Discover the Science Behind PathFinder
Depletion of methyl donors causes a cascade of metabolic disruptions that trigger Liver Fibrosis*
PathFinder is focused on three important Metabolic Pathways in the Liver*
Latest studies show that depletion of dietary one-carbon methyl donors causes a chain of disruption in the metabolic pathways of methionine and choline metabolism in people with both Non-Alcoholic Steatohepatitis (NASH) (1,2) and Alcohol Liver Disease (ALD) (3,4). These metabolic disturbances trigger stellate cell conversion and progressive liver fibrosis (1,4,5,6) which is the excessive accumulation of scar tissue (collagen) in the extracellular spaces of the liver.*
Liver fibrosis was once considered irreversible but studies have shown that reversal is possible in people in which the underlying fibrogenic impulse is eliminated – meaning their underlying chronic liver disease was cured (7,8,9,10). Examples are hepatitis B and hepatitis C patients who undergo antiviral therapy, obese people who undergo bariatric surgery, or forms of weight loss drugs. Studies have also shown that regression of liver fibrosis is possible even in people with deep cirrhosis (7). Once the fibrogenic trigger is eliminated collagenase enzymes called matrix metalloproteinases may resorb excess collagen from the extracellular matrix enzymatically (12).*
One-Carbon depletion is characterized by disruption of methionine and choline metabolism (1,2,3,4). Depletion of methyl donors causes elevated homocysteine (HCY) and S-adenosylhomocysteine (SAH) levels (1,17). Increased HCY and decreased SAM:SAH ratio causes downregulation of the enzymes (MATI&III) which produce S-adenosylmetnionine (SAM) from methionine (MET) (1,2,3,4). Decreased SAM levels have numerous negative metabolic consequences (13,14,15,16), including depletion of phosphatidylcholine (PC) (20,21,22) and decreased glutathione production (transsulfuration) (18,19). Another consequence of depleted SAM is aberrant DNA methylation patterns, reflecting impaired epigentic gene expression (13,14,15,16). Depletion of glutathione, contributes to decreased redox reduction capacity and extreme oxidative stress and depletion of small molecule antioxidants (23,24).*
Researchers have been aware of the contributions of choline, methionine and one-carbon depletion. In fact, in NASH drug studies study mice are fed a choline-defiencient diet (CD) to develop NAFLD, a methione-deficient diet (MD, or MCD)) to produce liver fibrosis and inflammation in the study mice, and a folate-deficient (FD) diet to product study mice with liver cancer (25).
According to Section 403(r)(6)(A) of the Federal Food, Drug & Cosmetic Act certain nutritional deficiencies can cause what are known as nutritional deficiency diseases.*
Science has shown that depletion of one-carbon methyl donors lead to a cascade of metabolic disruptions and associated nutritional depletions that trigger stellate cell conversion and the generation of liver fibrosis (1,2,3,4).*
PathFinder provides 34 specific key nutrients whose depletion triggers and drives Liver Fibrosis and Liver Cirrhosis. This special patented formula is designed to promote healthy nutritional balance in these disrupted metabolic pathways (choline, methionine and one carbon metabolism (see below).*
HepAssure Inc.’s PathFinder formula has been clinically studied on people with advanced Liver Fibrosis and Liver Cirrhosis (please see our Clinical Studies above).*
Between 5.5 million and 6.5 million people in the US have advanced Liver Fibrosis or Liver Cirrhosis (see below).*
PathFinder is a science-based nutritional management program that consists of 34 diet-derived nutrients involved in the linked Choline/Methionine/One-Carbon metabolic pathways.*
PathFinder also provides a broad spectrum of antioxidants to support the body’s natural defenses against oxidative stress and mitochondrial nutrients to aid in energy production.*
Additionally, PathFinder includes amino acids, minerals, and botanical ingredients carefully formulated to support liver metabolism. The formula is designed to provide balanced amounts of specific nutrients while avoiding excessive amounts that could result in un-metabolized by-products.*
Bibliography
(1) da Silva Robin P, Eudy Brandon J, Deminice Rafael, One-Carbon Metabolism in Fatty Liver Disease and Fibrosis: One-Carbon to Rule Them All,The Journal of Nutrition, Volume 150, Issue 5, 2020, Pages 994-1003, ISSN 0022-3166, https://doi.org/10.1093/jn/nxaa032.
(2) Amy Karol Walker, 1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver,Trends in Endocrinology & Metabolism, Volume 28, Issue 1, 2017, Pages 63-72, ISSN 1043-2760, https://doi.org/10.1016/j.tem.2016.10.004. (https://www.sciencedirect.com/science/article/pii/S1043276016301291)
(3) Kruman, Inna I., Fowler, Anna-Kate, Impaired one carbon metabolism and DNA methylation in alcohol toxicity, Journal of Neurochemistry, J. Neurochem. Vol 129, 5, ISSN 0022-3042 https://doi.org/10.1111/jnc.12677
(4) Halsted CH, Medici V. Vitamin-dependent methionine metabolism andalcoholic liver disease. Adv Nutr. 2011;2(5):421-427. doi:10.3945/an.111.000661
(5) Li D1, Friedman SL. Liver fibrogenesis and the role of hepatic stellate cells:new insights and prospects for therapy. J Gastroenterol Hepatol. 1999 Jul;14(7):618-33.
(6) Day, C. and James, O. Steatohepatitis: A Tale of Two “Hits”? Gastroenterology Vol. 114, No 4
(7) Detlef Schuppan, Rambabu Surabattula, Xiao Yu Wang, Determinants of fibrosis progression and regression in NASH, Journal of Hepatology, Volume 68, Issue 2, 2018, Pages 238-250, ISSN 0168-8278, https://doi.org/10.1016/j.jhep.2017.11.012. (https://www.sciencedirect.com/science/article/pii/S0168827817324352)
(8) Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence andexpectations. Korean J Intern Med. 2017;32(2):213–228. doi:10.3904/kjim.2016.268
(9) Jung YK, Yim HJ. Reversal of liver cirrhosis: current evidence andexpectations.Korean J Intern Med. 2017;32(2):213–228. doi:10.3904/kjim.2016.268
(10) Li D1, Friedman SL. Liver fibrogenesis and the role of hepatic stellate cells:new insights and prospects for therapy. J Gastroenterol Hepatol. 1999 Jul;14(7):618-33.
(11) Roeb E. Matrix metalloproteinases and liver fibrosis (translationalaspects).Matrix Biol. 2018;68-69:463-473. doi:10.1016/j.matbio.2017.12.012
(12) Roeb E. Matrix metalloproteinases and liver fibrosis (translationalaspects). Matrix Biol. 2018;68-69:463-473. doi:10.1016/j.matbio.2017.12.012
(13) Mato JM, Mart.nez-Chantar ML, Lu SC. S-adenosylmethionine metabolism andliver disease. Ann Hepatol. 2013;12(2):183-189.
(14) Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liverdisorders. Am J Clin Nutr. 2002 Nov;76(5):1183S-7S.
(15) Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, andcancer. Physiol Rev 2012; 92: 1515–42.
(16) Mazen Noureddin, Jose Mato and Shelly C Lu, Nonalcoholic fatty liverdisease: Update on pathogenesis, diagnosis, treatment and the role of SadenosylmethionineExperimental Biology and Medicine 2015; 240: 809–820. DOI: 10.1177/1535370215579161
(17) Huang RF, Hsu YC, Lin HL, Yang FL. Folate depletion and elevated plasmahomocysteine promote oxidative stress in rat livers. J Nutr. 2001;131(1):33–8.
(18) Lu, Shelly C. Regulation of hepatic glutathione synthesis: current concepts and controversiesThe FASEB Journal Vol. 13, July 1999, 1169-1183 https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fasebj.13.10.1169
(19) Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health.J Nutr. 2004;134(3):489-492. doi:10.1093/jn/134.3.489 https://academic.oup.com/jn/article/134/3/489/4688681
(20) Aleynik SI, Lieber CS Polyenylphosphatidylcholine corrects the alcohol inducedhepatic oxidative stress by restoring s-adenosylmethionine. Alcohol. 2003 May-Jun;38(3):208-12
(21) Zeisel SH, da Costa KA. Choline: an essential nutrient for public health.Nutr Rev. 2009;67(11):615–623. doi:10.1111/j.1753-4887.2009.00246.x
(22) Li Z, Vance DE. Phosphatidylcholine and choline homeostasis. J Lipid Res.
2008;49(6):1187-1194. doi:10.1194/jlr.R700019-JLR200
(23) Li S, Tan HY, Wang N, et al. The Role of Oxidative Stress and Antioxidants in Liver Diseases.Int J Mol Sci. 2015;16(11):26087–26124. Published 2015 Nov 2. doi:10.3390/ijms161125942 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661801/
(24) Lieber CS. Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.Adv Pharmacol. 1997;38:601-28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661801/
(25) Caballero F, Fern.ndez A, Mat.as N, et al. Specific Contribution of Methionine and Choline in Nutritional Nonalcoholic Steatohepatitis: IMPACT ON MITOCHONDRIAL S-ADENOSYL-l-METHIONINE AND GLUTATHIONE. The Journal of Biological Chemistry. 2010;285(24):18528-18536. doi:10.1074/jbc.M109.099333.
Please scroll down to explore the three powerful linked metabolic pathways of choline, methionine and one-carbon metabolism. Click on the metabolic charts to the right to see expanded versions.
Choline, Sulfur and Carbon Donation
PathFinder provides nutrients involved in Choline/Methionine/One-Carbon metabolic pathways, three powerful metabolic pathways that are important parts of liver metabolism.. These three pathways work together in a tightly-controlled manner. Homeostasis in these metabolic pathways is vital for liver health (see Diagram 1, right, click on diagram to see full-size image).*
The metabolic map on the right shows both biosynthetic pathways for phosphatidylcholine production, methionine metabolism, including transsulfuration for glutathione biosynthesis, and how they are all regulated and controlled by one-carbon metabolism including the folic acid cycle and betaine from choline metabolism.
What happens when dietary methyl donors are depleted…
Diagram 2 on the right (click on diagram to see full-size image) shows what happens when dietary methyl donors are depleted. Depletion of one-carbon methyl donors results in disruptions in methionine, glutathione and choline metaboilism. S-adnosylmethionine (SAM) levels are depleted while S-adenosylhomocysteine (SAH) and homocysteine (HCY) accumulate. Further, glutathione (GSH) is depleted and phosphatidylcholine (PC) is depleted. Glutathione depletion and extreme oxidative stress combine to deplete micronutrient small-molecule antioxidants across the board, including important mitochondrial nutrients.*
One-Carbon (…to Rule Them All)
Lord-of-the-Rings metaphors aside, one-carbon metabolism (also known as methyl donation) exerts extraordinary control over the methionine and choline pathways. One-carbon metabolism refers to the transfer of single carbon molecules (methyl groups) through the body in a process called transmethylation.*
One-carbon metabolism includes the folic acid cycle and betaine, either of which which may donate a carbon molecule (transmethylation) to homocysteine (HCY) in order to convert it back to methionine (MET).*
The most prolific methyl donor is S-adenosylmethionine (SAM). SAM is involved in over 100 transmethylation reactions, including phosphatidylcholine (PC) production, protein modification, and DNA methylation (a process that controls epigenetic gene expression) and more (see Diagram 1b, right, click on diagram to see full-size image).*
Depletion of dietary methyl donors causes a cascade of metabolic disruptions*
Depletion of dietary methyl donors causes disruption to methionine cycling (transmethylation), (see Diagram 2b, right). Depletion of methyl donors results in higher SAH and Homocysteine (HCY) levels, SAM depletion, and. Elevated SAM:SAH ratios and elevated homocysteine levels are know to inhibit the enzyme (MAT I&II) that produces SAM from methionine. Depletion of SAM is known to transform benign NAFLD to inflammatory NASH and it is also known to trigger liver fibrosis in alcohol abuse. Depletion of SAM also causes depletion of glutathione, contributing to extreme oxidative stress and depletion of small-molecule antioxidants (click on metabolic chart, right).*
Diagram2b
Glutathione (Transsulfuration)
The Second Fate of Homocysteine*
Depletion of dietary methyl donors causes depletion of glutathione due to depletion of SAM.*
Homocysteine sits at the crossroads of Transsulfuration and Transmethylation (see diagram, right). Transsulfuration is the process of Glutathione (GSH) biosynthesis. Glutathione is a sulfur containing tripeptide composed of L-Cysteine, L-Glutamate and L-Glycine.*
Glutathione is the body’s master antioxidant and it exerts control over the body’s oxidation/reduction (REDOX) balance. Glutathione also performs detoxification duties, scavenging heavy metals from the body. GSH is essential for cellular redox homeostasis and GSH synthesis is tightly regulated in the cytosol.*
Depletion of glutathione has numerous negative metabolic outcomes including contributinf to extreme oxidative stress and depletion of small-molecule non-enzymatic antixidants.*
The production of glutathione involves incorporating three amino acids—L-cysteine, L-glycine, and L-glutamate—into a tripeptide within the cytosol of cells. L-cysteine availability is a key factor in this process, as it is the rate-limiting step for glutathione production.*
PathFinder provides N-acetylcysteine, a bioavailable form of L-cysteine, as well as L-glycine and L-glutamate to support normal glutathione production (please see diagram 1c, right, click on image for full size).*
Phosphatidylcholine(phospholipid) production
Phosphatidylcholine (PC) is a major biosynthetic product of choline metabolism and makes up about 80% of our cell membranes. It plays a key role in lipid transport throughout the body. PC production occurs through two biosynthetic pathways: the PEMT pathway, which depends on SAM methylation, and the CDP-choline pathway, which is part of choline metabolism.
When one-carbon methyl donors are depleted, SAM decreases which in turn decreases PC production along the PEMT pathway. This increases demand on the second pathway, the CDP-choline pathway. Prolonged decrease of SAM availability can deplete PC availability due to impaied synthesis.
PPC is broken down into choline, which can then be recycled back to PC via the CDP-choline pathway. While PathFinder does not contain PC, we offer PPC as a complementary product in a special combination with PathFinder. PPC provides additional support for choline and phosphatidylcholine metabolism, complementing PathFinder’s support for methionine and one-carbon metabolism. Together, these linked pathways help support normal liver metabolism and promote overall liver health (please see diagram 1d, right, click on image for full size).*
Mitochondrial metabolism
PathFinder provides a comprehensive blend of nutrients, including Acetyl L-Carnitine, CoQ10, alpha-lipoic acid, B vitamins, vitamin E, selenium, molybdenum, and zinc, to support healthy mitochondrial function. Mitochondria are the energy powerhouses of the body, playing a key role in normal metabolic processes. PathFinder is formulated with nutrients that help maintain mitochondrial health and function, promoting overall energy production and metabolic support.*
47010474_mitochondria-is-one-of-the-cell-organelles
Small-molecule antioxidants work in cooperation to support the body’s natural antioxidant systems. In Liver Fibrosis they are depleted across the board.*
Small-molecule non-enzymatic antioxidants are critical players in protecting biological systems against oxidative damage. These molecules neutralize reactive oxygen species (ROS) and free radicals, preserving cellular integrity. People with liver fibrosis and liver cirrhosis are known to be depleted on small molecule antioxidants across the board.
Antioxidants may only quench one free radical in their reduced form. After quenching a free radical many of these antioxidants must be converted back to a reduced state in order to regenerate antioxidant activity again. PathFinder supports this system by supplying a broad range of cooperative vitamins, minerals, botanical ingredients, and sulfur-containing antioxidants including alpha-lipoic acid and N-acetylcysteine to promote glutathione production.*
Relationships Among Antioxidants:
The interplay of reducing agents is crucial for maintaining antioxidant activity in biological systems:
- Vitamin C regenerates: Vitamin E, glutathione, and alpha-lipoic acid.*
- Glutathione regenerates: Vitamin C and alpha-lipoic acid.*
- Alpha-lipoic acid regenerates: Vitamin C, glutathione, and indirectly Vitamin E.*
- Coenzyme Q10 cooperates with: Vitamin E to restore its active form.*
- Botanical Polyphenols regenerate: glutathione and Vitamin C.*
