Lipogenesis is a term used to describe a process of fatty acid and triglyceride synthesis from glucose or other substrates. This specific biosynthesis takes place predominantly in the liver, while its occurrence in the adipose tissue is of minor significance – even under conditions of substantial carbohydrate overfeeding.
Although our understanding of biochemistry and hormonal regulation of lipogenesis stems from in vitro research on rodents, the biological importance, activity and tissue distribution of the lipogenic pathways show considerable variation among different species. In humans, lipogenesis plays an important role in physiologic and pathophysiologic conditions.
Steps in lipogenesis
Different human cells show the ability to convert carbohydrates (but also amino acid carbons) into fatty acids via a biochemical pathway known as de novo lipogenesis. The initial step for such fatty acid synthesis is acetyl-CoA carboxylation to malonyl-CoA with the help of the enzyme acetyl-CoA carboxylase, which is mostly taking place in liver cells, but also in skeletal muscle and adipose tissue.
Further events include an iterative integration of malonyl-Coa carbons into a fatty acid chain which results with the synthesis of a palmitic acid, representing an energy-consuming process. Additional action of elongase and desaturase enzymes can lead to the synthesis of stearic acid.
De novo lipogenesis from carbohydrate is associated with significant amounts of energy lost as heat, irrespective of whether synthesized fat is oxidized or stored in form of a triglyceride. The process is activated by insulin and inhibited by hyperglucogonemia (excess glucagon secretion) and by cellular energy deprivation through 5’ AMP-activated protein kinase by glucagon.
Carbohydrates in the form of glucose, glycogen and lactate are considered to be the major precursors for de novo lipogenesis in the fetus and neonate. De novo synthesis of fatty acids in fetal lung has been studied extensively as the synthesis of surfactant is pivotal for normal pulmonary function at birth.
Measurement of lipogenesis
Until the 1990s, lipogenesis in humans has largely been assessed via indirect calorimetry. This measurement is based on the fact that synthesis of fatty acids from acetyl-CoA can be linked to a sizable carbon dioxide production, which in turn upsurges the respiratory exchange ratio. Still, with this method it was difficult to demonstrate net de novo lipid synthesis.
In the 1990s, new isotopic methods have been developed for the evaluation of hepatic lipogenesis which incorporate tracers to the fatty acids secreted in very low density lipoproteins. Using this method, de novo lipogenesis in the liver could be observed in individuals on high-carbohydrate diets – even without net fat synthesis.
Deuterium is also used to quantitate the relative proportions of dietary and newly synthesized triglyceride fatty acids. Measuring de novo lipogenesis by deuterium incorporation is considered to be a safe, precise and highly sensitive method which can be used with short measurement periods (i.e. less than 24 hours).