Tuesday, November 3, 2020

Linoleic Acid and Its Metabolites, a Primer

This post was originally designed as an outline for the podcast interview I did with Paul (Saladino 2020b). I cleaned it up a little and formatted it as a post, so that folks can see the references.


This is a big topic, steadily getting bigger:

PubMed: (linoleic) NOT (conjugated) 23,486 results.

Most studied metabolite is HNE (aka 4-HNE)

PubMed: (HNE) OR (4-HNE) NOT (human neutrophil elastase) 3,645 results.

Many others, including 13-HODE, MDA, leukotoxin, ONA, leukotoxin, 2-AG, ad nauseum. Full number not known.

But crucial to a much larger topic, Oxidative Stress (OxStr):

PubMed: (oxidative stress) 240,321 results.

But First, a Little Context and a Caveat. Cardiolipin and Essential Fatty Acids

Cardiolipin

Cardiolipin is a molecule that is found in mitochondria in the human body, and in bacteria and chloroplasts.

“Cardiolipin is a phospholipid located exclusively in energy transducing membranes and it was identified in mitochondria, bacteria, hydrogenosomes and chloroplasts. In eukaryotes, cardiolipin is the only lipid that is synthesized in the mitochondria.” (Rosa et al., 2008)

I very much enjoyed the podcast with Peter (Saladino, 2020a). His is one of two blogs where I have gone back to the first post and read everything that he has written. Peter and I have different, but complementary, focuses though. He is interested in what is happening in the ETC, I am interested in what happens around that. So I’m just going to posit that everything he says is correct, and talk about what’s going on around the ETC and the functionality he’s discussed.

Cardiolipin is comprised of four fatty acids (unlike a triglyceride, which is made from three). This structure is key to its function, as is demonstrated by Barth’s Syndrome, in which cardiolipin cannot be constructed properly, due to a genetic defect. Peter’s thread you discussed is titled Protons. Cardiolipins are what conducts protons and electrons along the ETC, and, as you discussed the various complexes that make up the ETC, those complexes are bound into functional supercomplexes comprised of cardiolipin. (Hoch, 1992)

The biological functions of cardiolipin in the mitochondria. a Cardiolipin (CL) plays a critical role in maintaining the efficiency of the electron transport chain (ETC). Cardiolipin stabilizes the respiratory supercomplexes,which are formed by the aggregation of complexes I, III, and IV of the electron transport chain. Cardiolipin also binds to and stabilizes complex V (ATP synthase), whereby it is capable of acting as a proton trap that helps maintain mitochondrial membrane potential and directly supplies protons for the synthesis of ATP. Figure 3A. (Pointer and Klegeris, 2017)

The very shape of the mitochondria is determined by cardiolipin:

“Energy production, a central role of mitochondria, demands highly folded structures of the mitochondrial inner membrane (MIM) called cristae and a dimeric phospholipid (PL) cardiolipin (CL).”

(Kojima et al., 2019)

Cardiolipin fatty acid composition is determined by diet and by cell-type-specific DNA. This is important since cardiolipin composition determines how susceptible the molecule is to oxidative damage

Quick summation of three blog posts: (Goodrich, 2016a, 2016b, 2016c):

Dietary linoleic acid controls cardiolipin composition, linoleic-acid-containing cardiolipin are uniquely susceptible to oxidative damage. Cardiolipin are in contact with cytochrome c, which is an iron-containing molecule. Iron in cytochrome causes adjacent LA molecules in CL to auto oxidize, this can become a self-sustaining reaction, in vitro will continue until all CL is gone. Oxidized CL releases oxylipins like those mentioned above. (Liu et al., 2011) Oxidized CL then becomes a trigger for mitosis and apoptosis.

This paper shows exactly what this process looks like in vivo, in mice. (Ghosh et al., 2004) In my blog post discussing it (Goodrich, 2018) I show the following two images:

A mitochondrion that has physically collapsed... (Red)

The first image shows a mitochondrion that has physically collapsed in the N-6+Hyperglycemia group...
...Near inability of these mice to burn glucose.

...And the next shows the near inability of these mice to burn glucose. Apparently Complex I has largely failed, leading to massive necrosis in the heart. This follows from a major loss of cardiolipin after n-6 feeding commences, which was similar in both N-6 and N-6+Hyperglycemia groups.
QED for those posts on cardiolipin above.

Mitochondria are essential to life. Cardiolipin, essential to mitochondria, is also essential to life. N-6 feeding seems to cause cardiolipin to become very fragle…

Essential Fatty Acids

When you read all these papers, you will continuously come across the claim that linoleic acid is an EFA. This is based on studies in rodents, dating back to 1930. (Burr & Burr, 1930)
More careful work recently has determined that LA is not an EFA, in rodents (Carlson et al., 2019) or in humans. (Gura et al., 2005)

So when you are told that you should eat seed oils because they are “essential”, you can snort in derision. The amount of LA in Gura 2005 was tiny, about ½%. Eating a diet based on real food an you will get that much, it’s only possible to become EFA “deficient” under the care of a physician.

Notable metabolites

Oxidized Cardiolipin

Anti-phospholipid syndrome is an auto-immune condition in which the body attacks its own phospholipids, specifically oxidized cardiolipin. (Tuominen Anu et al., 2006) This is an antigen in lupus, atherosclerosis, chronic fatigue syndrome, (Hokama et al., 2008) and fibromyalgia (Gräfe et al., 1999). It’s unclear what the role of oxCL is in these diseases, although as discussed above LA appears to be required for CL to oxidize in large quantities, and it induces it.

Several drugs have been developed to protect cardiolipin from oxidation, and they seem to show benefit in a variety of age-related and chronic diseases. (Chavez et al., 2020; Díaz-Quintana et al., 2020; Skulachev et al., 2010)

Oxidized LDL

OxLDL was demonstrated to be essential to the progression of atherosclerosis in the late 1980s, shortly after the LDL receptor was discovered and it was shown that non-oxidized LDL would not induce macrophages to become foam cells, and that dietary LA induced LDL to be more susceptible to oxidation, while fats such as oleic acid were protective (similar to what has been shown with cardiolipin). (Palinski W et al., 1990; Parthasarathy et al., 1990; Witztum & Steinberg, 1991) 

OxLDL is a normal part of immune function (Kaplan et al., 2017), but in an industrial diet context it seems to become pathogenic, playing a role in CVD, cancer, T2DM, and the metabolic syndrome. 
OxLDL is an auto-antigen, antibodies for oxLDL are cross-reactive to LPS and Staph.

Treatment of obese rhesus monkeys with an oxLDL antibody reduces insulin resistance and inflammation. (Crisby et al., 2009; Deleanu et al., 2016; González-Chavarría et al., 2018; Kruit et al., 2010; Marin et al., 2015)

Fig. 5: "Free 4-HNE and total MDA in native low density lipoproteins (nLDL), oxidized low density lipoproteins (oxLDL) and glycated low density lipoproteins (gLDL)." (Deleanu et al., 2016)

Anti-oxLDL blocking pathway from MDA and HNE to insulin resistance. Figure 3. (Li et al., 2013)

Leukotoxin (EpOME, (±)9(10)-epoxy-12Z- and (±)12(13)-epoxy-9Z-octadecenoic acid [9(10)- and 12(13)]-EpOME)

Leukotoxin is produced in leukocytes as part of the respiratory burst used as an anti-pathogen strategy. It is derived from linoleic acid, and is responsible for the effects of ARDS and diseases that induce ARDS, like COVID-19 in severe cases. Covered at length in this post (Goodrich, 2020) or (Hildreth et al., 2020). It’s also involved in brown adipose tissue regulation.

ONA (9-ONA, 9-oxononanoic acid)

ONA induces arterial calcification in mice, and appears to also do so in humans. (Riad et al., 2017). “These results indicated that 9-ONA is the primary inducer of PLA2 activity and TxA2 production, and is probably followed by the development of diseases such as thrombus formation.” It also appears to induce platelet aggregation. (Ren et al., 2013)

2-AG (2-arachidonoylglycerol)

An endocannabinoid derived from arachidonic acid (AA) which is derived from dietary LA. Induces over-consumption of carbohydrates and obesity in rodents and humans. (Alvheim et al., 2012; Silvestri & Di Marzo, 2013)

Figure 3 (Alvheim et al., 2012)

Rimonabant, which was a human-approved anti-obesity drug for a brief time, treated this pathway in humans. 
“Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight and obese individuals with weight loss significantly greater than a reduced calorie diet alone. In addition, multiple other cardiometabolic parameters were improved in the treatment groups including increased levels of high density lipoprotein cholesterol, reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in glycosylated hemoglobin percentage.” (Bronander & Bloch, 2007)
This phenomenon is the largest issue I have with Peter’s Protons hypothesis, as it seems odd that the endocannabinoid system might counteract the effect he describes, yet it does.

MDA (Malondialdehyde)

“Indeed, oxidation products such as oxidized phosphatidylcholine, MDA, 4-HNE and others have been documented in virtually all inflammatory diseases including atherosclerosis, pulmonary, renal, and liver diseases, as well as diseases affecting the central nervous system like multiple sclerosis and Alzheimer's disease [8–14].” (Weismann & Binder, 2012)

I frankly haven’t looked too closely at MDA for the simple reason that it can be made from n-6 or n-3 fats. Although in practice, it’s from n-6 fats.

MDA is the most-common marker of OxStr, which is the process of n-6 fats breaking down into toxins, via the rather inaccurate TBARS test. (Specialties, n.d.). It’s also the substance used for oxLDL, via the E06 test. (Yeang et al., 2016)

HNE (4-HNE, 4-Hydroxynonenal, or 4-hydroxy-2-nonenal)

HNE is the most-studied linoleic acid metabolite, since it’s rediscovery by Esterbauer. (Esterbauer et al., 1991). HNE is a major toxic component of oxLDL (see that section) along with MDA. Unlike MDA, HNE is derived exclusively from n-6 fats, linoleic and arachidonic acid, hence is a good tracker of their effects in the body.

HNE is used as a mitochondrial regulator, along with ROS (your discussion w/ Peter didn’t mention that point) (Speijer, 2016), so this is a fundamental part of the body with regular and pathological functions.

If you’ve heard that glutathione (GSH) is an important antioxidant, it’s in part because it protects the body from HNE. Depressed levels of GSH indicate excessive production of HNE, typically from LA. Aldehyde dehydrogenase (ALDH) is also involved in detoxifying HNE, HNE has the unique ability to damage both GSH and ALDH, thus breaking its own regulatory system.

HNE can be produced in the mitochondria from the oxidation of LA-containing cardiolipin (Liu et al., 2011).

Protein damage

HNE damages a significant subset of proteins in the cell (~27%) (Codreanu et al., 2009)
HNE is associated with the major type of DNA damage (Okamoto et al., 1994), which is induced by LA oxylipins (Kanazawa et al., 2016).

DNA damage

HNE induces the major mutation seen in cancer, it damages the TP53 cancer-protection gene:

“P53 is often mutated in solid tumors, in fact, somatic changes involving the gene encoding for p53 (TP53) have been discovered in more than 50% of human malignancies and several data confirmed that p53 mutations represent an early event in cancerogenesis.” ( et al., 2016)

“The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma” (Hu et al., 2002)

Lipid damage

"These reactive oxygen species readily attack the polyunsaturated fatty acids of the fatty acid membrane, initiating a self-propagating chain reaction." (Mylonas & Kouretas, 1999)

Alzheimer’s Disease

HNE induces beta-amyloid:

“The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-β production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-β42 species.” (Arimon et al., 2015)

It breaks pyruvate dehydrogenase. (Hardas et al., 2013; Humphries & Szweda, 1998)

It breaks ATP synthase. (Terni et al., 2010)

8-OHdG (8-oxo-dG , 8-Oxo-2'-deoxyguanosine)

“The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis.” (Valavanidis et al., 2009)

“Linoleic acid hydroperoxides (LOOH) formed 8-oxo-dG at a higher level than H2O2 in guanosine or double-stranded DNA.” (Kanazawa et al., 2016)

13-HODE (13-Hydroxyoctadecadienoic acid, 13(S)-HODE, 13(S)-hydroxy-9Z,11E-octadecadienoic acid)

Asthma: 

“13-S-HODE causes severe airway dysfunction, airway neutrophilia, mitochondrial dysfunction and epithelial injury in naïve mouse…” (Mabalirajan et al., 2013; Panda et al., 2017)

Insulin resistance and NAFLD

OxLDL antibody relieves insulin resistance in obese rhesus monkeys: (Li et al., 2013)

100% cure of NAFLD and IR in humans (pilot study), on high-carb diet. (Maciejewska et al., 2015)

“Effect of a 6-Month Intervention with Cooking Oils Containing a High Concentration of Monounsaturated Fatty Acids (Olive and Canola Oils) Compared with Control Oil in Male Asian Indians with Nonalcoholic Fatty Liver Disease”, “Improvement of fatty liver was accompanied by amelioration in insulin resistance and dyslipidemia.” (Nigam et al., 2014) 

“There was also a significant decrease in plasma concentrations of ALT (Figure 1), triglycerides (p=0.04) cholesterol (p=0.03), LDL (p=0.07) and an improvement of whole-body insulin resistance (p=0.01). There was a significant decrease of the OXLAM, 9- and 13-HODE (p=0.03 and p=0.01, respectively) and 9- and 13-oxo-ODE (p=0.05 and p=0.01, respectively). These data suggest that, independent of weight loss, a low n6/n3 PUFA diet is effective to ameliorate the metabolic phenotype of adolescents with fatty liver disease.” (Van Name et al., 2019)

 


Bibliography

Alvheim, A. R., Malde, M. K., Osei‐Hyiaman, D., Hong, Y. H., Pawlosky, R. J., Madsen, L., Kristiansen, K., Frøyland, L., & Hibbeln, J. R. (2012). Dietary Linoleic Acid Elevates Endogenous 2-AG and Anandamide and Induces Obesity. Obesity, 20(10), 1984–1994. https://doi.org/10.1038/oby.2012.38
Arimon, M., Takeda, S., Post, K. L., Svirsky, S., Hyman, B. T., & Berezovska, O. (2015). Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiology of Disease, 84, 109–119. https://doi.org/10.1016/j.nbd.2015.06.013
Bronander, K. A., & Bloch, M. J. (2007). Potential role of the endocannabinoid receptor antagonist rimonabant in the management of cardiometabolic risk: A narrative review of available data. Vascular Health and Risk Management, 3(2), 181–190. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994026/
Burr, G. O., & Burr, M. M. (1930). On the Nature and Rôle of the Fatty Acids Essential in Nutrition. Journal of Biological Chemistry, 86(2), 587–621. http://www.jbc.org/content/86/2/587
Carlson, S. J., O’Loughlin, A. A., Anez-Bustillos, L., Baker, M. A., Andrews, N. A., Gunner, G., Dao, D. T., Pan, A., Nandivada, P., Chang, M., Cowan, E., Mitchell, P. D., Gura, K. M., Fagiolini, M., & Puder, M. (2019). A Diet With Docosahexaenoic and Arachidonic Acids as the Sole Source of Polyunsaturated Fatty Acids Is Sufficient to Support Visual, Cognitive, Motor, and Social Development in Mice. Frontiers in Neuroscience, 13, 72. https://doi.org/10.3389/fnins.2019.00072
Chavez, J. D., Tang, X., Campbell, M. D., Reyes, G., Kramer, P. A., Stuppard, R., Keller, A., Zhang, H., Rabinovitch, P. S., Marcinek, D. J., & Bruce, J. E. (2020). Mitochondrial protein interaction landscape of SS-31. Proceedings of the National Academy of Sciences, 117(26), 15363–15373. https://doi.org/10.1073/pnas.2002250117
Codreanu, S. G., Zhang, B., Sobecki, S. M., Billheimer, D. D., & Liebler, D. C. (2009). Global Analysis of Protein Damage by the Lipid Electrophile 4-Hydroxy-2-nonenal. Molecular & Cellular Proteomics, 8(4), 670–680. https://doi.org/10.1074/mcp.M800070-MCP200
Crisby, M., Kublickiene, K., Henareh, L., & Agewall, S. (2009). Circulating levels of autoantibodies to oxidized low-density lipoprotein and C-reactive protein levels correlate with endothelial function in resistance arteries in men with coronary heart disease. Heart and Vessels, 24(2), 90–95. https://doi.org/10.1007/s00380-008-1089-y
Deleanu, M., Sanda, G. M., Stancu, C. S., Popa, M. E., & Sima, A. V. (2016). Profiles of Fatty Acids and the Main Lipid Peroxidation Products of Human Atherogenic Low Density Lipoproteins. Revista De Chimie, 67(1), 8–12. http://www.revistadechimie.ro/article_eng.asp?ID=4799
Díaz-Quintana, A., Pérez-Mejías, G., Guerra-Castellano, A., De la Rosa, M. A., & Díaz-Moreno, I. (2020). Wheel and Deal in the Mitochondrial Inner Membranes: The Tale of Cytochrome c and Cardiolipin. Oxidative Medicine and Cellular Longevity, 2020, e6813405. https://doi.org/10.1155/2020/6813405
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991). Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radical Biology and Medicine, 11(1), 81–128. https://doi.org/10.1016/0891-5849(91)90192-6
Ghosh, S., Qi, D., An, D., Pulinilkunnil, T., Abrahani, A., Kuo, K.-H., Wambolt, R. B., Allard, M., Innis, S. M., & Rodrigues, B. (2004). Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. American Journal of Physiology. Heart and Circulatory Physiology, 287(6), H2518-2527. https://doi.org/10.1152/ajpheart.00480.2004
González-Chavarría, I., Fernandez, E., Gutierrez, N., González-Horta, E. E., Sandoval, F., Cifuentes, P., Castillo, C., Cerro, R., Sanchez, O., & Toledo, J. R. (2018). LOX-1 activation by oxLDL triggers an epithelial mesenchymal transition and promotes tumorigenic potential in prostate cancer cells. Cancer Letters, 414, 34–43. https://doi.org/10.1016/j.canlet.2017.10.035
Goodrich, T. (2016a, February 5). The Cause of Metabolic Syndrome: Excess Omega-6 Fats (Linoleic Acid) in Your Mitochondria. Yelling Stop. http://yelling-stop.blogspot.com/2016/02/the-cause-of-metabolic-syndrome-excess.html
Goodrich, T. (2016b, February 23). How To Prevent Oxidative Damage In Your Mitochondria. Yelling Stop. http://yelling-stop.blogspot.com/2016/02/how-to-prevent-oxidative-damage-in-your.html
Goodrich, T. (2016c, February 24). What Effect Does Linoleic Acid Have On Mitochondria? Yelling Stop. http://yelling-stop.blogspot.com/2016/02/what-effect-does-linoleic-acid-have-on.html
Goodrich, T. (2018, June 28). What’s Worse—Carbs or Seed Oils? Understanding a High-PUFA Diet. Yelling Stop. http://yelling-stop.blogspot.com/2018/06/whats-worsecarbs-or-seed-oils.html
Goodrich, T. (2020, June 2). Does Consumption of Omega-6 Seed Oils Worsen ARDS and COVID-19? [Blog]. Yelling Stop. http://yelling-stop.blogspot.com/2020/06/does-consumption-of-omega-6-seed-oils.html
Gräfe, A., Wollina, U., Tebbe, B., Sprott, H., Uhlemann, C., & Hein, G. (1999). Fibromyalgia in lupus erythematosus. Acta Dermato-Venereologica, 79(1), 62–64. https://doi.org/10.1080/000155599750011732
Gura, K. M., Parsons, S. K., Bechard, L. J., Henderson, T., Dorsey, M., Phipatanakul, W., Duggan, C., Puder, M., & Lenders, C. (2005). Use of a fish oil-based lipid emulsion to treat essential fatty acid deficiency in a soy allergic patient receiving parenteral nutrition. Clinical Nutrition, 24(5), 839–847. https://doi.org/10.1016/j.clnu.2005.05.020
Hardas, S. S., Sultana, R., Clark, A. M., Beckett, T. L., Szweda, L. I., Murphy, M. P., & Butterfield, D. A. (2013). Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biology, 1(1), 80–85. https://doi.org/10.1016/j.redox.2013.01.002
Hildreth, K., Kodani, S. D., Hammock, B. D., & Zhao, L. (2020). Cytochrome P450-derived linoleic acid metabolites EpOMEs and DiHOMEs: A review of recent studies. The Journal of Nutritional Biochemistry, 86, 108484. https://doi.org/10.1016/j.jnutbio.2020.108484
Hoch, F. L. (1992). Cardiolipins and biomembrane function. Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1113(1), 71–133. https://doi.org/10.1016/0304-4157(92)90035-9
Hokama, Y., Empey‐Campora, C., Hara, C., Higa, N., Siu, N., Lau, R., Kuribayashi, T., & Yabusaki, K. (2008). Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. Journal of Clinical Laboratory Analysis, 22(2), 99–105. https://doi.org/10.1002/jcla.20217
Hu, W., Feng, Z., Eveleigh, J., Iyer, G., Pan, J., Amin, S., Chung, F.-L., & Tang, M. (2002). The major lipid peroxidation product, trans- 4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis, 23(11), 1781–1789. https://doi.org/10.1093/carcin/23.11.1781
Humphries, K. M., & Szweda, L. I. (1998). Selective Inactivation of α-Ketoglutarate Dehydrogenase and Pyruvate Dehydrogenase: Reaction of Lipoic Acid with 4-Hydroxy-2-nonenal. Biochemistry, 37(45), 15835–15841. https://doi.org/10.1021/bi981512h
Kanazawa, K., Sakamoto, M., Kanazawa, K., Ishigaki, Y., Aihara, Y., Hashimoto, T., & Mizuno, M. (2016). Lipid peroxides as endogenous oxidants forming 8-oxo-guanosine and lipid-soluble antioxidants as suppressing agents. Journal of Clinical Biochemistry and Nutrition, 59(1), 16–24. https://doi.org/10.3164/jcbn.15-122
Kaplan, H., Thompson, R. C., Trumble, B. C., Wann, L. S., Allam, A. H., Beheim, B., Frohlich, B., Sutherland, M. L., Sutherland, J. D., Stieglitz, J., Rodriguez, D. E., Michalik, D. E., Rowan, C. J., Lombardi, G. P., Bedi, R., Garcia, A. R., Min, J. K., Narula, J., Finch, C. E., … Thomas, G. S. (2017). Coronary atherosclerosis in indigenous South American Tsimane: A cross-sectional cohort study. The Lancet, 389(10080), 1730–1739. https://doi.org/10.1016/S0140-6736(17)30752-3
Kojima, R., Kakimoto, Y., Furuta, S., Itoh, K., Sesaki, H., Endo, T., & Tamura, Y. (2019). Maintenance of Cardiolipin and Crista Structure Requires Cooperative Functions of Mitochondrial Dynamics and Phospholipid Transport. Cell Reports, 26(3), 518-528.e6. https://doi.org/10.1016/j.celrep.2018.12.070
Kruit, J. K., Brunham, L. R., Verchere, C. B., & Hayden, M. R. (2010). HDL and LDL cholesterol significantly influence β-cell function in type 2 diabetes mellitus. Current Opinion in Lipidology, 21(3), 178. https://doi.org/10.1097/MOL.0b013e328339387b
Li, S., Kievit, P., Robertson, A.-K., Kolumam, G., Li, X., von Wachenfeldt, K., Valfridsson, C., Bullens, S., Messaoudi, I., Bader, L., Cowan, K. J., Kamath, A., van Bruggen, N., Bunting, S., Frendéus, B., & Grove, K. L. (2013). Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. Molecular Metabolism, 2(3), 256–269. https://doi.org/10.1016/j.molmet.2013.06.001
Liu, W., Porter, N. A., Schneider, C., Brash, A. R., & Yin, H. (2011). Formation Of 4-Hydroxynonenal From Cardiolipin Oxidation: Intramolecular Peroxyl Radical Addition And Decomposition. Free Radical Biology & Medicine, 50(1), 166–178. https://doi.org/10.1016/j.freeradbiomed.2010.10.709
Mabalirajan, U., Rehman, R., Ahmad, T., Kumar, S., Singh, S., Leishangthem, G. D., Aich, J., Kumar, M., Khanna, K., Singh, V. P., Dinda, A. K., Biswal, S., Agrawal, A., & Ghosh, B. (2013). Linoleic acid metabolite drives severe asthma by causing airway epithelial injury. Scientific Reports, 3(1), 1349. https://doi.org/10.1038/srep01349
Maciejewska, D., Ossowski, P., Drozd, A., Ryterska, K., Jamioł-Milc, D., Banaszczak, M., Kaczorowska, M., Sabinicz, A., Raszeja-Wyszomirska, J., & Stachowska, E. (2015). Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease—A pilot study. Prostaglandins & Other Lipid Mediators, 121, 184–189. https://doi.org/10.1016/j.prostaglandins.2015.09.003
Marin, M. T., Dasari, P. S., Tryggestad, J. B., Aston, C. E., Teague, A. M., & Short, K. R. (2015). Oxidized HDL and LDL in adolescents with type 2 diabetes compared to normal weight and obese peers. Journal of Diabetes and Its Complications, 29(5), 679–685. https://doi.org/10.1016/j.jdiacomp.2015.03.015
Mylonas, C., & Kouretas, D. (1999). Lipid peroxidation and tissue damage. In Vivo (Athens, Greece), 13(3), 295–309. http://europepmc.org/article/med/10459507
Nigam, P., Bhatt, S., Misra, A., Chadha, D. S., Vaidya, M., Dasgupta, J., & Pasha, Q. M. A. (2014). Effect of a 6-Month Intervention with Cooking Oils Containing a High Concentration of Monounsaturated Fatty Acids (Olive and Canola Oils) Compared with Control Oil in Male Asian Indians with Nonalcoholic Fatty Liver Disease. Diabetes Technology & Therapeutics, 16(4), 255–261. https://doi.org/10.1089/dia.2013.0178
Okamoto, K., Toyokuni, S., Uchida, K., Ogawa, O., Takenewa, J., Kakehi, Y., Kinoshita, H., Hattori-Nakakuki, Y., Hiai, H., & Yoshida, O. (1994). Formation of 8-hydroxy-2’-deoxyguanosine and 4-hydroxy-2-nonenal-modified proteins in human renal-cell carcinoma. International Journal of Cancer, 58(6), 825–829. https://doi.org/10.1002/ijc.2910580613
Palinski W, Ylä-Herttuala S, Rosenfeld M E, Butler S W, Socher S A, Parthasarathy S, Curtiss L K, & Witztum J L. (1990). Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis: An Official Journal of the American Heart Association, Inc., 10(3), 325–335. https://doi.org/10.1161/01.ATV.10.3.325
Panda, L., Gheware, A., Rehman, R., Yadav, M. K., Jayaraj, B. S., Madhunapantula, S. V., Mahesh, P. A., Ghosh, B., Agrawal, A., & Mabalirajan, U. (2017). Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB. Scientific Reports, 7. https://doi.org/10.1038/s41598-017-09869-9
Parthasarathy, S., Khoo, J. C., Miller, E., Barnett, J., Witztum, J. L., & Steinberg, D. (1990). Low density lipoprotein rich in oleic acid is protected against oxidative modification: Implications for dietary prevention of atherosclerosis. Proceedings of the National Academy of Sciences, 87(10), 3894–3898. https://doi.org/10.1073/pnas.87.10.3894
Perri, F., Pisconti, S., & Della Vittoria Scarpati, G. (2016). P53 mutations and cancer: A tight linkage. Annals of Translational Medicine, 4(24). https://doi.org/10.21037/atm.2016.12.40
Pointer, C. B., & Klegeris, A. (2017). Cardiolipin in Central Nervous System Physiology and Pathology. Cellular and Molecular Neurobiology, 37(7), 1161–1172. https://doi.org/10.1007/s10571-016-0458-9
Qin, E., Shi, H., Tang, L., Wang, C., Chang, G., Ding, Z., Zhao, K., Wang, J., Chen, Z., Yu, M., Si, B., Liu, J., Wu, D., Cheng, X., Yang, B., Peng, W., Meng, Q., Liu, B., Han, W., … Zhu, Q. (2006). Immunogenicity and protective efficacy in monkeys of purified inactivated Vero-cell SARS vaccine. Vaccine, 24(7), 1028–1034. https://doi.org/10.1016/j.vaccine.2005.06.038
Ren, R., Hashimoto, T., Mizuno, M., Takigawa, H., Yoshida, M., Azuma, T., & Kanazawa, K. (2013). A lipid peroxidation product 9-oxononanoic acid induces phospholipase A2 activity and thromboxane A2 production in human blood. Journal of Clinical Biochemistry and Nutrition, 52(3), 228–233. https://doi.org/10.3164/jcbn.12-110
Riad, A., Narasimhulu, C. A., Deme, P., & Parthasarathy, S. (2017). A Novel Mechanism for Atherosclerotic Calcification: Potential Resolution of the Oxidation Paradox. Antioxidants & Redox Signaling, 29(5), 471–483. https://doi.org/10.1089/ars.2017.7362
Rosa, I. de A., Einicker-Lamas, M., Bernardo, R. R., & Benchimol, M. (2008). Cardiolipin, a lipid found in mitochondria, hydrogenosomes and bacteria was not detected in Giardia lamblia. Experimental Parasitology, 120(3), 215–220. https://doi.org/10.1016/j.exppara.2008.07.009
Saladino, P. (2020a, October 12). Is it saturated fat or polyunsaturated fat that’s killing you? With Peter Dobromylskyj from Hyperlipid. (No. 90) [Mp3]. https://html5-player.libsyn.com/embed/episode/id/16374392/height/90/theme/custom/thumbnail/yes/direction/backward/render-playlist/no/custom-color/186e8e/
Saladino, P. (2020b, November 3). Fundamental Health with Paul Saladino, MD: How Seed Oils Destroy Your Mitochondria and Lead To Chronic Disease, with Tucker Goodrich (No. 96) [Mp3]. https://paulsaladinomd.libsyn.com/how-seed-oils-destroy-your-mitochondria-and-lead-to-chronic-disease-with-tucker-goodrich
Silvestri, C., & Di Marzo, V. (2013). The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders. Cell Metabolism, 17(4), 475–490. https://doi.org/10.1016/j.cmet.2013.03.001
Skulachev, V. P., Antonenko, Y. N., Cherepanov, D. A., Chernyak, B. V., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Pletjushkina, O. Yu., Roginsky, V. A., Rokitskaya, T. I., Severin, F. F., Severina, I. I., Simonyan, R. A., Skulachev, M. V., Sumbatyan, N. V., Sukhanova, E. I., Tashlitsky, V. N., … Zvyagilskaya, R. A. (2010). Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs). Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1797(6), 878–889. https://doi.org/10.1016/j.bbabio.2010.03.015
Solin, M.-L., Ahola, H., Haltia, A., Ursini, F., Montine, T., Roveri, A., Kerjaschki, D., & Holthöfer, H. (2001). Lipid peroxidation in human proteinuric disease. Kidney International, 59(2), 481–487. https://doi.org/10.1046/j.1523-1755.2001.059002481.x
Specialties, N. (n.d.). Trouble With TBARS [Store]. The Trouble with TBARS. Retrieved October 23, 2020, from https://www.nwlifescience.com/information/trouble-with-tbars
Speijer, D. (2016). Being right on Q: Shaping eukaryotic evolution. The Biochemical Journal, 473(22), 4103–4127. https://doi.org/10.1042/BCJ20160647
Steinbacher, P., & Eckl, P. (2015). Impact of Oxidative Stress on Exercising Skeletal Muscle. Biomolecules, 5(2), 356–377. https://doi.org/10.3390/biom5020356
Terni, B., Boada, J., Portero‐Otin, M., Pamplona, R., & Ferrer, I. (2010). Mitochondrial ATP-Synthase in the Entorhinal Cortex Is a Target of Oxidative Stress at Stages I/II of Alzheimer’s Disease Pathology. Brain Pathology, 20(1), 222–233. https://doi.org/10.1111/j.1750-3639.2009.00266.x
Tuominen Anu, Miller Yury I., Hansen Lotte F., Kesäniemi Y. Antero, Witztum Joseph L., & Hörkkö Sohvi. (2006). A Natural Antibody to Oxidized Cardiolipin Binds to Oxidized Low-Density Lipoprotein, Apoptotic Cells, and Atherosclerotic Lesions. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(9), 2096–2102. https://doi.org/10.1161/01.ATV.0000233333.07991.4a
Valavanidis, A., Vlachogianni, T., & Fiotakis, C. (2009). 8-hydroxy-2’ -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. Journal of Environmental Science and Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews, 27(2), 120–139. https://doi.org/10.1080/10590500902885684
Van Name, M. A., Chick, J. M., Savoye, M., Pierpont, B., Galuppo, B., Feldstein, A., & Santoro, N. (2019). Effect of a Low n6/n3 PUFA Diet on Intrahepatic Fat Content in Obese Adolescents. Diabetes, 68(Supplement 1). https://doi.org/10.2337/db19-772-P
Weismann, D., & Binder, C. J. (2012). The innate immune response to products of phospholipid peroxidation. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1818(10), 2465–2475. https://doi.org/10.1016/j.bbamem.2012.01.018
Witztum, J. L., & Steinberg, D. (1991). Role of oxidized low density lipoprotein in atherogenesis. Journal of Clinical Investigation, 88(6), 1785–1792. https://doi.org/10.1172/JCI115499
Yeang, C., Hung, M. Y., Pattison, J., Bowden, K., Dalton, N., Peterson, K. L., Witztum, J. L., Tsimikas, S., & Que, X. (2016). Expression of E06, a natural monoclonal antibody targeted to oxidized phospholipids (OXPL), attenuates the progression of aortic sclerosis in aged hyperlipidemic mice. Atherosclerosis, 252, e229. https://doi.org/10.1016/j.atherosclerosis.2016.07.212

9 comments:

  1. Absolutely brilliant article. Thank you for putting all this together. Just about to listen to your podcast with Paul Saladino.

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  2. I heard you speak about the connection with asthma. Do you know if this process is responsible for mast cell activation disorder/mast cell activation syndrome? Is there research connecting it to the over activation of the mast cell response?

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    1. I'd expect it's also connected. When they're using oxidized linoleic acid (HNE) as a marker for disease progress (see figure 3 in this paper), it's a pretty safe bet.

      But I really haven't looked into this one specifically.

      Wheat and seed oils are the two known causes of auto-immune disease, so it's not a longshot.

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  3. Hey Tucker,
    You talk about Complex I breaking down. As i understand it complex I is the prime ROS production site. Combining this with Peters theory this would lead to a massive descrease of insulin resistance. Dysfunctional mitochondria and insulin sensitivity sounds like cancer to me. Would like to hear your thoughts on that.
    Thanks,
    Marius

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  4. Enjoyed your blogpost as well as the discussion with Saladino.

    One question on cardiolipins: it seems to be normal, >80% normal, to find LA in those four lipid acid chain of TLCL? The textbook examples date back to 1990's, well bovine and rats.
    Or is there a new normal, because "everybody" is eating hidden omega-6 in copious foods?
    JR

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  5. Hi Tucker, I've been following you for several years after first seeing you on Hyperlipid's comments.

    Having always been a little curious about Ray Peat, who Peter seems to respect but whose ideas about protein I'm not sure I agree with, I found this 2013 blog post incredibly dense and thought-provoking. It seems to be a summary overview of fats and cellular processes. It touches on a couple of personally relevant health issues (a mystery peripheral motor neuropathy and a brief excursion into breast cancer last year), as well as possible impacts of polyunsaturated fats on COVID-19 symptoms.

    So as one of my go-to sources for information on dietary fat, I wonder what you think of it. If you feel like reading – it's long!

    http://www.raypeat.com/articles/articles/fats-functions-malfunctions.shtml

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  7. Hi Tucker, Thank you for the article and the podcast. Very informative. A small error in the 2nd paragraph: I think that when you say "His is one of two blogs where I have gone back to the first post and read everything that he has written" - you mean Peter at Hyperlipid, not Paul Saladino?

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  8. This is incredible. Thank you for putting together such a great resource.

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