-CoA (see preceding section) masked an increase in its concentration in the cytosol cannot
be ruled out, however.
How is malonyl-CoA utilized in muscle? The fact that the concentration of malonyl-CoA decreases by 50% within 20 min when an incubated soleus muscle is deprived of glucose (115), and even more rapidly during contraction (134), suggests that malonyl-CoA utilization, as well as synthesis, is regulated. In liver and other lipogenic tissues, the principal determinant of malonyl-CoA use is thought to be the rate of fatty acid synthesis, a process governed by the activity of fatty acid synthase (2). In nonlipogenic tissues, such as heart, fatty acid synthase activity is negligible, although not absent (6). Heart, like liver, contains a malonyl-CoA decarboxylase (61), a fatty acid elongation system (6), and possibly other enzymes that could utilize malonyl-CoA (1); however, essentially nothing is known about their role in skeletal muscle (Fig. 3). Adding to the perplexity is the fact that malonyl-CoA decarboxylase in all tissues studied, except the europygial gland of the goose, is predominantly a mitochondrial enzyme (53). Thus its role in degrading malonyl-CoA produced by ACC, which is thought to be a cytosolic or at least an extramitochondrial enzyme, is unclear. One possibility is that malonyl-CoA generated in the cytosol is transported into the mitochondria; however, to date such an event has not been described.
Malonyl-CoA, LCFA-CoA, and Insulin Resistance
Association of high concentrations of malonyl-CoA with insulin
resistance in skeletal muscle.
A number of lines of evidence suggest an association between sustained
elevations in the concentration of malonyl-CoA and insulin resistance
(i.e., a less than normal biological effect of insulin) in skeletal
muscle. Thus we have found high levels of malonyl-CoA in muscle of a
wide variety of hyperglycemic and/or hyperinsulinemic rodents,
including the fa/fa rat (117), the KKAy mouse (114), rats infused
with glucose for 1-4 days (63), and the Goto-Kakizaki (GK) rat
(109, and T. G. Kurowski, unpublished observations), as well as in
muscle of normoinsulinemic-normoglycemic rats made insulin resistant by
denervation (115) (Table 2). A high
concentration of malonyl-CoA, by restraining the entrance of LCFA-CoA
into the mitochondria, would in turn increase both their concentration
in the cytosol and incorporation into glycerolipids (Fig.
7). Thus a high level of malonyl-CoA could
contribute to the elevated concentrations of triglyceride,
diacylglycerol, and LCFA-CoA observed in many insulin-resistant muscles
(91) (Table 2). The effect of decreasing the concentration of
malonyl-CoA on the concentrations of these lipid metabolites and on
insulin resistance has received less attention, although prior
exercise, which acutely decreases the concentration of malonyl-CoA in
skeletal muscle (see
ACC
Regulation During Exercise and
Recovery), has been shown to increase the sensitivity
and responsiveness of glucose transport and glycogen synthesis to
stimulation by insulin (86, 101). Likewise, decreases in the
concentration of malonyl-CoA have been observed in muscle and liver of
the KKAy mouse (114), and
decreases of triglycerides and diacylglycerol have been demonstrated in
muscle of fat-fed rats (87) when their insulin resistance is diminished
by treatment with thiazolidinediones.
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The LCFA-CoA/malonyl-CoA hypothesis.
A scheme that both links malonyl-CoA to insulin resistance in skeletal
muscle and accounts for the occasional presence of insulin resistance
when malonyl-CoA levels are not increased (108, 114) is depicted in
Fig. 8. The common denominator in the
proposed model is an increase in the cytosolic concentration of
LCFA-CoA, which can result from increases in malonyl-CoA or FFA, and
especially the two in combination. Increases in LCFA-CoA could
secondarily lead to increases in the concentration of diacylglycerol
(DAG), phosphatidic acid, and triglycerides and activation of one or more protein kinase C (PKC) isoforms (Table 2). The PKC isoforms are
attractive candidates for study, because changes in the distribution and/or activity of PKC,
and in some instances PKC
, have
been demonstrated in insulin-resistant muscles by a number of
investigators (5, 28, 63, 111, 120, 121). In addition, PKCs have been
shown to phosphorylate and inhibit both the insulin receptor (80, 92)
and glycogen synthase (13), and their activation at least in fat cells
leads to inhibition of PKB/Akt (8), a distal component of the
insulin-signaling cascade that appears to be involved in the regulation
of glucose transport and glycogen synthesis (136). Other proposed
mechanisms by which increases in LCFA-CoA could lead to insulin
resistance include alterations in protein acylation, membrane fluidity
(94, 108, 114), gene transcription and hexosamine synthesis (49), and direct inhibition of enzymes such as glycogen synthase (144). Increased
hexosamine synthesis has been linked to the insulin resistance in
skeletal muscle and adipose tissue caused by hyperglycemia (68). It has
recently been shown that hexosamine accumulation observed in rat muscle
during a euglycemic-hyperinsulinemic clamp is increased further, as is
insulin resistance, if the rat is also infused with lipid (49). Even in
the absence of extra lipid, incubation with glucosamine has been
demonstrated to alter PKC distribution in rat adipocytes (32). Whether
PKC is the common link in the insulin resistance attributed to the
hexosamine and LCFA-CoA/malonyl-CoA mechanisms will clearly be the
object of considerable investigation.
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The LCFA-CoA/malonyl-CoA hypothesis, the glucose-fatty acid cycle, and insulin resistance in humans. Since the first description of the glucose-fatty acid cycle in the perfused rat heart, the notion that increases in plasma FFA, and secondary to this of fatty acid oxidation, lead to insulin resistance in skeletal muscle and other tissues has been both widely accepted and disputed (37, 43, 97, 98, 110). Recently, the role of this mechanism in causing insulin resistance has been examined in humans undergoing a euglycemic-hyperinsulinemic clamp, in which the usual decrease in plasma FFA was prevented by coinfusing a fat emulsion or a fat emulsion plus heparin (14, 15, 55). As reviewed by Boden and Jadal (15), the results clearly show that infusion of fat inhibits glucose oxidation within 1-2 h by inhibiting pyruvate dehydrogenase, as originally proposed (97). They also show that the fat infusion inhibits glucose utilization, but only after 4 h, suggesting that this effect is due to a mechanism that is not acutely related to fatty acid oxidation (15, 55). In support of this contention, impaired glucose incorporation into glycogen rather than diminished glycolysis [which should occur if increased fatty acid oxidation were the primary event (97)] accounted for most of the decrease in glucose utilization; indeed, in some studies (55) no decrease in muscle glycolysis was observed. Also, in the one investigation in which it was measured (15), no increase in muscle citrate was observed. Thus the classic glucose-fatty acid cycle mechanism, in which increased fatty acid oxidation inhibits glucose utilization by raising the cytosolic concentration of citrate and secondarily inhibiting glycolysis and glucose phosphorylation (98), does not appear to explain these findings. A noteworthy aspect of these studies in humans was that the experimental subjects were all undergoing a euglycemic clamp. This would raise the concentration of malonyl-CoA in muscle (9), leading to a decrease in the entrance of cytosolic LCFA-CoA into the mitochondria and an increase in its incorporation into glycerolipids (Fig. 7). Thus, when plasma FFA levels are concurrently increased, changes in DAG-PKC signaling would be more likely to occur (Figs. 7 and 8). As mentioned in The LCFA-CoA/malonyl-CoA hypothesis, such a mechanism has been put forth to explain insulin resistance in muscle in a variety of rodents.
Finally, increases in plasma FFA, induced by an intralipid infusion and heparin in a rat undergoing a euglycemic-hyperinsulinemic clamp, have also been shown to inhibit glucose utilization by skeletal muscle. In contrast to the findings in humans, glucose incorporation into glycogen was enhanced and glycolysis was inhibited, suggesting operation of a glucose-fatty acid cycle type of mechanism (56). Whether the apparently disparate results in humans and rats reflect species variability or differences in experimental design remains to be determined.Fuel Sensing by Cellular Stresses: the 5'-AMPK
As pointed out in Acetyl-CoA Carboxylase: Isoforms, nutritional and hormonal regulation of ACC
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Although ACC is a multisite phosphorylated enzyme, it is clear that the
major regulatory protein kinase that acts on it is the AMPK. AMPK
phosphorylates ACC on at least
three serine residues (S79, S1200, S1215), all of which are preserved
on ACC
(1, 44, 47, 48). As will
also be discussed in
ACC
Regulation During Exercise and
Recovery, phosphorylation is associated with marked
enzyme inactivation and decreased sensitivity to the allosteric
activator citrate (47, 48, 134). ACC isozymes in liver, adipose tissue,
skeletal muscle, and heart are all identically affected after
phosphorylation by AMPK (44, 47, 48, 61, 81, 134, 140). These changes
in enzyme phosphorylation and activity are readily reversed on
incubation with protein phosphatases; protein phosphatases 2A and 2C
are the predominant phosphatases active on ACC in most tissues (47,
48).
AMPK was described originally as a protein kinase that phosphorylates
and inhibits hydroxymethyl glutaryl-CoA reductase (47). It derives its
name from the fact that it is potently activated by AMP
(Michaelis-Menten constant
Ka = 20 µM). As
first shown by Hardie (47), alterations in AMP levels in intact cells
and tissues are associated with reciprocal changes in AMPK and ACC activities. AMPK is also activated by phosphorylation of specific serine/threonine residues by an "upstream" kinase/kinase (AMPKK) (48). Increases in AMP concentration have been shown to activate AMPK
in four distinct ways. These include direct allosteric regulation of
AMPK, direct activation of AMPKK, enhancement of AMPK phosphorylation by AMPKK, and diminution of the susceptibility of AMPK to
dephosphorylation by phosphatases (48). These multiple mechanisms
permit substantial signal amplification with high sensitivity, even
when changes in cellular AMP (or in the ratio AMP/ATP) are small. It is
logical to assume that they come into play when ATP is depleted in
response to substrate limitation (in some tissues), changes in
oxidative phosphorylation, ischemia, hypoxia, and many other
physiological and pathophysiological circumstances. In these
conditions, AMP formation is increased as a result of the adenylate
kinase reaction in which ATP and AMP are formed from two molecules of
ADP in an effort to maintain ATP concentration. Thus, even with minimal reductions in cellular ATP, changes in the concentration of AMP can
cause AMPK to become a sensor and/or effector of
the cell's energy state. Evidence has recently been presented that
changes in the creatine phosphate-to-creatine ratio (CrP/Cr) in muscle may supply a second tier of allosteric regulation of AMPK (93) (see
ACC
Regulation During Exercise and Recovery).
Purification, partial amino acid sequencing, and cDNA cloning have
shown that AMPK consists of three subunits: the catalytic subunit and two noncatalytic subunits
and
(31, 39, 40, 48, 75, 77, 78,
125-127). The catalytic
-subunit of AMPK is a member of the
SNF1 protein kinase subfamily that includes protein kinases of yeast,
plants, C. elegans, and humans (39, 48, 78, 125-127). The structural relationship of
AMPK
to the S. cerevisiae protein kinase SNF1 is especially
intriguing, because the latter is directly involved in fuel sensing.
Thus it regulates the induction of invertase (SUC2) under conditions of
nutritional stress (carbon catabolite derepression), as well as other
glucose-responsive genes in yeast (39, 48, 78, 125). Recent cloning
data indicate that, for each of the AMPK subunits, there exists at
least one other mammalian protein isoform. For example, two different
catalytic subunits,
-1 and
-2, that are the products of unique
genes, have been identified (126). The AMPK
-subunits (
1,
2,
3) are homologous to the yeast protein Snf4p, and the AMPK
-subunits (
1,
2) are related to the yeast Sip1p/Sip2p/Gal83p
family of proteins (39). Genetic evidence suggests that both of these
yeast protein families positively regulate SNF1 protein kinase activity
(149). The expression of all three subunits and the formation of an
enzyme heterotrimer are necessary for optimal catalytic activity (31).
Taken together, these observations indicate a high evolutionary
conservation of this fuel-sensing protein kinase family that responds
to nutrient signals in the absence of hormones. AMPK subunits (protein
or mRNA) have been detected in virtually all mammalian tissues examined to date (39, 40, 48, 75, 126). Rat skeletal and heart muscles express
the highest concentrations of both catalytic
-isoforms (75, 126).
Overall, the AMPK-ACC link appears to serve a sensor-effector function
to alert the cell to changes in adenylate charge. As currently
understood in skeletal and cardiac muscle (see
ACC Regulation During Exercise and Recovery), these
adjustments are primarily compensatory, serving to alert the cell to
diminished ATP and then to increase ATP generation through changes in
fuel utilization or availability (Fig. 9). In liver, activation of AMPK
leads not only to a compensatory increase in fatty acid oxidation through a malonyl-CoA-dependent mechanism, but also to diminutions in
the rates of fatty acid and sterol biosynthesis. Thus it decreases flux
through two pathways that use large amounts of ATP and are not
necessary for immediate cell survival or function. It seems possible
that AMPK might regulate similar adaptive events in muscle (e.g.,
diminished protein synthesis) during periods of hypoxia, ischemia, or exercise. It is also possible that AMPK
activation, if sustained, in muscle (cardiac or skeletal) during
hypoxia, ischemia, or exercise might be maladaptive, resulting
in muscle dysfunction.
ACC Regulation
During Exercise and Recovery
Role of AMPK.
As initially demonstrated by Winder et al. (139), the concentration of
malonyl-CoA diminishes in rat skeletal muscle during exercise. Studies
in which muscle has been made to contract by electrical stimulation of
its nerve supply for 5 min have revealed that this decrease in
malonyl-CoA (29, 134) is associated with a diminution in
ACC activity that is evident
within seconds and persists for upwards of an hour after the cessation
of contraction (134, 140) (Fig. 10).
Evidence from our laboratory that this decrease in assayable
ACC
activity is due to
phosphorylation includes the following observations:
1) A gel shift of immunopurified ACC
, which parallels the
decrease in activity, is observed in muscle sampled within seconds
after the onset of contraction (134).
2) Reversal of the gel shift and the
decrease in ACC activity is induced by treatment of the immunopurified
enzyme with phosphatases (134). 3)
The decrease in ACC
activity
during contraction and the increase in activity during recovery are
associated with reciprocal changes in the activity of the
2 (but not
the
1) isoform of AMPK (134) (Fig. 10). In addition, it has been
shown that incubation of purified
ACC
with AMPK markedly
diminishes its activity, whereas a variety of other protein kinases
have no effect (142) (Vavvas, unpublished observations). Collectively, these findings suggest that activation of an AMPK, most likely the
2
isoform, mediates the inhibition of
ACC
during contraction in rat
muscle. Similar changes appear to account for the decreases in ACC
activity and malonyl-CoA as a result of voluntary exercise (140).
Because free AMP levels are increased and CrP levels are decreased
during contraction and exercise (3, 30), a logical conclusion is that
changes in their concentrations are the initiating event (93, 134).
|
Loss of ACC regulation by
citrate.
A noteworthy feature of the inhibition of
ACC
when it is phosphorylated
by AMPK in rat muscle is that it can occur in the face of substantial
increases in whole cell concentrations of both citrate and malate
(134). In addition, the ability of citrate to activate
ACC
immunopurified from such
muscles is substantially diminished (Fig.
11). These observations strongly suggest
that, when the energy expenditure of the muscle cell and its need for
fatty acid oxidation are increased, changes in the concentration of
high-energy phosphate compounds overcome the effects of citrate on
ACC
activity and are the
dominant mechanism for its regulation.
|
Dual regulation of
ACC and
phosphofructokinase-1.
The dual regulation of ACC
by
citrate and AMP (ATP/AMP ratio) closely parallels the regulation by
these substances of another key metabolic enzyme, phosphofructokinase-1
(PFK-1). PFK-1 is inhibited by ATP, and this inhibition is enhanced by
citrate and diminished by AMP (85, 129). We have hypothesized that "by virtue of their dual effects on
ACC
and PFK, AMP and citrate
complement each other in controlling the activities of these enzymes
and, secondarily, the use of glucose and fatty acids as fuels for
muscle" (134) (Fig. 11). Presumably changes in CrP/Cr, which also
appear to alter the activity of AMPK (93) and possibly PFK (85) fit
into this scheme.
AMPK and insulin sensitivity. As noted earlier, increases in the concentrations of malonyl-CoA and DAG and alterations in PKC distribution are associated with insulin resistance in skeletal muscle and could play a role in its development (see Table 2 and Malonyl-CoA, LCFA-CoA, and Insulin Resistance). Conversely, a single bout of exercise has been shown to increase insulin sensitivity in skeletal muscle in both humans (27) and experimental animals (101). An attractive notion is that exercise might exert this effect by activating AMPK, leading to changes in lipid metabolites and PKC contrary to those observed in insulin-resistant muscle. The observation that incubation of muscle with AICAR mimics the action of insulin on glucose transport (74) by a mechanism similar to that of exercise (50) is consistent with this possibility (74), as is the fact that exercise acutely lowers malonyl-CoA levels in rat muscle (139).
The Malonyl-CoA Fuel-Sensing and Signaling Mechanism: Other Implications
Link to cellular signaling.
By definition, a malonyl-CoA fuel-sensing and signaling mechanism
exists in all cells in which the concentration of malonyl-CoA is
acutely regulated by the availability of glucose or other fuels and/or by changes in ATP/AMP or CrP/Cr (see
Fuel Sensing by Cellular Stresses: the
5'-AMPK and
ACC
Regulation During Exercise and Recovery). With
respect to regulation by glucose, such a mechanism operating via
cytosolic citrate appears to be present in skeletal (115) and cardiac
(118) muscle, the pancreatic
-cell (23, 102), and brain (107). We
would also predict that it will be found in neural cells in the
hypothalamus that contain glucokinase or GLUT-4 glucose transporters.
In addition to regulating fatty acid oxidation, changes in the
concentration of malonyl-CoA could link fuel availability to signaling
events and biological functions in these cells. As already discussed
(see Malonyl-CoA, LCFA-CoA, and Insulin
Resistance), one site where such a linkage to signal transduction appears to occur is skeletal muscle, where sustained high
levels of malonyl-CoA are associated with insulin resistance (109).
Another is the pancreatic
-cell, in which the stimulation of insulin
secretion by glucose is associated with increases in the concentrations
of malonyl-CoA, citrate, malate, and DAG (23, 95, 102), and insulin
secretion is blocked by hydroxycitrate, an inhibitor of ATP-citrate
lyase and secondarily of malonyl-CoA formation (22) (see Fig. 3) and by
stable transfection with an ACC-specific antisense mRNA (152). It
remains to be determined whether at a molecular level the links between
malonyl-CoA and insulin resistance in muscle and insulin secretion in
the
-cell are mediated by PKC isozymes (94, 108, 109) or by other
signaling molecules. Nevertheless, these observations strongly suggest
that malonyl-CoA plays a pivotal role in modulating the effects of glucose and possibly other fuels on the functions of these tissues.
Fat partitioning, thrifty genes, and obesity. One of the most intriguing implications of the malonyl-CoA fuel-sensing and signaling mechanism is its possible relationship to the pathogenesis of obesity. Obesity has classically been defined as a disorder in which, for a period of time, energy intake exceeds energy expenditure and the caloric excess accumulates as fat (33). As first suggested by Neel (83) in his "thrifty gene" hypothesis, factors that predispose to obesity, and to type 2 diabetes with which it is closely associated, may during evolution have improved survival in humans better able to store energy as fat. More specifically, he proposed that in the feast-famine environment of our ancestors, individuals "exceptionally efficient in the uptake and utilization of food" would have had a selective advantage. Also relevant to this issue is the notion that obesity is a disorder of fat partitioning. This conception is based on the observation that humans and experimental animals generally are able to adjust rates of carbohydrate and amino acid oxidation to the amounts of these nutrients in their diet, but they are less able to adjust fat oxidation to fat intake (34). It has been suggested that for this reason some humans and experimental animals are more prone to obesity than others when placed on a diet with a high-fat content (17, 35, 119). Although the notion of fat partitioning has led to many recommendations concerning the fat content of our diet, a mechanistic explanation for the adipogenic effect of a high-fat, high-calorie diet has not come forth, nor is it clear why certain individuals and animals are more likely to become obese than others when ingesting it (17, 35, 119). It is our premise that dysregulation of the malonyl-CoA fuel-sensing and signaling mechanism, resulting in an inappropriately high concentration of malonyl-CoA (i.e., high for a given cytosolic LCFA-CoA level) in muscle and other tissues, could be a contributory factor. The following characteristics of humans and experimental animals at risk for obesity are supportive of this view: 1) a decreased ability to oxidize fatty acids as reflected by a high respiratory quotient (RQ) (4, 17, 19, 99); 2) decreased physical activity (99, 103), which would be expected to raise the concentration of malonyl-CoA in muscle; 3) hyperinsulinemia and insulin resistance (in children and some adults) (16, 88); and 4) high tissue levels of malonyl-CoA (in the Dahl-S rat, a lean rodent that becomes more obese than a control rat when fed a high fat-high sucrose diet) (62). That skeletal muscle may be a specific site of malonyl-CoA dysregulation is suggested by the finding of a much higher RQ across leg muscle of humans with established obesity than in lean control subjects, despite twofold higher plasma levels of FFA in the obese group (67).
Yet another connection between malonyl-CoA and the pathophysiology of obesity is its apparent relationship to leptin, the product of the ob gene. Although classically thought of as an appetite suppressant by virtue of its effects on the arcuate and perhaps other nuclei in the hypothalamus, leptin has also been demonstrated to increase total body energy expenditure (36) and carbohydrate metabolism (54). In addition, it increases fat oxidation in muscle (82, 124) and the pancreaticThe insulin resistance syndrome.
The combination of hyperinsulinemia, insulin resistance in skeletal
muscle and possibly liver, and an increase in abdominal adiposity has
been shown to antedate a cluster of disorders that include type 2 diabetes, essential hypertension, endogenous hypertriglyceridemia, and
premature coronary artery disease. This association has been referred
to as the insulin resistance syndrome or syndrome X (18, 60, 100, 109).
Despite the unquestioned clinical importance of this syndrome, it is
still uncertain whether a -cell defect leading to hyperinsulinemia
or insulin resistance in muscle is the primary event (71) or whether
they occur together (94, 114). Also unclear is what role increases in
intra-abdominal fat play in its pathogenesis (12, 59). As noted
earlier, a mechanism for the regulation of malonyl-CoA and LCFA-CoA by
glucose and fatty acids, similar to that observed in muscle, has been described in the pancreatic
-cell, where it may have an important role in the regulation of insulin secretion (22, 84, 94, 102). It has
been suggested that such a mechanism will also be found in adipocytes
(94), glucose-sensing cells in the central nervous system, and other
cells in which the use of glucose as a fuel is a function of its
availability (108). The notion that concurrent alterations in
malonyl-CoA and cytosolic LCFA-CoA in these cells could produce
signaling abnormalities that in turn cause hyperinsulinemia, impaired
insulin action, and other manifestations of the insulin resistance
syndrome, as well as obesity itself, has also been proposed (94, 108,
114) (see Fig. 8 and Table 2). As pointed out by Prentki and Corkey
(94), such an hypothesis offers a novel explanation both for the
presence of the multiple alterations of the insulin resistance syndrome
in some individuals and for the fact that it has been difficult to
determine the nature of the primary event. The numerous observations
that exercise, caloric restriction, and thiazolidinediones, all of
which improve insulin sensitivity, can concurrently diminish
malonyl-CoA levels and many manifestations of the insulin resistance
syndrome support this contention.
Concluding Remarks
The elucidation of how the concentration of malonyl-CoA is regulated in muscle and other cells has broad implications. Apart from enhancing our understanding of the intracellular control of fatty acid oxidation, it offers a potential mechanism by which fuels, and in particular glucose, create signals that regulate cellular function. In addition, an increasing body of evidence suggests that dysregulation of the malonyl-CoA fuel-sensing and signaling mechanism could play a role in the pathogenesis of obesity and the insulin resistance syndrome. How changes in malonyl-CoA concentration relate to the formation and action of leptin, uncoupling proteins, TNF- ![]() |
ACKNOWLEDGEMENTS |
---|
We thank Drs. J. P. Flatt, Keith Tornheim, and Barbara Corkey for many constructive discussions about the content of the manuscript, and Tomoko Akishino for assistance in its preparation and in particular for drawing a number of the figures.
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FOOTNOTES |
---|
This review was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-19514, DK-49147, and DK-35712, and a grant from the Juvenile Diabetes Foundation.
Address for reprint requests: N. Ruderman or A. K. Saha, Diabetes and Metabolism Unit, Boston University Medical Center Hospital, 88 E. Newton St., E-211, Boston, MA 02118-2393.
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