The Horton lab is interested in defining the molecular and metabolic alterations that result in excessive fat accumulation in liver. Our current focus is characterizing enzymes involved in microsomal fatty acid elongation and defining the

potential roles the products of these enzymes have in regulating lipid homeostasis.

Fatty acids are synthesized from acetyl-CoA and malonyl-CoA through a series of reactions shown in Figure 1. The de novo synthesis of fatty acids occurs in two distinct cellular compartments. Palmitate (16:0) is synthesized from acetyl-CoA and malonyl-CoA in the cytoplasm by the enzymes acetyl-CoA carboxylase-1 and fatty acid synthase. The synthesis of fatty acids longer than 16 carbons takes place in microsomes and utilizes malonyl-CoA as the carbon source. These enzymes have only been partially characterized and not all have been identified.

The mammalian enzymes that elongate palmitic acid (16:0) and very long chain fatty acids (>C18) have been localized to the endoplasmic reticulum (ER) and are shown schematically in Figure 2. The initial condensation reaction is the regulated and rate-controlling step in microsomal fatty acyl elongation. We reported the cDNA cloning and characterization of a murine long chain fatty acyl elongase (LCE), now designated ELOVL6. Overexpression of ELOVL6 in cells resulted in the enhanced addition of 2-carbon units to C12-C16 fatty acids and evidence was provided that LCE catalyzed the initial condensation reaction of long chain fatty acid elongation. A line of knockout mice with a disrupted ELOVL6 gene is now being characterized to determine the physiological consequences of the induced mutation for lipid homeostasis and in the development of obesity.