Fatty Acid Synthesis
Brett A. Gardner
Introduction
At the beginning of the 20th Century, it would have been hard to imagine that as we
approach the end of the millenium, obesity, rather than hunger, would be a major public health
problem for much of the developed world. The condition of being overweight affects 58 million
Americans who spend $30 billion a year fighting excess pounds, often futilely. However, obesity
is not just a problem in the U.S., it is an international health problem. Now recognized as a
chronic disease, obesity is second only to smoking as a contributor to illness and premature
death throughout the world. Complications that result from obesity include hypertension,
hyperlipidemia, cardiovascular disease, diabetes, and cancer (1). By understanding and
developing pharmacological agents that regulate fatty acid metabolism, the huge medical,
social, and financial toll that obesity causes could be reduced.
Acetyl-CoA Carboxylase
Fatty acid biosynthesis occurs through the condensation of C2 units and is coupled to the
hydrolysis of ATP (2). The process of fatty acid synthesis involves two regulatory steps. The
first step is the carboxylation of acetyl-CoA in the cytosol to form malonyl CoA (Figure 1).
Catalyzed by the biotin-dependent acetyl-CoA carboxylase, an enzyme that transfers CO2 to
substrates, this step is the rate-limiting step and therefore a very important site in the regulation
of fat accumulation. If sufficient biotin is not available for carboxylation of acetyl-CoA, fatty acid
synthesis will not occur. The second major point of regulation in fatty acid synthesis is the
decarboxylation of the malonyl group, catalyzed by fatty acid synthase. The multienzymatic
activity of fatty acid synthase regulates fatty acid synthesis (Figure 2).
Figure 1.
Carboxylation reaction of acetyl-CoA in the cytosol to form malonyl CoA via acetylCoA carboxylase (ACC).
The rate of fatty acid synthesis is controlled by the equilibrium between the monomeric
and polymeric acetyl-CoA carboxylase. Control of the acetyl-CoA carboxylase enzyme involves
phosphorylation-dephosphorylation reactions (3). Metabolically, this conformational change is
enhanced by citrate and is inhibited by long-chain fatty acids (i.e. palmitoyl-CoA). The
accumulation of citrate in the cytosol of adipose cells shifts equilibrium to the polymeric acetylCoA carboxylase, thus activating fatty acid biosynthesis. Palmitoyl-CoA promotes polymer
disaggregation and is a primary feedback inhibitor of fatty acid synthesis.
Hormones play an important role in lipid metabolism (Figure 3). Fatty acid synthesis is
regulated by phosphorylation-dephosphorylation reactions.
Insulin stimulates the
dephosphorylation of acetyl-CoA carboxylase, activating fatty acid synthesis. Phosphorylation
of acetyl-CoA carboxylase by the hormones epinephrine, norepinephrine, and glucagon result in
the inactivation of this enzyme, inhibiting synthesis of fatty acids from acetyl-CoA.
Figure 2.
The reaction sequence for the biosynthesis of fatty acids.
Dietary Regulation
The level of food intake has profound effects on the rate of incorporation of lipogenic
precursors into fatty acids in ruminant adipose tissue (4, 5). Smith et al. (4) demonstrated that
graded increases in the level of food intake markedly increased de novo lipogenesis. Smith and
Prior (6) suggested that ATP-citrate lyase is rate limiting to the incorporation of lactate into fatty
acids because of the high correlation between the intracellular concentration of citrate and the
rate of lipogenesis from lactate. Studies conducted using chickens demonstrated that shortterm fasting reduces lipogenesis (7), while meal size increased the proportion of glycogen
synthesized by rats (8).
Nutritional manipulation exerts a more long-term effect on hepatic lipogenesis and thus
potentially on whole body lipid metabolism. For instance, in vivo lipogenesis is observed to be
increased following the feeding of a diet with a high calorie:protein ratio but decreased following
the feeding of a diet that includes fat (9). Restricted feed intake elevated fatty acid synthesis,
while low-protein (12%) diets have been shown to elevate lipogenesis compared to high-protein
(30%) diets (10, 11).
Hudgins et al. (12) demonstrated that fatty acid synthesis was markedly stimulated in
weight-stable normal human volunteers by a very-low-fat formula diet with 10% of energy as fat
and 75% as short glucose polymers. Recently, researchers (13) concluded that fatty acid
synthesis was reduced by the substitution of dietary starch for sugar and resulted in potential
beneficial effects on cardiovascular health. Even though the mechanism(s) by which nutrition
influences lipogenesis have not been established this influence may be via metabolic hormones
or nutrient availability.
Figure 3.
Schematic of lipid metabolism in poultry and the points of hormone interaction.
Genetic Regulation
In the 1950s, researchers at the Jackson Laboratory in Bar Harbor, Maine found a series
of genes that appeared to be responsible for obesity in mice; two of the genes, the ob (for
obese) and the db (for diabetes) appeared to play a crucial role in fat regulation (14). In 1986,
Dr. Jeffrey Friedman of the Howard Hughes Medical Institute at Rockefeller University and a
team of Rockefeller researchers successfully cloned the obesity gene which has been shown to
affect fat synthesis (15, 16, 17). Mice that exhibited the db/db gene were found to produce an
anti-obesity factor within the circulatory system but were non-responsive to the factor, while
mice with ob/ob did not produce the anti-obesity factor (were phenotypically obese) but were
responsive (18) to the anti-obesity factor. This factor, named leptin, is a protein that is encoded
by the obesity gene. It signals to the brain when sufficient energy has been consumed to
maintain body weight. Mutation of the ob gene, which prevents the manufacture of functional
leptin, results in morbidly obese mice (19).
Hormones may control the regulation of leptin synthesis. When glucocorticoids or cAMP
were administered, ob mRNA and leptin secretion was decreased (20), while insulin and
corticosterone increased leptin production in both rodent and human adipose cells (21). Leptin
also appears to be under the control of metabolic factors. Fasting markedly reduced ob mRNA
levels, but upon re-feeding, mRNA levels were restored (21).
Heiman et al. (22) demonstrated that among rats, leptin could inhibit hypothalamic CRH
release, either directly or indirectly through another hypothalamic neuropeptide such as
neuropeptide-Y. Neuropeptide Y stimulates appetite centers in the brain and appears to be a
partner of leptin in the regulation of body fat through participation in maintenance of energy
balance and neuroendocrine signaling. As more fat is produced, leptin levels go up, causing a
sharp drop in neuropeptide Y and a decrease in appetite. Neuropeptide-Y may be involved in
the regulation of body fat and development of obesity because of its involvement in the
regulation of feeding behavior, including food intake and carbohydrate preference, and the
control it has on metabolism and lipogenesis.
Conclusions
Biosynthesis of fatty acids is strictly regulated. The primary determination of lipogenesis
or lipolysis is the equilibrium between monomeric and polymeric acetyl-CoA carboxylase.
Several hormones, including insulin, glucagon, glucocorticoids, epinephrine, the secondary
messenger cAMP, as well as diet composition and nutrient manipulation all exert important
regulatory action on lipid metabolism. However, the recent discovery that genetics play an
integral part in determining the extent of fatty acid synthesis may prove to be the most beneficial
breakthrough in the “War on Fat”. Future investigations and studies of leptin and its method of
transduction may unveil the mystery of fat synthesis and allow the development of
pharmacological agents to prevent obesity.
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