How Metabolic Dysfunction is Implicated in Cancer, Liver and Neurodegenerative Disease

At each moment within a cell, 130,000 interactions are occurring between enzymes, proteins, and the many other biomolecular compounds involved in metabolism and cell signalling pathways. The production of metabolites is automatic, and takes place at the nanosecond level in a staggering amount of spontaneous complexity. Metabolomics is the study of all of the resulting metabolites and antioxidants in these interactions, such as the many enzymes created in the citric acid cycle. The 'metabolon' is the term for the total system of metabolism and its by-products, and research is increasingly showing it is highly involved in diseases like cancer, liver disease, and neurodegenerative disease.

Cancer and the Metabolon

Cancer development depends for its cellular respiration on three enzymes: fumarase, dehydrogenase, and pyruvate dehydrogenase. Because cancer cells selectively need to metabolize glucose in the presence of oxygen, they cause mutations that alter these enzymes, which are all regulated by the transcription factor HIF-1, which upregulates the glycolysis in hypoxia (low oxygen) conditions. This transcription factor is protein-based, and so it is naturally broken-down by protylitic enzymes, which prevent it from promoting glycolysis. The key factor in initiating this breakdown of HIF-1 requires oxygen (and vitamin c) and therefore, in low oxygen and low vitamin C states, it simply cannot be broken down, and therefore stimulates the production of new proteins that promote glycolysis. Additionally, if the citric acid cycle produces defective enzymes, like the defective version of succinate dehydrogenase, then this causes the saturation of mitochondria with succinate, which then crosses into the cytoplasm and promotes cancer glycolysis. This connection between the enzymes created in the citric acid cycle, and the progression of cancer glycolysis, is indicative of cancer being largely a metabolic disease.

Liver Disease

When our metabolic system gets to the point that it allows greater accumulation of sugar, fat and metabolic waste, than the body’s ability to correct it, this is the definition of metabolon dysfunction. In non-alcoholic fatty liver disease, something impairs fat metabolism this disease is a precursor to cancer of the liver, GI tract and other organs, that causes trans fat accumulation in the liver. This disease is called metabolic dysfunction-associated steatotic liver disease (MASLD), or metabolic dysfunction-associated steatohepatitis (MASH), and can progress to cirrhosis and fibrosis of the liver. In metabolic dysfunction, the necessary protein-digesting enzymes are not being produced, or are defective, compounding disease progression.

As a metabolic disease, this means that MASLD is the result of the pathogenesis of multiple signaling pathways, such as the insulin pathway, the AMP-activated Protein Kinase Pathway, the mTOR Signaling Pathway, the SIRT1 Pathway which protects the liver, the nuclear receptor pathways, and inflammatory signaling pathways such as the nuclear factor kappa-B. which is the transcription factor involved in the expression of pro-inflammatory genes.

Neurodegenerative Diseases

Another result of metabolic dysfunction is neurodegenerative disease. Alzheimer’s, Parkinsons, and other similar diseases are strongly associated with metabolon dysfunction. This is not surprising since the brain consumes such a large amount of glucose, and so any resulting dysfunction in glucose metabolism will have an impact on neuronal function. But it also has to do with the ability to create enzymes and other metabolites involved in protecting neuronal cells. While there are rare genetic conditions, such as the amyloid precursor protein gene, other gene mutations, these only comprise less than 1% of the total number of Alzheimer’s cases. Characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, the cause of the formation of these plaques is considered to be currently unknown, and appears to be spontaneous and unpredictable. However, the cognitive dysfunction of the disease has been linked to poor glycemic control and hyperglycemia. The reason is that hyperglycemia initiates the formation of AGEs (advanced glycation end products) which are highly carcinogenic and composed of complexes of protein and sugar that cause a large increase free-radicals. Hyperglycemia has also been shown to impair important neurotransmitters, such as acetylcholine, serotonin, dopamine and norepinephrine.

Metabolic hormones like leptin, ghrelin, and GLP-1, are widely implicated in metabolic disorders, and have also been shown to be involved in neurodegenerative disease. Therefore, research are suggesting that therapies should holistically target the whole body, including the endocrine system, as well as the metabolon. Other disease resulting from metabolon dysfunction include diabetes myelitis, disorders of energy metabolism and the nervous system.

Causes and Remedies for Metabolic Disorders

Metabolic disorders are caused by the inability to break down large molecules, resulting in energy inefficiency in the case of carbohydrate metabolic dysfunction, plaque in protein regulation, and liver disease in impaired fat metabolism. Enzymes are the most critical for breaking down these carbs, fats, and proteins that cause excess metabolic waste products to accumulate, and burden certain organs. If the body is burdened, either systemically, or digestively, by low enzyme production, or inability to properly regulate protein synthesis and breakdown, it can be greatly aided through taking the various enzymes for protein, lipid and carbohydrate metabolism. The body has many different specific enzymes for proteins to facilitate the creation of new biomolecules, but can produce them in limited amounts, and be overburdened with dysfunction in the metabolism.

To reduce the risk of metabolic dysfunction, the number one recommendation by even mainstream medical establishments, is to eat fresh fruits and vegetables. The reason is their enzymes are intact, and their breakdown and assimilation requires less biochemical work. With cooked food, the increased AGEs, and other byproducts use-up critical enzymes and metabolites, while also failing to supply critical nutrients that serve as inputs into the many metabolic processes, like the citric acid cycle.

Top Dr. Clark Supplements for Metabolic Disorders:

Digestive Enzymes: Digestive enzymes are specialized proteins that help facilitate the proper breakdown of the foods we eat. They jump start metabolism and enhance the body’s natural ability to break down food into basic nutrient forms, which are absorbed into the body and perform life-sustaining functions.*

Pancreatic Enzymes:  This trio of digestive enzymes breaks down carbohydrates, proteins and fat from the diet. Pancreatin 8X contains eight times the enzyme activity as regular strength pancreatin USP.

Co-Q10: Co Q10 plays a crucial role in the chemical reactions that turn nutrients into energy inside the cells.*

Vitamin C : Vitamin C provides antioxidant protection for many of the body's important enzyme systems. White blood cells (neutrophils) utilize vitamin C to help produce cytotoxic enzymes which they use to eliminate foreign matter. It also helps strengthen collagen, a major connective protein. Vitamin C also plays an important role in the P450 enzyme detoxification system. *

Turmeric: Curcumin is also believed to increase bile production and flow from the liver, enhancing the breakdown of fats during digestion.*

Iodine: Supports thyroid function. Natural digestive aid. Exerts antioxidative, antimicrobial, immunomodulatory, and molecular regulatory effectsIodine also interacts with PPARγ receptors to enhance adipocyte differentiation, fatty acid uptake, and glucose metabolism by improving insulin sensitivity.

Omega-3s: Studies suggest that omega-3 fatty acids have a calming effect on heartbeat and may promote blood circulation. Additional benefits of optimal omega-3 fatty acid consumption include blood lipid regulation and vision support.*

Alpha Lipoic Acid (Thiotic Acid) ALA: In terms of energy production, thioctic acid is thought to reduce mitochondrial decay and boost energy output. It also functions as a co-factor in enzymes responsible for converting food into usable energy.*

Sources

Barbara, D., Pachikian., Céline, Druart., Emilie, Catry., Laure, B., Bindels., Audrey, M., Neyrinck., Yvan, Larondelle., Patrice, D., Cani., Nathalie, M., Delzenne. (2018). 5. Implication of trans-11,trans-13 conjugated linoleic acid in the development of hepatic steatosis.. PLOS ONE, doi: 10.1371/JOURNAL.PONE.0192447

Cheng, Xie., Yixin, Xie., Shun, Liu., Bai, Ji. (2023). Metabolism-related signalling pathways involved in the pathogenesis and development of metabolic dysfunction-associated steatotic liver disease.. Clinics and Research in Hepatology and Gastroenterology, 48(2).

Rongrong, Han., Jing, Liang., Bing, Zhou. (2021). 12. Glucose Metabolic Dysfunction in Neurodegenerative Diseases—New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming. International Journal of Molecular Sciences

Seyfried, T. N., & Shelton, L. M. (2010). Cancer as a metabolic disease. Nutrition & metabolism, 7, 1-22.