AMP-activated protein kinase (AMPK) was originally discovered as 3-hydroxy 3-methylglutaryl CoA reductase (HMG-CoA reductase, HMGR) and acetyl-CoA carboxylase (ACC) inhibitor.
It stimulates various activities within cells caused by ever-changing cellular energy charge. AMPK’s key role is to regulate the energy charge of cells, hence sustaining energy homeostasis.
A recent study showed that AMPK movement can be controlled through physiological stimuli that are self-sufficient of cellular energy charge – including nutrients and hormones. But how does it improve fatty acid synthesis?
What Is Fatty Acid Synthesis?
Fatty acid synthesis uses NADPH and acetyl-CoA to create fatty acids through enzyme activities called fatty acid synthases. The process occurs inside a cell’s cytoplasm that converts acetyl-CoA into fatty acids from carbohydrates through glycolytic pathway.
The purpose of glycolytic pathway is to produce glycerol where 3 fatty acids can fuse in order to create triglycerides or triacylglycerols. It distinguishes triglycerides from fats as a result of lipogenic process.
However, when 2 fatty acids fuse with glycerol while the alcohol group is phosphorylated with phosphatidylcholine, the end product is called phospholipid.
Basically, phospholipids create bulky layers of lipid to form cell membranes. It then surrounds organelles inside the cell including mitochondria, Golgi apparatus, endoplasmic reticulum, and cell nucleus among others.
Fatty Acid Synthesis Explained Further
The end products of glycolytic are essential in converting carbohydrates into fatty acids. In humans, fatty acid synthesis usually takes place in adipose tissues and liver. But during lactation, fatty acid synthesis occurs in the mammary glands.
With the help of glycolysis, pyruvate is produced that essentially serves as intermediary in converting carbohydrates into cholesterol and fats. It takes place by means of converting pyruvate into acetyl CoA in the mitochondria.
But before that, the acetyl CoA requires to be carried in the cytosol in order to successfully synthesize cholesterol and fatty acids. Hence, the process doesn’t occur directly.
For cytosolic acetyl CoA to be obtained, citrate should be eliminated from the cycle of citric acid. If it does, cytosolic acetyl CoA is then transported into the internal membrane of the mitochondria until it reaches the cytosol.
As the process continues, the cytosolic acetyl CoA cleaves with ATP citrate lyase to produce oxaloacetate and acetyl CoA. The oxaloacetate is important in gluconeogenesis which occurs in the liver.
Otherwise, it is returned in the mitochondria to produce malate. The acetyl CoA carboxylases will then carboxylate the cytosolic acetyl CoA to create malonyl CoA. And this is the primary committed step in fatty acid synthesis.
The AMPK in the human body consist of trimeric enzyme produced by catalytic “a” subunit as well as non-catalytic B and y units. There are 2 genes that encode isoforms of “a” and B subunits along with 3 genes that encode isoforms of y subunits.
PRKAA1 is the gene that encodes a1 protein, PRKAA2 for the a2 protein, PRKAB1 for the B1 protein, PRKAB2 for the B2 protein, PRKAG1 for the y1 protein, PRKAG2 for the y2 protein, and PRKAG3 for the y3 protein.
The PRKAA1 gene occurs in chromosome 5p12. It contains 5 exons which are essential in generating 2 alternatively joined mRNAs that encode a1 isoform 1 or 559 amino acids and a1 isoform 2 or 574 amino acids.
The PRKAA2 gene occurs in chromosome 1p31. It contains 9 exons encoding 552 amino acid proteins. PRKAB1 gene occurs in chromosome 12q24.1-q24.3. It contains 7 exons encoding 270 amino acid proteins.
The PRKAB2 gene occurs in chromosome 1q21.1. It contains 9 exons generating 3 alternatively joined mRNAs. The PRKAG1 gene occurs in chromosome 12q12-q14. It contains 14 exons generating 3 alternatively joined mRNAs that encode y1 isoform 1 or 331 amino acids, y1 isoform 3 or 340 amino acids, and y1 isoform 4 or 299 amino acids.
The PRKAG2 gene occurs in chromosome 7q36.1. It contains 21 exons generating 5 alternatively joined mRNAs that encode 4 unique isoforms namely: y2 isoform a or 569 amino acids, y2 isoforms B and E or 328 amino acids, y2 isoform c or 525 amino acids, and y2 isoform D or 444 amino acids.
Lastly, the PRKAG3 gene occurs in chromosome 2q35. It contains 14 exons encoding 489 amino acid proteins.
Improve Fatty Acid Synthesis by Activating AMPK
Once AMPK is activated, it’s easier to improve fatty acid synthesis through an activity called AMPK mediated phosphorylation. It switches the cells from cholesterol biosynthesis and fat into glucose oxidation and fatty acid.
When these activities are quickly instigated, it is then called short term regulatory process. AMPK activation also puts forth long term effects in protein synthesis as well as in gene expression.
Other important events in the activation of AMPK are the secretion in the B-cells of pancreatic islets, modulation in the functions of hypothalamus, and the regulation when insulin is synthesized. These processes heavily affect diabetes and obesity in humans.
Exercise and stress are two powerful stimuli of AMPK activities within the skeletal muscle. Drugs that sensitize insulin and hypoglycemia drug metformin use some of their effects via AMPK activity regulation.
LKB1 or the AMPK activity that activates kinase is essential in regulating glucose homeostasis and gluconeogenic flux. With metformin, blood glucose levels are reduced through LKB1 activity within the liver.
In addition, some hormones which are secreted by adipocytes called adipokines induce AMPK activation. Studies show that adiponectin and leptin can induce AMPK activation while resistin stimulates AMPK activation as well.
AMPK’s primary function is to phosphorylate and regulate various activities of metabolic enzymes. On the other hand, when ATP depletion stays protracted, AMPK will then phosphorylate some transcription factors and co-regulators like HNF 4a, FoxO3A, PGC 1a, and CBP p300.
As a result, SIRT1 targets to regulate these factors. AMPK, like other distinct molecules, can also regulate mammalian longevity. It increases the lifespan of living things like the roundworm C. elegans.
But in humans, it increases fatty acid oxidation and mitochondrial biogenesis. AMPK serves as heterotrimeric complexes which comprise regulatory beta and gamma subunits as well as catalytic alpha subunits.
Essentials to Boost Fatty Acid Synthesis
Linoleic acid (LA) is an omega 6 fatty acid that is essential in fatty acid synthesis. Just like LA, a-linoleic acid (ALA) also helps boost the process since it can’t be synthesized by the human body.
On the other hand, the long-chain omega 3 fatty acids, docosahexaenoic (DHA), and eicosapentaenoic (EPA) can be synthesized through ALA. But because of low-conversion efficiency, it’s advised to obtain DHA and EPA from other sources.
Omega 6 and omega 3 fatty acids essentially comprise cell membranes. They work as precursors for bioactive lipids while providing sufficient energy. These healthy fatty acids are required by the body to improve synthesis in general.