The lipogenesis is the main metabolic pathway by which fatty acids are long chain synthesized from carbohydrates consumed in excess in the diet. These fatty acids can be incorporated into triglycerides through their esterification to glycerol molecules.
Under normal conditions, lipogenesis occurs in the liver and adipose tissue and is considered one of the main contributors to the maintenance of triglyceride homeostasis in blood serum.
Structure of human fatty acid synthase (FASN) (Source: Emw
via
Wikimedia Commons)
Triglycerides are the body's main energy reservoir and the energy contained in them is extracted thanks to a process known as lipolysis, which, contrary to lipogenesis, consists of the separation and release of glycerol and fatty acid molecules into the bloodstream.
The glycerol released serves as a substrate for the gluconeogenic pathway and the fatty acids can be transported to other compartments complexed with serum albumin.
These fatty acids are taken up by almost all tissues except the brain and erythrocytes, then they are esterified to triacylglycerols again to be oxidized as fuels or stored as an energy reserve.
High-fat diets are the main cause of obesity, since excess calories must be stored and adipose tissue must expand to accommodate both excess ingested lipids and those that are endogenously synthesized.
Features and functions
In the human body, for example, fatty acids arise either from biosynthetic processes from acetyl-CoA or as a product of the hydrolytic processing of fats and membrane phospholipids.
Many mammals are unable to synthesize some fatty acids, which makes these essential components of their diet.
The main function of lipogenesis has to do with the storage of energy in the form of fats (lipids) that occurs when consuming a greater amount of carbohydrates than the body needs, even exceeding the hepatic storage capacities of glycogen.
The lipids synthesized by this route are stored in white adipose tissue, the main lipid storage site in the body.
Lipogenesis occurs in all cells of the body, however, adipose tissues and the liver are the main sites of synthesis. This pathway occurs in the cell cytoplasm, while fatty acid oxidation occurs in the mitochondrial compartments.
Lipogenesis and the subsequent synthesis of triglycerides is followed by the synthesis and secretion of very low-density lipoprotein particles known as VLDL (Very Low Density Lipoprotein) particles, which are capable of entering the bloodstream.
Both VLDL particles and triglycerides can be hydrolyzed in the capillaries of extra-hepatic tissues, mainly in muscle and adipose tissues for the release or storage of energy.
Reactions
The flow of carbon atoms from glucose present in carbohydrates to fatty acids is modulated by lipogenesis and includes a series of perfectly coordinated enzymatic reactions.
1-The glycolytic pathway in the cytosol of cells is responsible for processing the glucose that enters from the bloodstream to produce pyruvate, which is converted into acetyl-CoA, capable of entering the Krebs cycle in the mitochondria, where citrate is produced.
2-The first step of the lipogenic pathway consists of the conversion of the citrate that leaves the mitochondria into acetyl-CoA by the action of an enzyme known as ATP-citrate lyase (ACLY).
3-The resulting acetyl-CoA is carboxylated to form malonyl-CoA, a reaction catalyzed by an acetyl-CoA carboxylase (ACACA).
4-The third reaction is the reaction that imposes the limiting step of the entire route, that is, the slowest reaction, and consists of the conversion of malonyl-CoA to palmitate by a fatty acid synthase (FAS) enzyme.
5-Other downstream reactions help to convert palmitate into other more complex fatty acids, however, palmitate is the main product of de novo lipogenesis.
Fatty acid synthesis
The synthesis of fatty acids in mammals begins with the fatty acid synthase complex (FAS), a multifunctional and multimeric complex in the cytosol that synthesizes palmitate (a saturated 16-carbon fatty acid). For this reaction, it uses, as already mentioned, malonyl-CoA as carbon donor and NADPH as cofactor.
The FAS homodimer subunits catalyze the synthesis and elongation of fatty acids two carbon atoms at a time. These subunits have six different enzymatic activities: acetyl transferase, B-ketoacyl synthase, malonyl transferase, B-ketoacyl reductase, B-hydroxyacyl dehydratase, and enoyl reductase.
Different members of a family of very long chain fatty acid elongation proteins (Elovl) are responsible for the elongation of fatty acids produced by FAS. Downstream are other enzymes responsible for the introduction of double bonds (desaturation) in the chains of fatty acids.
Regulation
Numerous pathophysiological conditions have to do with defective regulation of the lipogenic pathway, since irregularities in it interrupt body lipid homeostasis.
A diet rich in carbohydrates activates liver lipogenesis, but it has been shown that it is not only the amount of carbohydrates ingested, but also the type of carbohydrates.
Experimental data shows, for example, that simple sugars such as fructose have much more potent effects in activating liver lipogenesis than other more complex carbohydrates.
Glucolytic metabolism of glucose represents a great source of carbon for the synthesis of fatty acids.
Glucose also induces the expression of the enzymes involved in the lipogenic pathway by means of proteins that bind carbohydrate response elements.
Glucose levels in the blood also stimulate the expression of these enzymes by stimulating insulin release and inhibiting glucagon release in the pancreas. This effect is controlled via the sterol regulatory element binding protein 1 (SREBP-1) in liver cells and adipocytes.
Other regulatory pathways have much to do with the endocrine system and different hormones indirectly related to the expression of many of the lipogenic enzymes.
References
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