Lutfi Abu-Elheiga, Ph.D.
Biochemistry & Molecular
Biology
Salih J. Wakil, Ph.D.
Biochemistry & Molecular
Biology
The role of acetyl-CoA carboxylasas in fatty acid metabolism and energy homeostasis
In a collaborative effort, Salih J.Waki and Lutfi Abu-Elheiga discovered the enzyme
critical to the metabolic pathways that govern the body's ability to burn fat.
Malonyl-Coenzyme A, generated by acetyl-CoA carboxylase reaction, is a key intermediate
in the metabolism of fatty acids. It is the substrate for the synthesis of long-chain
fatty acids by the fatty acid synthase and it regulates the mitochondrial oxidation
of fatty acids and energy homeostasis. To perform these two vital, but opposite
metabolic functions, animals, including humans, were evolved with two acetyl-CoA
carboxylases, ACC1 and ACC2, that are encoded by separate genes and display distinct
tissue expression and regulation. ACC1 is predominantly expressed in lipogenic tissues,
liver and adipose, whereas ACC2 is highly expressed in heart and muscle, tissues
that are dependent on energy production and utilization. The levels and activities
of ACC1 and ACC2 are highly affected by the dietary, hormonal, and physical states
of the animals. The amino acid sequences of human ACC1 (M r~265,000)and ACC2 (M
r~280,000), predicted from their cDNA sequences, show about 70% similarity. However,
ACC2 has an additional 140 amino acids located at the N-terminus of the molecule
and functions as a lead peptide that targets ACC2 to cellular membranes. Indeed,
we demonstrated that ACC2 is associated with the mitochondrial membranes, whereas
ACC1, lacking the N-terminal lead sequence, is located in the cytosol. To understand
the roles of ACC1 and ACC2 in energy metabolism, we made targeted deletions of the
genes in mice. Acc1 -/- mutant mice were embryonically lethal, possibly due to lack
of fatty acid synthesis needed for biomembrane synthesis. Acc2 -/- mutant mice bred
normally and had normal life spans. Acc2 -/- mice fed normal diets accumulated significantly
less fat in their livers and adipose than the wild-type mice. Overnight fasting
resulted in a 5-fold increase in ketone bodies production, indicating higher fatty
acid oxidation. ACC1 and fatty acid synthase activities and malonyl-CoA contents
of the livers of the Acc2 -/- and ACC2 +/+ mice were the same, indicating that fatty
acid synthesis is unperturbed. Yet, the malonyl-CoA was not available for the inhibition
of the mitochondrial carnitine palmitoyl-CoA shuttle system; hence, fatty acid oxidation
was relatively high. Also, it indicated that the ACC1-generated malonyl-CoA occupies
distinct compartments of the liver cell than that generated by ACC2. The absence
of ACC2 in the mutant mice resulted in 10- and 30-fold lower malonyl-CoA contents
of heart and muscle, respectively. Fatty acid oxidation in the Acc2 -/- soleus muscles
was 30% higher than the wild-type muscle. The addition of insulin did not affect
fatty acid oxidation in the Acc2 -/- soleus muscle, but as expected, it did reduce
fatty acid oxidation by 50% in the wild-type soleus muscle compared to that of the
mutant muscle. Isproterenol, an analog of glucagon, had little effect on fatty acid
oxidation in the muscle of the Acc2 -/- mice, but caused a 50% increase in fatty
oxidation in the wild-type soleus muscle. The higher fatty acid oxidation in the
mutant mice resulted in a 50% reduction of fat storage in the adipose tissue, compared
to that of the wild-type mice. This is a state humans try to achieve by physical
exercise. The decrease in the size of adipose in Acc2 -/- mice resulted in a 35%
decrease in plasma leptin, compared to that of the wild-type. In comparison, the
Acc2 -/- mice had relatively higher appetites, consuming 20 to 30% more food than
the wild-type mice, yet weighed 10-15% less. These results are valuable to our understanding
and control of fatty acid metabolism and energy homeostasis in normal, diabetic,
and obese animals. They also highlight the acetyl-CoA carboxylase 2 as a potential
target for controlling body weight.
Dr. Wakil and Abu-Elheiga’s nomination was based on the following publications:
Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ."
The subcellular localization of acetyl-CoA carboxylase 2. ". Proc Natl Acad
Sci U S A. 2000 Feb 15;97(4):1444-9.
Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ. "
Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA
carboxylase 2 ".Science. 2001 Mar 30;291(5513):2613-6.