The disease vortex agents in human Biology
In my personal view, the disease vortex agents in human biochemistry consists of some of the following elements:
- Endotoxin
- Lactate
- Polyunsaturated Fatty Acids (PUFA)
Today, we are going to look at how lactate can be produced and significantly elevated even under fully aerobic conditions.
A Danish study from 2003, “Endotoxemia stimulates skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans”, investigates how endotoxin can trigger an increase in lactate levels without the presence of hypoxia.
Normal Lactate Production and Hypoxia
Normally, an increase in lactate is seen as a sign of tissue hypoxia. When the electron transport chain and the TCA cycle slow down due to a reduced redox balance, electrons are transferred to pyruvate, leading to the production of lactate. This happens because the final electron acceptor in the electron transport chain, oxygen, is not sufficiently available to be reduced to water. In this situation, pyruvate acts as a substitute electron acceptor, allowing the production of new ATP and the oxidation of NADH to NAD+.
“Patients with trauma or sepsis hyperlactacidemia are usually managed from the point of view that it reflects anaerobic glycolysis caused by tissue hypoxia. However, it has been suggested that increased activity of skeletal muscle Na+-K+-ATPase caused by the epinephrine surge present in such patients causes aerobic glycolysis and lactate production (12, 13).”
https://journals.physiology.org/doi/full/10.1152/ajpheart.00639.2002
However, the researchers in the study highlight that an increase in adrenaline may lead to an increase in the activity of Na+-K+-ATPase, which then triggers glycolysis and lactate production, even in the presence of oxygen.
Aerobic Glycolysis and Lactate Production
“The production of 2 mol ATP by glycolysis compared with 38 mol by complete oxidation of 1 mol of glucose may not be a consequence of anaerobic conditions, but an effect linked to the Na+-K+-ATPase activity.”
https://journals.physiology.org/doi/full/10.1152/ajpheart.00639.2002
For example, in well-oxygenated muscles, increased Na+-K+-ATPase activity (induced by substances such as monensin, epinephrine, amylin, or insulin) leads to an increase in lactate production. On the other hand, when Na+-K+-ATPase is inhibited (e.g., by ouabain or reduced extracellular K+ concentration), lactate production decreases:
“In well-oxygenated skeletal muscles, increased Na+-K+-ATPase activity induced by monensin (12), epinephrine, amylin (14), or insulin (21) leads to increased lactate production, and, on the other hand, inhibition of the Na+-K+-ATPase by ouabain or reduced extracellular K+ concentration reduces lactate production (14).”
https://journals.physiology.org/doi/full/10.1152/ajpheart.00639.2002
The Role of Adrenaline
Adrenaline stimulates an increase in Na+-K+-ATPase activity:
“It is well known that the catecholamine stimulation of the skeletal muscle Na+-K+-ATPase is achieved via β2-adrenoceptors (2), and that increased activity of the Na+-K+-ATPase, caused by pumping Na+ out and K+ into the cell in a 3:2 relationship, leads to increased cellular K+ uptake (2). This may lead to hypokalemia, which is actually a frequent finding at admission of severely ill patients.”
https://journals.physiology.org/doi/full/10.1152/ajpheart.00639.2002
From clinical practice, we know that administering β2-adrenergic agonists is the fastest way to stabilize hyperkalemia. This likely happens through the activation of Na+-K+-ATPase, which moves potassium into the cells and sodium out in a 3:2 ratio. This also explains the clinical phenomenon where highly stressed trauma or sepsis patients sometimes present with hypokalemia.
How Does Endotoxin Play a Role in This?
The study examined whether endotoxin-induced adrenaline/catecholamine release leads to an increase in lactate. Eight young participants were intravenously injected with endotoxin and studied. The results showed that the group injected with endotoxin had a significant increase in plasma lactate and hypokalemia, without signs of hypoperfusion or a drop in pH. In other words, lactate increased despite fully aerobic conditions!
Discussion: Why is Lactate Harmful?
Lactate has several potential harmful effects:
- Oncometabolite and Inflammation Cascade Activator: Lactate may act as an oncometabolite, enhancing the transcription of various oncogenes and growth factors. For example, a study demonstrates that both endogenous and exogenous lactate can activate oncogenes such as MYC and RAS (related to uncontrolled cell signaling and transcription), as well as Hypoxia-Inducible Factor (HIF), which is linked to angiogenesis (formation of new blood vessels).
“We found that both endogenous, glucose-derived lactate and exogenous lactate supplementation significantly affected the transcription of key oncogenes (MYC, RAS, and PI3KCA), transcription factors (HIF1A and E2F1), tumor suppressors (BRCA1, BRCA2) as well as cell cycle and proliferation genes involved in breast cancer (AKT1, ATM, CCND1, CDK4, CDKN1A, CDK2B).”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971189/
Lactate might also be involved in a range of inflammation cascades, possibly even acting synergistically with endotoxin through increased expression and activity of TLR receptors.
“Although the stimulatory effect of lactate on these genes was relatively less potent than that of LPS, lactate markedly augmented LPS-stimulated gene expression. For example, lactate and LPS stimulated IL-1β by 2.78- and 7.03-fold, respectively, but the combination of lactate and LPS up-regulated IL-1β by 59.2-fold.”
Lactate also increases pro-inflammatory markers such as NF-κB:
“Second, we determined the NF-κB transcriptional activity. Results (Fig. 4) showed that either lactate or LPS stimulated NF-κB transcriptional activity, although lactate was less potent than LPS, and the combination of both had a synergistic effect.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673542/
- TLR4 Activation, Systemic Inflammation, and Insulin Resistance: Lactate may contribute to TLR4 activation in macrophages and thereby drive systemic inflammation and insulin resistance. For example, in patients with obesity or type 2 diabetes, macrophages in adipose tissue may be exposed to high concentrations of lactate. Studies suggest that this could contribute to insulin resistance by activating macrophage TLR4:
“Given the importance of macrophage TLR4 in insulin resistance in adipose tissue as reported by recent studies, it is appealing to appraise the role of lactate in macrophage TLR4 activation.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673542/
- Increased Blood Viscosity and Red Blood Cell Aggregation: Lactate may also increase blood viscosity and promote the aggregation of red blood cells. The slower the clearance of lactate, the more aggregation occurs:
“Lactate can lead to an increase in blood viscosity and aggregation of red blood cells. The slower the lactate clearance, the more aggregation occurs.”
https://pubmed.ncbi.nlm.nih.gov/12122228/
Conclusion
Another time we shall discuss the connection between gut flora and cancer, where both endotoxin and lactate are involved. Endotoxin leads to increased lactate, which in turn promotes transcriptional activity of tumor-promoting genes.
Seabridge Bioenergetics 
Leave a comment