November 2013

Fatty acid synthase and Galen of Pergamon

Galen of Pergamon
Galen of Pergamon

A considerable proportion of extant Greek texts are attributed to the physician-scientist Galen (AD 130 to ∼210), likely because an army of amanuenses recorded everything he said. He is credited with the notion that disease is the consequence of discrete causes, so the biological pursuit of mechanism may have originated with Galen. His original contributions were substantial, dominating life sciences for 1,500 years, and he was a proponent of the role of lipid metabolism in pathophysiology. His study of the active properties of lipids perhaps began with his appointment as physician to the gladiators of the high priest of Asia when he treated injured muscle with a mixture of olive oil (oleate), beeswax (palmitate, palmitoleate, oleate) and rose petals.
 
Even before Galen, nature figured out that lipids are critical for biology. Mammalian fatty acid synthase, known as FAS, is a type I fatty acid synthase, indicating that all of the activities required to synthesize palmitate from simple precursors are present in a single multifunctional polypeptide. FAS is required for life, because conventional deletion of the fasn gene in mice is embryonically lethal. However, tissue-specific deletion of fasn has revealed an amazing spectrum of biological functions driven by de novo lipogenesis.
 
Mice with a deficiency of FAS in the liver resemble mice with deficiency of the nuclear receptor PPARα. Both are prone to the development of fatty liver and hypoglycemia due to defects in fatty acid oxidation and gluconeogenesis. Treatment with chemical PPARα ligands corrects the phenotype in mice with hepatic FAS deficiency, implicating FAS in the generation of an endogenous ligand for PPARα. An FAS-dependent phosphatidylcholine species linked to the Kennedy pathway of phospholipid synthesis was identified as an endogenous PPARα ligand.
 
Connecting FAS (induced by feeding) with PPARα (induced by fasting) initially seemed paradoxical, but recent evidence indicates that FAS is compartmentalized in the liver, with different fractions subject to differential regulation of enzyme activity to promote PPARα activation with fasting. FAS-mediated activation of PPARα also occurs in the brain and in macrophages. FAS affects the function of another nuclear receptor, PPARα. Deficiency of FAS in adipose tissue decreases the association of certain ether lipids (synthesized in peroxisomes) with PPARα, resulting in protection from obesity through induction of cells resembling brown fat.

infographic about fatty acid synthesase
Mammalian fatty acid synthase (FAS), a multifunctional enzyme that synthesizes predominantly palmitate, has complex tissue-specific effects mediated by several molecular mechanisms.

FAS influences other key processes. It is involved in preserving the integrity of structures that protect mammals from the environment. At the vascular endothelium and at the intestinal epithelium, FAS appears to be the predominant source of fatty acids for palmitoylation of proteins (eNOS at the endothelium and Muc2 in the intestine) critical for maintaining barrier function. In neural tissues, FAS is required for stem-cell renewal. In cardiac and skeletal muscle, FAS regulates calcium flux, likely by modulating the phospholipid composition of the sarcoplasmic reticulum.
 
FAS generates palmitate, but exogenous palmitate does not rescue the phenotype induced by FAS deficiency (see Jensen-Urstad et al and Razani et al). Thus, Galen may have been correct in principle but not in detail. Lipids modulate numerous stress responses, but instead of exogenous fat, endogenous fat produced by FAS and channeled to specific compartments regulates integrative physiology relevant to disease.

Clay SemenkovichClay F. Semenkovich (csemenko@wustl.edu) is the Herbert S. Gasser professor at Washington University in St. Louis’ medicine department and cell biology and physiology department.


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