Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy
Abstract
:1. Introduction
1.1. Obesity, Type 2 Diabetes, and Non-Alcoholic Fatty Liver Disease as Cancer Risk Factors
1.2. Flaxseed’s Role as an Anti-Cancer Food
1.3. Vitamin B6, 1-Amino D-Proline, and Flaxseed’s Effect on One-Carbon Metabolism
1.4. SAM Biosynthesis and AMPK Activation
1.5. Type 2 Diabetes, Vitamin B6 Insufficiency, and Cancer: Human Studies Strongly Indicate That Flaxseed Is Safe in Populations That Are at Risk of Vitamin B6 Insufficiency
1.6. Approach and Aim of This Study
2. Materials and Methods
2.1. Animal Studies and Diet Descriptions
2.2. Plasma Collection and Animal Necropsy
2.3. LC-MS/MS Analysis of Plasma Metabolites
2.4. Plasma Fatty Acid Methyl Ester (FAME) Gas Chromatography
2.5. Plasma Glucagon Analysis
2.6. Statistical Analysis
3. Results
3.1. Effect of Diet on Hen Body Mass
3.2. Pyruvate Metabolism: Evidence for Increased Pyruvate Oxidation via the Pyruvate Dehydrogenase Complex (PDC) in Hens That Consume Defatted Flaxseed
3.3. Flaxseed Reduces the Risk of Advanced Liver Steatosis in Laying Hens
3.4. Evidence for Upregulated Mitochondrial FAO and Downregulated Lipogenesis in the Livers of Whole-Flaxseed-Fed Hens
3.5. Acylcarnitines: Evidence for Metabolic Adaptations That Prevent Mitochondrial Overload
3.6. Ornithine Accumulation: Evidence for Flaxseed’s Inhibition of Ornithine Decarboxylase
3.7. Flaxseed Induces the Highest HbA1c% Ever Recorded in Birds: The Strangest Paradox
4. Discussion and Conclusions
4.1. Does Our Work Address Liver Metabolism, and Is Our Work Reproducible in Humans?
4.2. Defatted Flaxseed’s Effect on Glucose Uptake, Glycolysis, and PDC Activity in the Liver: Have We Discovered “Avian Metformin”?
4.3. Synergy between One-Carbon Metabolism and Glycolysis When Hens Consume 10% Defatted Flaxseed: Implications for Aging and Longevity in Avian Species
4.4. We Propose That Flaxseed Attenuates Body Mass and Hepatic Steatosis by Upregulating Hepatic Mitochondrial FAO and Downregulating Hepatic Lipogenesis in Hens
4.5. Synergy between One-Carbon Metabolism and Phosphatidylcholine Catabolism in Hens Consuming a 15% Whole Flaxseed Supplemented Diet
4.6. Acylcarnitine Synthesis: Protecting Mitochondria from Metabolic Overload When Bioenergetic Pathways Are Accelerated
4.7. Evidence for Whole Flaxseed’s Inhibition of Ornithine Decarboxylase (ODC): A Potential Biomarker for Highly Elevated AMPK Activity
4.8. The Exaggerated Catabolic Phenotype of Whole-Flaxseed-Fed Hens Might Be Explained by the Phosphatidylethanolamine Methyltransferase (PEMT) Pathway
4.9. Flaxseed and Elevated HbA1c%: Possibly the Result of 1ADP’s Anti-Vitamin B6 Effect
4.10. Proposed Therapeutic Model in Humans
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
1ADP | 1-amino D-proline |
ACC | Acetyl-CoA carboxylase |
ADK | Adenosine kinase |
ADP | Adenosine diphosphate |
AICAR | 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside |
AMP | Adenosine monophosphate |
AMPK | AMP-activated protein kinase |
AST | Aspartate aminotransferase |
ATP | Adenosine triphosphate |
BCAA | Branch-chain amino acid |
C3, C5, C6, C8, C16-carnitine | Acylcarnitines with either 3, 5, 6, 8, or 16 carbons in the fatty acid |
CBS | Cystathionine beta synthase |
CSE | Cystathionase |
dAMP | Deoxyadenosine monophosphate |
DHA | Docosahexaenoic acid |
DNA | Deoxyribonucleic acid |
ERE | Estrogen response element |
FAO | Fatty acid oxidation (mitochondrial) |
FASN | Fatty acid synthase |
HbA1c% | Glycated hemoglobin (percentage) |
HDL | High density lipoprotein |
IDL | Intermediate-density lipoprotein |
IGF1 | Insulin-like growth factor 1 |
IGF1BP | Insulin-like growth factor 1 binding protein |
IGF1R | Insulin-like growth factor 1 receptor |
LA | Linoleic acid |
LC-MS/MS | Liquid chromatography tandem mass spectrometry |
LDL | Low-density lipoprotein |
MAT | Methionine adenosyltransferase |
MDH | Malate dehydrogenase |
mRNA | Messenger RNA |
MS-B12 | Methionine synthase complexed with vitamin B12 |
NADH | Nicotine adenine dinucleotide (protonated form) |
NAFLD | Non-alcoholic fatty liver disease |
NCBI | National Center for Biotechnology Information |
OA | Oleic acid |
ODC | Ornithine decarboxylase |
PC | Phosphatidylcholine |
PDC | Pyruvate dehydrogenase complex |
PE | Phosphatidylethanolamine |
PEMT | Phosphatidylethanolamine methyltransferase |
PTP1 | Protein tyrosine phosphatase 1 |
SAH | S-adenosylhomocysteine |
SAHH | S-adenosylhomocysteine hydrolase |
SAM | S-adenosylmethionine |
SREBF1 | Sterol regulatory binding factor 1 (aka SREBP1) |
VIP | Variable importance of projection score |
References
- Mitchell, N.S.; Catenacci, V.A.; Wyatt, H.R.; Hill, J.O. Obesity: Overview of an Epidemic. Psychiatr. Clin. N. Am. 2011, 34, 717–732. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Beydoun, M.A.; Min, J.; Xue, H.; Kaminsky, L.A.; Cheskin, L.J. Has the Prevalence of Overweight, Obesity and Central Obesity Levelled off in the United States? Trends, Patterns, Disparities, and Future Projections for the Obesity Epidemic. Int. J. Epidemiol. 2020, 49, 810–823. [Google Scholar] [CrossRef] [PubMed]
- De Pergola, G.; Silvestris, F. Obesity as a Major Risk Factor for Cancer. J. Obes. 2013, 2013, 291546. [Google Scholar] [CrossRef] [PubMed]
- Avgerinos, K.I.; Spyrou, N.; Mantzoros, C.S.; Dalamaga, M. Obesity and Cancer Risk: Emerging Biological Mechanisms and Perspectives. Metabolism 2019, 92, 121–135. [Google Scholar] [CrossRef]
- Mehrgou, A.; Akouchekian, M. The Importance of BRCA1 and BRCA2 Genes Mutations in Breast Cancer Development. Med. J. Islam. Repub. Iran 2016, 30, 369. [Google Scholar]
- White, M.C.; Holman, D.M.; Boehm, J.E.; Peipins, L.A.; Grossman, M.; Henley, S.J. Age and Cancer Risk: A Potentially Modifiable Relationship. Am. J. Prev. Med. 2014, 46, S7–S15. [Google Scholar] [CrossRef]
- Aronson, D.; Bartha, P.; Zinder, O.; Kerner, A.; Markiewicz, W.; Avizohar, O.; Brook, G.J.; Levy, Y. Obesity Is the Major Determinant of Elevated C-Reactive Protein in Subjects with the Metabolic Syndrome. Int. J. Obes. Relat. Metab. Disord 2004, 28, 674–679. [Google Scholar] [CrossRef]
- El-Mikkawy, D.M.E.; EL-Sadek, M.A.; EL-Badawy, M.A.; Samaha, D. Circulating Level of Interleukin-6 in Relation to Body Mass Indices and Lipid Profile in Egyptian Adults with Overweight and Obesity. Egypt. Rheumatol. Rehabil. 2020, 47, 7. [Google Scholar] [CrossRef]
- Xu, L.; Kitade, H.; Ni, Y.; Ota, T. Roles of Chemokines and Chemokine Receptors in Obesity-Associated Insulin Resistance and Nonalcoholic Fatty Liver Disease. Biomolecules 2015, 5, 1563–1579. [Google Scholar] [CrossRef]
- Hotamisligil, G.S.; Spiegelman, B.M. Tumor Necrosis Factor Alpha: A Key Component of the Obesity-Diabetes Link. Diabetes 1994, 43, 1271–1278. [Google Scholar] [CrossRef]
- Nieman, K.M.; Kenny, H.A.; Penicka, C.V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M.R.; Romero, I.L.; Carey, M.S.; Mills, G.B.; Hotamisligil, G.S.; et al. Adipocytes Promote Ovarian Cancer Metastasis and Provide Energy for Rapid Tumor Growth. Nat. Med. 2011, 17, 1498–1503. [Google Scholar] [CrossRef] [PubMed]
- Koca, T.T. Does Obesity Cause Chronic Inflammation? The Association between Complete Blood Parameters with Body Mass Index and Fasting Glucose. Pak. J. Med. Sci. 2017, 33, 65–69. [Google Scholar] [CrossRef] [PubMed]
- Maeda, H.; Akaike, T. Nitric Oxide and Oxygen Radicals in Infection, Inflammation, and Cancer. Biochemistry 1998, 63, 854–865. [Google Scholar] [PubMed]
- Lin, Y.; Xu, J.; Lan, H. Tumor-Associated Macrophages in Tumor Metastasis: Biological Roles and Clinical Therapeutic Applications. J. Hematol. Oncol. 2019, 12, 76. [Google Scholar] [CrossRef]
- Ling, S.; Brown, K.; Miksza, J.K.; Howells, L.; Morrison, A.; Issa, E.; Yates, T.; Khunti, K.; Davies, M.J.; Zaccardi, F. Association of Type 2 Diabetes With Cancer: A Meta-Analysis With Bias Analysis for Unmeasured Confounding in 151 Cohorts Comprising 32 Million People. Diabetes Care 2020, 43, 2313–2322. [Google Scholar] [CrossRef]
- González, N.; Prieto, I.; Del Puerto-Nevado, L.; Portal-Nuñez, S.; Ardura, J.A.; Corton, M.; Fernández-Fernández, B.; Aguilera, O.; Gomez-Guerrero, C.; Mas, S.; et al. 2017 Update on the Relationship between Diabetes and Colorectal Cancer: Epidemiology, Potential Molecular Mechanisms and Therapeutic Implications. Oncotarget 2017, 8, 18456–18485. [Google Scholar] [CrossRef]
- Lee, J.Y.; Jeon, I.; Kim, J.W.; Song, Y.-S.; Yoon, J.-M.; Park, S.M. Diabetes Mellitus and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies. Int. J. Gynecol. Cancer 2013, 23, 402–412. [Google Scholar] [CrossRef]
- Barnes, A.S. The Epidemic of Obesity and Diabetes: Trends and Treatments. Tex. Heart Inst. J. 2011, 38, 142–144. [Google Scholar]
- Scully, T.; Ettela, A.; LeRoith, D.; Gallagher, E.J. Obesity, Type 2 Diabetes, and Cancer Risk. Front. Oncol. 2020, 10, 615375. [Google Scholar] [CrossRef]
- Polyzos, S.A.; Kountouras, J.; Mantzoros, C.S. Obesity and Nonalcoholic Fatty Liver Disease: From Pathophysiology to Therapeutics. Metabolism 2019, 92, 82–97. [Google Scholar] [CrossRef]
- Targher, G.; Corey, K.E.; Byrne, C.D.; Roden, M. The Complex Link between NAFLD and Type 2 Diabetes Mellitus—Mechanisms and Treatments. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 599–612. [Google Scholar] [CrossRef] [PubMed]
- Tomah, S.; Alkhouri, N.; Hamdy, O. Nonalcoholic Fatty Liver Disease and Type 2 Diabetes: Where Do Diabetologists Stand? Clin. Diabetes Endocrinol. 2020, 6, 9. [Google Scholar] [CrossRef] [PubMed]
- Cho, H.J.; Hwang, S.; Park, J.I.; Yang, M.J.; Hwang, J.C.; Yoo, B.M.; Lee, K.M.; Shin, S.J.; Lee, K.J.; Kim, J.H.; et al. Improvement of Nonalcoholic Fatty Liver Disease Reduces the Risk of Type 2 Diabetes Mellitus. Gut Liver 2019, 13, 440–449. [Google Scholar] [CrossRef]
- Mohammadi-Sartang, M.; Mazloom, Z.; Raeisi-Dehkordi, H.; Barati-Boldaji, R.; Bellissimo, N.; Totosy de Zepetnek, J.O. The Effect of Flaxseed Supplementation on Body Weight and Body Composition: A Systematic Review and Meta-Analysis of 45 Randomized Placebo-Controlled Trials. Obes. Rev. 2017, 18, 1096–1107. [Google Scholar] [CrossRef] [PubMed]
- Ahmadniay Motlagh, H.; Aalipanah, E.; Mazidi, M.; Faghih, S. Effect of Flaxseed Consumption on Central Obesity, Serum Lipids, and Adiponectin Level in Overweight or Obese Women: A Randomised Controlled Clinical Trial. Int. J. Clin. Pract. 2021, 75, e14592. [Google Scholar] [CrossRef]
- Mohammadi-Sartang, M.; Sohrabi, Z.; Barati-Boldaji, R.; Raeisi-Dehkordi, H.; Mazloom, Z. Flaxseed Supplementation on Glucose Control and Insulin Sensitivity: A Systematic Review and Meta-Analysis of 25 Randomized, Placebo-Controlled Trials. Nutr. Rev. 2018, 76, 125–139. [Google Scholar] [CrossRef]
- Xi, H.; Zhou, W.; Sohaib, M.; Niu, Y.; Zhu, R.; Guo, Y.; Wang, S.; Mao, J.; Wang, X.; Guo, L. Flaxseed Supplementation Significantly Reduces Hemoglobin A1c in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Nutr. Res. 2023, 110, 23–32. [Google Scholar] [CrossRef]
- Haidari, F.; Banaei-Jahromi, N.; Zakerkish, M.; Ahmadi, K. The Effects of Flaxseed Supplementation on Metabolic Status in Women with Polycystic Ovary Syndrome: A Randomized Open-Labeled Controlled Clinical Trial. Nutr. J. 2020, 19, 8. [Google Scholar] [CrossRef]
- Morshedzadeh, N.; Rahimlou, M.; Shahrokh, S.; Karimi, S.; Mirmiran, P.; Zali, M.R. The Effects of Flaxseed Supplementation on Metabolic Syndrome Parameters, Insulin Resistance and Inflammation in Ulcerative Colitis Patients: An Open-Labeled Randomized Controlled Trial. Phytother. Res. 2021, 35, 3781–3791. [Google Scholar] [CrossRef]
- Yari, Z.; Cheraghpour, M.; Hekmatdoost, A. Flaxseed and/or Hesperidin Supplementation in Metabolic Syndrome: An Open-Labeled Randomized Controlled Trial. Eur. J. Nutr. 2021, 60, 287–298. [Google Scholar] [CrossRef]
- Yari, Z.; Rahimlou, M.; Eslamparast, T.; Ebrahimi-Daryani, N.; Poustchi, H.; Hekmatdoost, A. Flaxseed Supplementation in Non-Alcoholic Fatty Liver Disease: A Pilot Randomized, Open Labeled, Controlled Study. Int. J. Food Sci. Nutr. 2016, 67, 461–469. [Google Scholar] [CrossRef] [PubMed]
- Kristensen, M.; Jensen, M.G.; Aarestrup, J.; Petersen, K.E.; Søndergaard, L.; Mikkelsen, M.S.; Astrup, A. Flaxseed Dietary Fibers Lower Cholesterol and Increase Fecal Fat Excretion, but Magnitude of Effect Depend on Food Type. Nutr. Metab. 2012, 9, 8. [Google Scholar] [CrossRef] [PubMed]
- Edel, A.L.; Rodriguez-Leyva, D.; Maddaford, T.G.; Caligiuri, S.P.B.; Austria, J.A.; Weighell, W.; Guzman, R.; Aliani, M.; Pierce, G.N. Dietary Flaxseed Independently Lowers Circulating Cholesterol and Lowers It beyond the Effects of Cholesterol-Lowering Medications Alone in Patients with Peripheral Artery Disease. J. Nutr. 2015, 145, 749–757. [Google Scholar] [CrossRef] [PubMed]
- Johnson, P.A.; Giles, J.R. The Hen as a Model of Ovarian Cancer. Nat. Rev. Cancer 2013, 13, 432–436. [Google Scholar] [CrossRef]
- Ansenberger, K.; Richards, C.; Zhuge, Y.; Barua, A.; Bahr, J.M.; Luborsky, J.L.; Hales, D.B. Decreased Severity of Ovarian Cancer and Increased Survival in Hens Fed a Flaxseed-Enriched Diet for 1 Year. Gynecol. Oncol. 2010, 117, 341–347. [Google Scholar] [CrossRef]
- Eilati, E.; Bahr, J.M.; Hales, D.B. Long Term Consumption of Flaxseed Enriched Diet Decreased Ovarian Cancer Incidence and Prostaglandin E2in Hens. Gynecol. Oncol. 2013, 130, 620–628. [Google Scholar] [CrossRef]
- Hakim, A.A.; Barry, C.P.; Barnes, H.J.; Anderson, K.E.; Petitte, J.; Whitaker, R.; Lancaster, J.M.; Wenham, R.M.; Carver, D.K.; Turbov, J.; et al. Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in P53, Ras, and HER-2/Neu. Cancer Prev. Res. 2009, 2, 114–121. [Google Scholar] [CrossRef]
- Barua, A.; Bitterman, P.; Abramowicz, J.S.; Dirks, A.L.; Bahr, J.M.; Hales, D.B.; Bradaric, M.J.; Edassery, S.L.; Rotmensch, J.; Luborsky, J.L. Histopathology of Ovarian Tumors in Laying Hens: A Preclinical Model of Human Ovarian Cancer. Int. J. Gynecol. Cancer 2009, 19, 531–539. [Google Scholar] [CrossRef]
- Dikshit, A.; Hales, K.; Hales, D.B. Whole Flaxseed Diet Alters Estrogen Metabolism to Promote 2-Methoxtestradiol-Induced Apoptosis in Hen Ovarian Cancer. J. Nutr. Biochem. 2017, 42, 117–125. [Google Scholar] [CrossRef]
- Hales, K.H.; Speckman, S.C.; Kurrey, N.K.; Hales, D.B. Uncovering Molecular Events Associated with the Chemosuppressive Effects of Flaxseed: A Microarray Analysis of the Laying Hen Model of Ovarian Cancer. BMC Genom. 2014, 15, 709. [Google Scholar] [CrossRef] [PubMed]
- Pal, P.; Hales, K.; Petrik, J.; Hales, D.B. Pro-Apoptotic and Anti-Angiogenic Actions of 2-Methoxyestradiol and Docosahexaenoic Acid, the Biologically Derived Active Compounds from Flaxseed Diet, in Preventing Ovarian Cancer. J. Ovarian Res. 2019, 12, 49. [Google Scholar] [CrossRef]
- Weston, W.C.; Hales, K.H.; Hales, D.B. Flaxseed Increases Animal Lifespan and Reduces Ovarian Cancer Severity by Toxically Augmenting One-Carbon Metabolism. Molecules 2021, 26, 5674. [Google Scholar] [CrossRef] [PubMed]
- Liang, J.; Han, Q.; Tan, Y.; Ding, H.; Li, J. Current Advances on Structure-Function Relationships of Pyridoxal 5′-Phosphate-Dependent Enzymes. Front. Mol. Biosci. 2019, 6, 4. [Google Scholar] [CrossRef]
- Cellini, B.; Zelante, T.; Dindo, M.; Bellet, M.M.; Renga, G.; Romani, L.; Costantini, C. Pyridoxal 5′-Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism. Int. J. Mol. Sci. 2020, 21, 5823. [Google Scholar] [CrossRef] [PubMed]
- Parra, M.; Stahl, S.; Hellmann, H. Vitamin B6 and Its Role in Cell Metabolism and Physiology. Cells 2018, 7, 84. [Google Scholar] [CrossRef] [PubMed]
- Mooney, S.; Leuendorf, J.-E.; Hendrickson, C.; Hellmann, H. Vitamin B6: A Long Known Compound of Surprising Complexity. Molecules 2009, 14, 329–351. [Google Scholar] [CrossRef] [PubMed]
- Klosterman, H.J.; Lamoureux, G.L.; Parsons, J.L. Isolation, Characterization, and Synthesis of Linatine. A Vitamin B6 Antagonist from Flaxseed (Linum Usitatissimum). Biochemistry 1967, 6, 170–177. [Google Scholar] [CrossRef]
- Mayengbam, S.; Raposo, S.; House, J. Effect of Vitamin B6-Antagonist from Flaxseed on Amino Acid Metabolism in Moderately Vitamin B6-Deficient Rats. FASEB J. 2015, 29, 134.6. [Google Scholar] [CrossRef]
- Mayengbam, S.; Raposo, S.; Aliani, M.; House, J.D. Oral Exposure to the Anti-Pyridoxine Compound 1-Amino d-Proline Further Perturbs Homocysteine Metabolism through the Transsulfuration Pathway in Moderately Vitamin B6 Deficient Rats. J. Nutr. Biochem. 2015, 26, 241–249. [Google Scholar] [CrossRef]
- Takafumi, O.; Ryohei, T.; Muneyoshi, K.; Tetsuya, K.; Tsutomu, F.; Haruyuki, I.; Tomoyoshi, S.; Kazunori, K.; Tokichi, M.; Dai, H.; et al. Stimulating S-Adenosyl-l-Methionine Synthesis Extends Lifespan via Activation of AMPK. Proc. Natl. Acad. Sci. USA 2016, 113, 11913–11918. [Google Scholar] [CrossRef]
- Ross, F.A.; Jensen, T.E.; Hardie, D.G. Differential Regulation by AMP and ADP of AMPK Complexes Containing Different γ Subunit Isoforms. Biochem. J. 2016, 473, 189–199. [Google Scholar] [CrossRef]
- Gowans, G.J.; Hawley, S.A.; Ross, F.A.; Hardie, D.G. AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation. Cell Metab. 2013, 18, 556–566. [Google Scholar] [CrossRef] [PubMed]
- Cai, Z.; Li, C.-F.; Han, F.; Liu, C.; Zhang, A.; Hsu, C.-C.; Peng, D.; Zhang, X.; Jin, G.; Rezaeian, A.-H.; et al. Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis. Mol. Cell 2020, 80, 263–278.e7. [Google Scholar] [CrossRef] [PubMed]
- Zammit, V.A.; Arduini, A. The AMPK-Malonyl-CoA-CPT1 Axis in the Control of Hypothalamic Neuronal Function. Cell Metab. 2008, 8, 175. [Google Scholar] [CrossRef]
- Herzig, S.; Shaw, R.J. AMPK: Guardian of Metabolism and Mitochondrial Homeostasis. Nat. Rev. Mol. Cell Biol. 2018, 19, 121–135. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.; Katerelos, M.; Gleich, K.; Galic, S.; Kemp, B.E.; Mount, P.F.; Power, D.A. Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin. J. Am. Soc. Nephrol. 2018, 29, 2326–2336. [Google Scholar] [CrossRef]
- Zhang, T.; Hu, L.; Tang, J.-F.; Xu, H.; Tian, K.; Wu, M.-N.; Huang, S.-Y.; Du, Y.-M.; Zhou, P.; Lu, R.-J.; et al. Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines. Molecules 2021, 26, 1990. [Google Scholar] [CrossRef]
- Passariello, C.L.; Gottardi, D.; Cetrullo, S.; Zini, M.; Campana, G.; Tantini, B.; Pignatti, C.; Flamigni, F.; Guarnieri, C.; Caldarera, C.M.; et al. Evidence That AMP-Activated Protein Kinase Can Negatively Modulate Ornithine Decarboxylase Activity in Cardiac Myoblasts. Biochim. Biophys. Acta (BBA)—Mol. Cell Res. 2012, 1823, 800–807. [Google Scholar] [CrossRef]
- Lazzarino, G.; Amorini, A.M.; Signoretti, S.; Musumeci, G.; Lazzarino, G.; Caruso, G.; Pastore, F.S.; Di Pietro, V.; Tavazzi, B.; Belli, A. Pyruvate Dehydrogenase and Tricarboxylic Acid Cycle Enzymes Are Sensitive Targets of Traumatic Brain Injury Induced Metabolic Derangement. Int. J. Mol. Sci. 2019, 20, 5774. [Google Scholar] [CrossRef]
- Randle, P.J.; Garland, P.B.; Hales, C.N.; Newsholme, E.A. The Glucose Fatty-Acid Cycle its Role in Insulin Sensitivity and the Metabolic Disturbances of Diabetes Mellitus. Lancet 1963, 281, 785–789. [Google Scholar] [CrossRef]
- Hue, L.; Taegtmeyer, H. The Randle Cycle Revisited: A New Head for an Old Hat. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E578–E591. [Google Scholar] [CrossRef] [PubMed]
- Alabduladhem, T.O.; Bordoni, B. Physiology, Krebs Cycle; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
- Birsoy, K.; Wang, T.; Chen, W.W.; Freinkman, E.; Abu-Remaileh, M.; Sabatini, D.M. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell 2015, 162, 540–551. [Google Scholar] [CrossRef] [PubMed]
- Maynard, A.G.; Kanarek, N. NADH Ties One-Carbon Metabolism to Cellular Respiration. Cell Metab. 2020, 31, 660–662. [Google Scholar] [CrossRef] [PubMed]
- Mascolo, E.; Vernì, F. Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms. Int. J. Mol. Sci. 2020, 21, 3669. [Google Scholar] [CrossRef]
- Iwakawa, H.; Nakamura, Y.; Fukui, T.; Fukuwatari, T.; Ugi, S.; Maegawa, H.; Doi, Y.; Shibata, K. Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus. Nutr. Metab. Insights 2016, 9, NMI.S40595. [Google Scholar] [CrossRef]
- Ramis, R.; Ortega-Castro, J.; Caballero, C.; Casasnovas, R.; Cerrillo, A.; Vilanova, B.; Adrover, M.; Frau, J. How Does Pyridoxamine Inhibit the Formation of Advanced Glycation End Products? The Role of Its Primary Antioxidant Activity. Antioxidants 2019, 8, 344. [Google Scholar] [CrossRef]
- Booth, A.A.; Khalifah, R.G.; Todd, P.; Hudson, B.G. Kinetic Studies of Formation of Antigenic Advanced Glycation End Products (AGEs): Novel inhibition of post-amadori glycation pathways. J. Biol. Chem. 1997, 272, 5430–5437. [Google Scholar] [CrossRef]
- Higuchi, O.; Nakagawa, K.; Tsuzuki, T.; Suzuki, T.; Oikawa, S.; Miyazawa, T. Aminophospholipid Glycation and Its Inhibitor Screening System: A New Role of Pyridoxal 5′-Phosphate as the Inhibitor. J. Lipid. Res. 2006, 47, 964–974. [Google Scholar] [CrossRef]
- Kim, H.H.; Kang, Y.-R.; Lee, J.-Y.; Chang, H.-B.; Lee, K.W.; Apostolidis, E.; Kwon, Y.-I. The Postprandial Anti-Hyperglycemic Effect of Pyridoxine and Its Derivatives Using In Vitro and In Vivo Animal Models. Nutrients 2018, 10, 285. [Google Scholar] [CrossRef]
- Havaux, M.; Ksas, B.; Szewczyk, A.; Rumeau, D.; Franck, F.; Caffarri, S.; Triantaphylidès, C. Vitamin B6 Deficient Plants Display Increased Sensitivity to High Light and Photo-Oxidative Stress. BMC Plant Biol. 2009, 9, 130. [Google Scholar] [CrossRef]
- Bilski, P.; Li, M.Y.; Ehrenshaft, M.; Daub, M.E.; Chignell, C.F. Vitamin B6 (Pyridoxine) and Its Derivatives Are Efficient Singlet Oxygen Quenchers and Potential Fungal Antioxidants. Photochem. Photobiol. 2000, 71, 129–134. [Google Scholar] [CrossRef] [PubMed]
- Clark, W.F.; Kortas, C.; Heidenheim, A.P.; Garland, J.; Spanner, E.; Parbtani, A. Flaxseed in Lupus Nephritis: A Two-Year Nonplacebo-Controlled Crossover Study. J. Am. Coll. Nutr. 2001, 20, 143–148. [Google Scholar] [CrossRef] [PubMed]
- Al Za’abi, M.; Ali, H.; Ali, B.H. Effect of Flaxseed on Systemic Inflammation and Oxidative Stress in Diabetic Rats with or without Chronic Kidney Disease. PLoS ONE 2021, 16, e0258800. [Google Scholar] [CrossRef] [PubMed]
- Velasquez, M.T.; Bhathena, S.A.M.J.; Ranich, T.; Schwartz, A.M.; Kardon, D.E.; Ali, A.L.I.A.; Haudenschild, C.C.; Hansen, C.T. Dietary Flaxseed Meal Reduces Proteinuria and Ameliorates Nephropathy in an Animal Model of Type II Diabetes Mellitus. Kidney Int. 2003, 64, 2100–2107. [Google Scholar] [CrossRef]
- Stuglin, C.; Prasad, K. Effect of Flaxseed Consumption on Blood Pressure, Serum Lipids, Hemopoietic System and Liver and Kidney Enzymes in Healthy Humans. J. Cardiovasc. Pharmacol. Ther. 2005, 10, 23–27. [Google Scholar] [CrossRef] [PubMed]
- Mayengbam, S.; Raposo, S.; Aliani, M.; House, J.D. A Vitamin B-6 Antagonist from Flaxseed Perturbs Amino Acid Metabolism in Moderately Vitamin B-6–Deficient Male Rats. J. Nutr. 2015, 146, 14–20. [Google Scholar] [CrossRef]
- Brown, M.J.; Ameer, M.A.; Beier, K. Vitamin B6 Deficiency; StatPearls Publishing: Treasure Island, FL, USA, 2020. [Google Scholar]
- Mir, A.R.; Habib, S.; Uddin, M. Recent Advances in Histone Glycation: Emerging Role in Diabetes and Cancer. Glycobiology 2021, 31, 1072–1079. [Google Scholar] [CrossRef]
- Deo, P.; McCullough, C.L.; Almond, T.; Jaunay, E.L.; Donnellan, L.; Dhillon, V.S.; Fenech, M. Dietary Sugars and Related Endogenous Advanced Glycation End-Products Increase Chromosomal DNA Damage in WIL2-NS Cells, Measured Using Cytokinesis-Block Micronucleus Cytome Assay. Mutagenesis 2020, 35, 169–177. [Google Scholar] [CrossRef]
- Thornalley, P.J. Protein and Nucleotide Damage by Glyoxal and Methylglyoxal in Physiological Systems—Role in Ageing and Disease. Drug Metab. Drug Interact. 2008, 23, 125–150. [Google Scholar] [CrossRef]
- Ciminera, A.K.; Shuck, S.C.; Termini, J. Elevated Glucose Increases Genomic Instability by Inhibiting Nucleotide Excision Repair. Life Sci. Alliance 2021, 4, e202101159. [Google Scholar] [CrossRef]
- Nowotny, K.; Jung, T.; Höhn, A.; Weber, D.; Grune, T. Advanced Glycation End Products and Oxidative Stress in Type 2 Diabetes Mellitus. Biomolecules 2015, 5, 194–222. [Google Scholar] [CrossRef] [PubMed]
- Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does It Benefit Cancer Cells? Trends Biochem. Sci. 2016, 41, 211–218. [Google Scholar] [CrossRef] [PubMed]
- Davis, J.E.; Cain, J.; Small, C.; Hales, D.B. Therapeutic Effect of Flax-Based Diets on Fatty Liver in Aged Laying Hens. Poult. Sci. 2016, 95, 2624–2632. [Google Scholar] [CrossRef] [PubMed]
- Luo, J.; Qi, J.; Wang, W.; Luo, Z.; Liu, L.; Zhang, G.; Zhou, Q.; Liu, J.; Peng, X. Antiobesity Effect of Flaxseed Polysaccharide via Inducing Satiety Due to Leptin Resistance Removal and Promoting Lipid Metabolism through the AMP-Activated Protein Kinase (AMPK) Signaling Pathway. J. Agric. Food Chem. 2019, 67, 7040–7049. [Google Scholar] [CrossRef]
- Kang, J.; Park, J.; Kim, H.-L.; Jung, Y.; Youn, D.-H.; Lim, S.; Song, G.; Park, H.; Jin, J.S.; Kwak, H.J.; et al. Secoisolariciresinol Diglucoside Inhibits Adipogenesis through the AMPK Pathway. Eur. J. Pharmacol. 2018, 820, 235–244. [Google Scholar] [CrossRef]
- Newman, L.A.; Sorich, M.J.; Rowland, A. Role of Extracellular Vesicles in the Pathophysiology, Diagnosis and Tracking of Non-Alcoholic Fatty Liver Disease. J. Clin. Med. 2020, 9, 2032. [Google Scholar] [CrossRef]
- Zhang, Y.; Liu, Z.; Liu, R.; Wang, J.; Zheng, M.; Li, Q.; Cui, H.; Zhao, G.; Wen, J. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken. Genes 2018, 9, 199. [Google Scholar] [CrossRef] [PubMed]
- Mullen, A.R.; Hu, Z.; Shi, X.; Jiang, L.; Boroughs, L.K.; Kovacs, Z.; Boriack, R.; Rakheja, D.; Sullivan, L.B.; Linehan, W.M.; et al. Oxidation of Alpha-Ketoglutarate Is Required for Reductive Carboxylation in Cancer Cells with Mitochondrial Defects. Cell Rep. 2014, 7, 1679–1690. [Google Scholar] [CrossRef]
- Jenkins, T.C. Technical Note: Common Analytical Errors Yielding Inaccurate Results during Analysis of Fatty Acids in Feed and Digesta Samples. J. Dairy Sci. 2010, 93, 1170–1174. [Google Scholar] [CrossRef]
- Yerevanian, A.; Soukas, A.A. Metformin: Mechanisms in Human Obesity and Weight Loss. Curr. Obes. Rep. 2019, 8, 156–164. [Google Scholar] [CrossRef]
- Watford, M.; Hod, Y.; Chiao, Y.B.; Utter, M.F.; Hanson, R.W. The Unique Role of the Kidney in Gluconeogenesis in the Chicken. The Significance of a Cytosolic Form of Phosphoenolpyruvate Carboxykinase. J. Biol. Chem. 1981, 256, 10023–10027. [Google Scholar] [CrossRef]
- Davis, J.E.; Cain, J.; Small, C.; Hales, D.B. Supplementation of Whole Flaxseed Reduced Hepatic Steatosis in Aged Laying Hens. FASEB J. 2016, 30, 692.28. [Google Scholar]
- Hazelwood, R.L. The Avian Endocrine Pancreas. Am. Zool 1973, 13, 699–709. [Google Scholar] [CrossRef]
- Klandorf, H.; Holt, S.B.; McGowan, J.A.; Pinchasov, Y.; Deyette, D.; Peterson, R.A. Hyperglycemia and Non-Enzymatic Glycation of Serum and Tissue Proteins in Chickens. Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol. 1995, 110, 215–220. [Google Scholar] [CrossRef] [PubMed]
- Holmes, D.J.; Ottinger, M.A. Birds as Long-Lived Animal Models for the Study of Aging. Exp. Gerontol. 2003, 38, 1365–1375. [Google Scholar] [CrossRef] [PubMed]
- Beuchat, C.A.; Chong, C.R. Hyperglycemia in Hummingbirds and Its Consequences for Hemoglobin Glycation. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 1998, 120, 409–416. [Google Scholar] [CrossRef] [PubMed]
- Chaudhuri, C.R.; Chatterjee, I.B. L-Ascorbic Acid Synthesis in Birds: Phylogenetic Trend. Science 1969, 164, 435–436. [Google Scholar] [CrossRef]
- Davie, S.J.; Gould, B.J.; Yudkin, J.S. Effect of Vitamin C on Glycosylation of Proteins. Diabetes 1992, 41, 167–173. [Google Scholar] [CrossRef]
- Szwergold, B.S.; Miller, C.B. Potential of Birds to Serve as Pathology-Free Models of Type 2 Diabetes, Part 2: Do High Levels of Carbonyl-Scavenging Amino Acids (e.g., Taurine) and Low Concentrations of Methylglyoxal Limit the Production of Advanced Glycation End-Products? Rejuvenation Res. 2014, 17, 347–358. [Google Scholar] [CrossRef]
- Grande, F.; Prigge, W.F. Glucagon Infusion, Plasma FFA and Triglycerides, Blood Sugar, and Liver Lipids in Birds. Am. J. Physiol. -Leg. Content 1970, 218, 1406–1411. [Google Scholar] [CrossRef]
- Watford, M. Gluconeogenesis in the Chicken: Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression. Fed. Proc. 1985, 44, 2469–2474. [Google Scholar] [PubMed]
- Duclos, M.J. Insulin-like Growth Factor-I (IGF-1) MRNA Levels and Chicken Muscle Growth. J. Physiol. Pharmacol. 2005, 56 (Suppl. S3), 25–35. [Google Scholar] [PubMed]
- Duclos, M.J.; Wilkie, R.S.; Goddard, C. Stimulation of DNA Synthesis in Chicken Muscle Satellite Cells by Insulin and Insulin-like Growth Factors: Evidence for Exclusive Mediation by a Type-I Insulin-like Growth Factor Receptor. J. Endocrinol. 1991, 128, 35-NP. [Google Scholar] [CrossRef]
- Duclos, M.J.; Chevalier, B.; Le Marchand-Brustel, Y.; Tanti, J.F.; Goddard, C.; Simon, J. Insulin-like Growth Factor-I-Stimulated Glucose Transport in Myotubes Derived from Chicken Muscle Satellite Cells. J. Endocrinol. 1993, 137, 465–472. [Google Scholar] [CrossRef]
- Plavnik, I.; Hurwitz, S. Organ Weights and Body Composition in Chickens as Related to the Energy and Amino Acid Requirements: Effects of Strain, Sex, and Age. Poult. Sci. 1983, 62, 152–163. [Google Scholar] [CrossRef]
- Chan, S.C.; Liu, C.L.; Lo, C.M.; Lam, B.K.; Lee, E.W.; Wong, Y.; Fan, S.T. Estimating Liver Weight of Adults by Body Weight and Gender. World J. Gastroenterol. 2006, 12, 2217–2222. [Google Scholar] [CrossRef]
- Rogers, A.B.; Dintzis, R.Z. 13—Hepatobiliary System; Treuting, P.M., Dintzis, S.M., Montine, K.S., Eds.; Academic Press: San Diego, CA, USA, 2018; pp. 229–239. ISBN 978-0-12-802900-8. [Google Scholar]
- Omini, J.; Wojciechowska, I.; Skirycz, A.; Moriyama, H.; Obata, T. Association of the Malate Dehydrogenase-Citrate Synthase Metabolon Is Modulated by Intermediates of the Krebs Tricarboxylic Acid Cycle. Sci. Rep. 2021, 11, 18770. [Google Scholar] [CrossRef]
- KITA, K. Refeeding Increases Hepatic Insulin-like Growth Factor-I (IGF-I) Gene Expression and Plasma IGF-I Concentration in Fasted Chicks. Br. Poult. Sci. 1998, 39, 679–682. [Google Scholar] [CrossRef]
- Burnside, J.; Cogburn, L.A. Developmental Expression of Hepatic Growth Hormone Receptor and Insulin-like Growth Factor-I MRNA in the Chicken. Mol. Cell Endocrinol. 1992, 89, 91–96. [Google Scholar] [CrossRef] [PubMed]
- Singh, K.; Maity, P.; Krug, L.; Meyer, P.; Treiber, N.; Lucas, T.; Basu, A.; Kochanek, S.; Wlaschek, M.; Geiger, H.; et al. Superoxide Anion Radicals Induce IGF-1 Resistance through Concomitant Activation of PTP1B and PTEN. EMBO Mol. Med. 2015, 7, 59–77. [Google Scholar] [CrossRef]
- Amelio, I.; Cutruzzolá, F.; Antonov, A.; Agostini, M.; Melino, G. Serine and Glycine Metabolism in Cancer. Trends Biochem. Sci. 2014, 39, 191–198. [Google Scholar] [CrossRef]
- Tajan, M.; Hennequart, M.; Cheung, E.C.; Zani, F.; Hock, A.K.; Legrave, N.; Maddocks, O.D.K.; Ridgway, R.A.; Athineos, D.; Suárez-Bonnet, A.; et al. Serine Synthesis Pathway Inhibition Cooperates with Dietary Serine and Glycine Limitation for Cancer Therapy. Nat. Commun. 2021, 12, 366. [Google Scholar] [CrossRef] [PubMed]
- Ho, A.; Sinick, J.; Esko, T.; Fischer, K.; Menni, C.; Zierer, J.; Matey-Hernandez, M.; Fortney, K.; Morgen, E.K. Circulating Glucuronic Acid Predicts Healthspan and Longevity in Humans and Mice. Aging 2019, 11, 7694–7706. [Google Scholar] [CrossRef]
- Aon, M.A.; Bernier, M.; Mitchell, S.J.; Di Germanio, C.; Mattison, J.A.; Ehrlich, M.R.; Colman, R.J.; Anderson, R.M.; de Cabo, R. Untangling Determinants of Enhanced Health and Lifespan through a Multi-Omics Approach in Mice. Cell Metab. 2020, 32, 100–116.e4. [Google Scholar] [CrossRef]
- He, L.; Ding, Y.; Zhou, X.; Li, T.; Yin, Y. Serine Signaling Governs Metabolic Homeostasis and Health. Trends Endocrinol. Metab. 2023, 34, 361–372. [Google Scholar] [CrossRef] [PubMed]
- Gao, X.; Liu, P.; Wu, C.; Wang, T.; Liu, G.; Cao, H.; Zhang, C.; Hu, G.; Guo, X. Effects of Fatty Liver Hemorrhagic Syndrome on the AMP-Activated Protein Kinase Signaling Pathway in Laying Hens. Poult. Sci. 2019, 98, 2201–2210. [Google Scholar] [CrossRef] [PubMed]
- Zhang, K.; Shi, Y.; Huang, C.; Huang, C.; Xu, P.; Zhou, C.; Liu, P.; Hu, R.; Zhuang, Y.; Li, G.; et al. Activation of AMP-Activated Protein Kinase Signaling Pathway Ameliorates Steatosis in Laying Hen Hepatocytes. Poult. Sci. 2021, 100, 100805. [Google Scholar] [CrossRef] [PubMed]
- Cherian, G.; Holsonbake, T.B.; Goeger, M.P.; Bildfell, R. Dietary CLA Alters Yolk and Tissue FA Composition and Hepatic Histopathology of Laying Hens. Lipids 2002, 37, 751–757. [Google Scholar] [CrossRef]
- Hermier, D. Lipoprotein Metabolism and Fattening in Poultry. J. Nutr. 1997, 127, 805S–808S. [Google Scholar] [CrossRef]
- Zając, M.; Kiczorowska, B.; Samolińska, W.; Klebaniuk, R.; Andrejko, D.; Kiczorowski, P.; Milewski, S.; Winiarska-Mieczan, A. Supplementation of Broiler Chicken Feed Mixtures with Micronised Oilseeds and the Effects on Nutrient Contents and Mineral Profiles of Meat and Some Organs, Carcass Composition Parameters, and Health Status. Animals 2022, 12, 1623. [Google Scholar] [CrossRef]
- Shahid, M.S.; Wu, Y.; Xiao, Z.; Raza, T.; Dong, X.; Yuan, J. Duration of the Flaxseed Diet Promotes Deposition of N-3 Fatty Acids in the Meat and Skin of Peking Ducks. Food Nutr. Res. 2019, 63, 3590. [Google Scholar] [CrossRef] [PubMed]
- Tamasgen, N.; Urge, M.; Girma, M.; Nurfeta, A. Effect of Dietary Replacement of Soybean Meal with Linseed Meal on Feed Intake, Growth Performance and Carcass Quality of Broilers. Heliyon 2021, 7, e08297. [Google Scholar] [CrossRef]
- Najib, H.; Al-Yousef, Y.M. Performance and Essential Fatty Acids Content of Dark Meat as Affected by Supplementing the Broiler Diet with Different Levels of Flaxseeds. Annu. Rev. Res. Biol. 2011, 1, 22–32. [Google Scholar]
- Dixon, J.B. Mechanisms of Chylomicron Uptake into Lacteals. Ann. N. Y. Acad. Sci. 2010, 1207, E52–E57. [Google Scholar] [CrossRef]
- Dixon, J.B. Lymphatic Lipid Transport: Sewer or Subway? Trends Endocrinol. Metab. 2010, 21, 480–487. [Google Scholar] [CrossRef]
- Scheideler, S.E.; Froning, G.W. The Combined Influence of Dietary Flaxseed Variety, Level, Form, and Storage Conditions on Egg Production and Composition Among Vitamin E-Supplemented Hens. Poult. Sci. 1996, 75, 1221–1226. [Google Scholar] [CrossRef]
- Novak, C.; Scheideler, S.E. Long-Term Effects of Feeding Flaxseed-Based Diets. 1. Egg Production Parameters, Components, and Eggshell Quality in Two Strains of Laying Hens1. Poult. Sci. 2001, 80, 1480–1489. [Google Scholar] [CrossRef]
- Schumann, B.E.; Squires, E.J.; Leeson, S. Effect of Dietary Flaxseed, Flax Oil and n-3 Fatty Acid Supplement on Hepatic and Plasma Characteristics Relevant to Fatty Liver Haemorrhagic Syndrome in Laying Hens. Br. Poult. Sci. 2000, 41, 465–472. [Google Scholar] [CrossRef] [PubMed]
- Huang, S.; Baurhoo, B.; Mustafa, A. Effects of Feeding Extruded Flaxseed on Layer Performance, Total Tract Nutrient Digestibility, and Fatty Acid Concentrations of Egg Yolk, Plasma and Liver. J. Anim. Physiol. Anim. Nutr. 2020, 104, 1365–1374. [Google Scholar] [CrossRef]
- Kim, J.H.; Park, J.-M.; Yea, K.; Kim, H.W.; Suh, P.-G.; Ryu, S.H. Phospholipase D1 Mediates AMP-Activated Protein Kinase Signaling for Glucose Uptake. PLoS ONE 2010, 5, e9600. [Google Scholar] [CrossRef]
- Lazarow, P.B. Rat Liver Peroxisomes Catalyze the Beta Oxidation of Fatty Acids. J. Biol. Chem. 1978, 253, 1522–1528. [Google Scholar] [CrossRef]
- Ferdinandusse, S.; Denis, S.; Hogenhout, E.M.; Koster, J.; van Roermund, C.W.T.; IJlst, L.; Moser, A.B.; Wanders, R.J.A.; Waterham, H.R. Clinical, Biochemical, and Mutational Spectrum of Peroxisomal Acyl–Coenzyme A Oxidase Deficiency. Hum. Mutat. 2007, 28, 904–912. [Google Scholar] [CrossRef] [PubMed]
- Violante, S.; Achetib, N.; van Roermund, C.W.T.; Hagen, J.; Dodatko, T.; Vaz, F.M.; Waterham, H.R.; Chen, H.; Baes, M.; Yu, C.; et al. Peroxisomes Can Oxidize Medium- and Long-Chain Fatty Acids through a Pathway Involving ABCD3 and HSD17B4. FASEB J. 2019, 33, 4355–4364. [Google Scholar] [CrossRef]
- Violante, S.; IJlst, L.; te Brinke, H.; Koster, J.; Tavares de Almeida, I.; Wanders, R.J.A.; Ventura, F.V.; Houten, S.M. Peroxisomes Contribute to the Acylcarnitine Production When the Carnitine Shuttle Is Deficient. Biochim. Et Biophys. Acta (BBA)—Mol. Cell Biol. Lipids 2013, 1831, 1467–1474. [Google Scholar] [CrossRef] [PubMed]
- Bian, F.; Kasumov, T.; Thomas, K.R.; Jobbins, K.A.; David, F.; Minkler, P.E.; Hoppel, C.L.; Brunengraber, H. Peroxisomal and Mitochondrial Oxidation of Fatty Acids in the Heart, Assessed from the 13C Labeling of Malonyl-CoA and the Acetyl Moiety of Citrate. J. Biol. Chem. 2005, 280, 9265–9271. [Google Scholar] [CrossRef] [PubMed]
- Reszko, A.E.; Kasumov, T.; David, F.; Jobbins, K.A.; Thomas, K.R.; Hoppel, C.L.; Brunengraber, H.; Des Rosiers, C. Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart. J. Biol. Chem. 2004, 279, 19574–19579. [Google Scholar] [CrossRef]
- Baes, M.; Huyghe, S.; Carmeliet, P.; Declercq, P.E.; Collen, D.; Mannaerts, G.P.; Van Veldhoven, P.P. Inactivation of the Peroxisomal Multifunctional Protein-2 in Mice Impedes the Degradation of Not Only 2-Methyl-Branched Fatty Acids and Bile Acid Intermediates but Also of Very Long Chain Fatty Acids. J. Biol. Chem. 2000, 275, 16329–16336. [Google Scholar] [CrossRef]
- Foster, D.W. Malonyl-CoA: The Regulator of Fatty Acid Synthesis and Oxidation. J. Clin. Investig. 2012, 122, 1958–1959. [Google Scholar] [CrossRef]
- Chegary, M.; te Brinke, H.; Doolaard, M.; IJlst, L.; Wijburg, F.A.; Wanders, R.J.A.; Houten, S.M. Characterization of L-Aminocarnitine, an Inhibitor of Fatty Acid Oxidation. Mol. Genet. Metab. 2008, 93, 403–410. [Google Scholar] [CrossRef]
- Randle, P.J. Regulatory Interactions between Lipids and Carbohydrates: The Glucose Fatty Acid Cycle after 35 Years. Diabetes Metab. Rev. 1998, 14, 263–283. [Google Scholar] [CrossRef]
- Neinast, M.; Murashige, D.; Arany, Z. Branched Chain Amino Acids. Annu. Rev. Physiol. 2019, 81, 139–164. [Google Scholar] [CrossRef] [PubMed]
- Sánchez-González, C.; Nuevo-Tapioles, C.; Herrero Martín, J.C.; Pereira, M.P.; Serrano Sanz, S.; Ramírez de Molina, A.; Cuezva, J.M.; Formentini, L. Dysfunctional Oxidative Phosphorylation Shunts Branched-Chain Amino Acid Catabolism onto Lipogenesis in Skeletal Muscle. EMBO J. 2020, 39, e103812. [Google Scholar] [CrossRef]
- Endo, Y.; Matsushima, K.; Onozaki, K.; Oppenheim, J.J. Role of Ornithine Decarboxylase in the Regulation of Cell Growth by IL-1 and Tumor Necrosis Factor. J. Immunol. 1988, 141, 2342–2348. [Google Scholar] [CrossRef] [PubMed]
- Heby, O.; Persson, L. Molecular Genetics of Polyamine Synthesis in Eukaryotic Cells. Trends Biochem. Sci. 1990, 15, 153–158. [Google Scholar] [CrossRef] [PubMed]
- Steglich, C.; Grens, A.; Scheffler, I.E. Chinese Hamster Cells Deficient in Ornithine Decarboxylase Activity: Reversion by Gene Amplification and by Azacytidine Treatment. Somat. Cell Mol. Genet 1985, 11, 11–23. [Google Scholar] [CrossRef] [PubMed]
- Hibasami, H.; Borchardt, R.T.; Chen, S.Y.; Coward, J.K.; Pegg, A.E. Studies of Inhibition of Rat Spermidine Synthase and Spermine Synthase. Biochem. J. 1980, 187, 419–428. [Google Scholar] [CrossRef]
- Pajula, R.-L.; Raina, A. Methylthioadenosine, a Potent Inhibitor of Spermine Synthase from Bovine Brain. FEBS Lett. 1979, 99, 343–345. [Google Scholar] [CrossRef]
- Nagórna-Stasiak, B.; Lechowski, J.; Lazuga-Adamczyk, A. The Effect of Iron on Metabolism of Vitamin C in Chickens. Arch. Vet. Pol. 1994, 34, 99–106. [Google Scholar]
- Hansen, S.H.; Andersen, M.L.; Cornett, C.; Gradinaru, R.; Grunnet, N. A Role for Taurine in Mitochondrial Function. J. Biomed. Sci. 2010, 17 (Suppl. S1), S23. [Google Scholar] [CrossRef]
- Jong, C.J.; Sandal, P.; Schaffer, S.W. The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant. Molecules 2021, 26, 4913. [Google Scholar] [CrossRef]
- Vance, D.E.; Walkey, C.J.; Cui, Z. Phosphatidylethanolamine N-Methyltransferase from Liver. Biochim. Et Biophys. Acta (BBA)—Lipids Lipid Metab. 1997, 1348, 142–150. [Google Scholar] [CrossRef]
- Ye, C.; Sutter, B.M.; Wang, Y.; Kuang, Z.; Tu, B.P. A Metabolic Function for Phospholipid and Histone Methylation. Mol. Cell 2017, 66, 180–193.e8. [Google Scholar] [CrossRef] [PubMed]
- Stead, L.M.; Brosnan, J.T.; Brosnan, M.E.; Vance, D.E.; Jacobs, R.L. Is It Time to Reevaluate Methyl Balance in Humans? Am. J. Clin. Nutr. 2006, 83, 5–10. [Google Scholar] [CrossRef]
- Jacobs, R.L.; Stead, L.M.; Devlin, C.; Tabas, I.; Brosnan, M.E.; Brosnan, J.T.; Vance, D.E. Physiological Regulation of Phospholipid Methylation Alters Plasma Homocysteine in Mice. J. Biol. Chem. 2005, 280, 28299–28305. [Google Scholar] [CrossRef]
- Fournier, N.; Paul, J.-L.; Atger, V.; Cogny, A.; Soni, T.; de la Llera-Moya, M.; Rothblat, G.; Moatti, N. HDL Phospholipid Content and Composition as a Major Factor Determining Cholesterol Efflux Capacity From Fu5AH Cells to Human Serum. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 2685–2691. [Google Scholar] [CrossRef]
- Gordon, S.M.; Amar, M.J.; Jeiran, K.; Stagliano, M.; Staller, E.; Playford, M.P.; Mehta, N.N.; Vaisar, T.; Remaley, A.T. Effect of Niacin Monotherapy on High Density Lipoprotein Composition and Function. Lipids Health Dis. 2020, 19, 190. [Google Scholar] [CrossRef]
- Yadav, R.K.; Magan, D.; Yadav, R.; Sarvottam, K.; Netam, R. High-Density Lipoprotein Cholesterol Increases Following a Short-Term Yoga-Based Lifestyle Intervention: A Non-Pharmacological Modulation. Acta Cardiol. 2014, 69, 543–549. [Google Scholar] [CrossRef] [PubMed]
- Dawaliby, R.; Trubbia, C.; Delporte, C.; Noyon, C.; Ruysschaert, J.-M.; Van Antwerpen, P.; Govaerts, C. Phosphatidylethanolamine Is a Key Regulator of Membrane Fluidity in Eukaryotic Cells. J. Biol. Chem. 2016, 291, 3658–3667. [Google Scholar] [CrossRef]
- Lee, C.; Kim, J.; Jung, Y. Potential Therapeutic Application of Estrogen in Gender Disparity of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Cells 2019, 8, 1259. [Google Scholar] [CrossRef]
- Resseguie, M.; Song, J.; Niculescu, M.D.; da Costa, K.-A.; Randall, T.A.; Zeisel, S.H. Phosphatidylethanolamine N-Methyltransferase (PEMT) Gene Expression Is Induced by Estrogen in Human and Mouse Primary Hepatocytes. FASEB J. 2007, 21, 2622–2632. [Google Scholar] [CrossRef]
- Resseguie, M.E.; da Costa, K.-A.; Galanko, J.A.; Patel, M.; Davis, I.J.; Zeisel, S.H. Aberrant Estrogen Regulation of PEMT Results in Choline Deficiency-Associated Liver Dysfunction. J. Biol. Chem. 2011, 286, 1649–1658. [Google Scholar] [CrossRef] [PubMed]
- Sikaris, K. The Correlation of Hemoglobin A1c to Blood Glucose. J. Diabetes Sci. Technol. 2009, 3, 429–438. [Google Scholar] [CrossRef] [PubMed]
- Ahmad, S.; Khan, M.S.; Akhter, F.; Khan, M.S.; Khan, A.; Ashraf, J.M.; Pandey, R.P.; Shahab, U. Glycoxidation of Biological Macromolecules: A Critical Approach to Halt the Menace of Glycation. Glycobiology 2014, 24, 979–990. [Google Scholar] [CrossRef] [PubMed]
- Guo, F.; Moellering, D.R.; Garvey, W.T. Use of HbA1c for Diagnoses of Diabetes and Prediabetes: Comparison with Diagnoses Based on Fasting and 2-Hr Glucose Values and Effects of Gender, Race, and Age. Metab. Syndr. Relat. Disord. 2014, 12, 258–268. [Google Scholar] [CrossRef]
- Hosseini, H.; Esmaeili, N.; Sepehr, A.; Zare, M.; Rombenso, A.; Badierah, R.; Redwan, E.M. Does Supplementing Laying Hen Diets with a Herb Mixture Mitigate the Negative Impacts of Excessive Inclusion of Extruded Flaxseed? Anim. Biosci. 2022, 36, 629–641. [Google Scholar] [CrossRef] [PubMed]
- Rendell, M.; Stephen, P.M.; Paulsen, R.; Valentine, J.L.; Rasbold, K.; Hestorff, T.; Eastberg, S.; Shint, D.C. An Interspecies Comparison of Normal Levels of Glycosylated Hemoglobin and Glycosylated Albumin. Comp. Biochem. Physiol. Part B Comp. Biochem. 1985, 81, 819–822. [Google Scholar] [CrossRef]
- Mandal, A.; Bhattarai, B.; Kafle, P.; Khalid, M.; Jonnadula, S.K.; Lamicchane, J.; Kanth, R.; Gayam, V. Elevated Liver Enzymes in Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease. Cureus 2018, 10, e3626. [Google Scholar] [CrossRef]
- Okada, M.; Shibuya, M.; Yamamoto, E.; Murakami, Y. Effect of Diabetes on Vitamin B6 Requirement in Experimental Animals. Diabetes Obes. Metab. 1999, 1, 221–225. [Google Scholar] [CrossRef]
Ingredient (g/100 g) | Control | 10% Defatted Flaxseed Meal | 15% Whole Flaxseed | 5% Flax Oil | 5% Corn Oil | 5% Menhaden Fish Oil |
---|---|---|---|---|---|---|
Corn | 67.40 | 54.90 | 47.58 | 52.00 | 52.00 | 52.00 |
Soybean Meal | 18.30 | 18.30 | 18.30 | 18.30 | 18.30 | 18.30 |
Whole Flaxseed | 15.00 | |||||
Corn Gluten Meal | 3.00 | 5.00 | 5.00 | 5.00 | ||
Corn Oil | 5.00 | |||||
Flax Oil | 5.00 | |||||
Fish Oil | 5.00 | |||||
Defatted Flaxseed Meal | 10.00 | |||||
Qual Fat | 3.80 | 2.50 | ||||
Solka Floc | 0.30 | 2.00 | 5.62 | 8.70 | 8.70 | 8.70 |
Each diet received the following in g/100 g of diet: Limestone (8.75), Dical (1.5), Salt (0.3), Vitamin Mix 1 (0.2), Mineral Mix 2 (0.15) and DL-Methionine (0.1) |
Calculated Analysis | Control | 10% Defatted Flaxseed Meal | 15% Whole Flaxseed | 5% Flax Oil | 5% Corn Oil | 5% Menhaden Fish Oil |
---|---|---|---|---|---|---|
TME 1, kcal/kg | 2816 | 2816 | 2815 | 2815 | 2815 | 2815 |
CP 2, % TME | 16.56 | 17.04 | 16.50 | 16.49 | 16.49 | 16.49 |
Calcium, % TME | 3.73 | 3.77 | 3.75 | 3.73 | 3.73 | 3.73 |
aPhosphorus 3, % TME | 0.38 | 0.40 | 0.38 | 0.37 | 0.37 | 0.37 |
Met + Cys, % TME | 0.67 | 0.72 | 0.64 | 0.67 | 0.67 | 0.67 |
Parameter | Control | Defatted Flax | Whole Flax | Flax Oil | Corn Oil | Fish Oil |
---|---|---|---|---|---|---|
Body Mass (kg) | 2.11 | 1.93 | 1.84 | 2.10 | 2.07 | 2.02 |
Significance Group | c | b | a | c | c | bc |
Standard Deviation | 0.33 | 0.29 | 0.28 | 0.31 | 0.35 | 0.32 |
Sample Size (n) | 86 | 85 | 71 | 84 | 62 | 70 |
Diet Group | Hens with Advanced Liver Steatosis (n Hens) | Total Hens at Necropsy (n Hens) | Percentage of Hens with Advanced Liver Steatosis | Odds Ratio of Advanced Liver Steatosis, versus the Control Diet (Odds Ratio, 95% c.i.) | Mean Body Mass (kg) of Hens with Advanced Liver Steatosis (mean ± sd) |
---|---|---|---|---|---|
Control | 25 | 126 | 19.84% | NA | 2.16 ± 0.36 (b) |
Defatted Flax | 9 | 116 | 7.76% | 0.34 (0.14, 0.75) | 2.04 ± 0.26 (ab) |
Whole Flax | 5 | 106 | 4.72% | 0.21 (0.07, 0.52) | 1.65 ± 0.26 (a) |
Flax Oil | 13 | 102 | 12.75% | 0.59 (0.28, 1.21) | 2.13 ± 0.34 (ab) |
Corn Oil | 12 | 120 | 10.00% | 0.45 (0.21, 0.94) | 1.91 ± 0.28 (ab) |
Fish Oil | 11 | 103 | 10.68% | 0.49 (0.22, 1.03) | 2.25 ± 0.42 (b) |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Weston, W.C.; Hales, K.H.; Hales, D.B. Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy. Metabolites 2023, 13, 945. https://doi.org/10.3390/metabo13080945
Weston WC, Hales KH, Hales DB. Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy. Metabolites. 2023; 13(8):945. https://doi.org/10.3390/metabo13080945
Chicago/Turabian StyleWeston, William C., Karen H. Hales, and Dale B. Hales. 2023. "Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy" Metabolites 13, no. 8: 945. https://doi.org/10.3390/metabo13080945
APA StyleWeston, W. C., Hales, K. H., & Hales, D. B. (2023). Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy. Metabolites, 13(8), 945. https://doi.org/10.3390/metabo13080945