Monday, December 14, 2020

Bill Lands (aka William E.M. Lands, PhD) Resources on n-6 and n-3 PUFAs

Bill Lands is one of the titans in the field of human PUFA metabolism. As Wikipedia puts it: "...[he] is an American nutritional biochemist who is among the world's foremost authorities on essential fatty acids."

I don't call him "Bill" to be familiar, after he retired he switched from publishing as William E.M. to Bill.

Here's a select bibliography of interesting things he's written and done.

He's pretty fiery, so be sure to watch those video of his speech in (I think) 1999 at the NIH workshop, whence this quote:

It's in four parts, but it's well worth it. 

Or this:

"Fifty years later, I still cannot cite a definite mechanism or mediator by which saturated fat is shown to kill people." (Lands 2008)


Graff, G., Sacks, R. W., & Lands, W. E. M. (1983). Selective loss of mitochondrial genome can be caused by certain unsaturated fatty acids. Archives of Biochemistry and Biophysics, 224(1), 342–350. https://doi.org/10.1016/0003-9861(83)90218-7

Lands, B. (2008). A critique of paradoxes in current advice on dietary lipids. Progress in Lipid Research, 47(2), 77–106. https://doi.org/10.1016/j.plipres.2007.12.001
Lands, B. (2014). Historical perspectives on the impact of n-3 and n-6 nutrients on health. Progress in Lipid Research, 55, 17–29. https://doi.org/10.1016/j.plipres.2014.04.002
Lands, B. (2020, February 1). Essential Fatty Acids Home Page. EFA Education. https://efaeducation.org/
NIH. (1999a, April 7). 1 of 4—Dr William Lands on Cardiovascular Disease Omega-6. https://www.youtube.com/watch?v=kivrYNjiXk8&feature=youtu.be
NIH. (1999b, April 7). 2 of 4—Dr William Lands on Cardiovascular Disease Omega-6. https://www.youtube.com/watch?v=02OlzB9zfV4
NIH. (1999c, April 7). 3 of 4—Dr William Lands on Cardiovascular Disease Omega-6. https://www.youtube.com/watch?v=A1qKhY24szQ
NIH. (1999d, April 7). 4 of 4—Dr William Lands on Cardiovascular Disease Omega-6. https://www.youtube.com/watch?v=YObL5KeDLXc
NIH. (1999e, April 7). Workshop on the Essentiality of Omega-6 and Omega-3 Fatty Acids. https://ods.od.nih.gov/pubs/conferences/w6w3_abstracts.html
Strandjord, S. E., Lands, B., & Hibbeln, J. R. (2018). Validation of an equation predicting highly unsaturated fatty acid (HUFA) compositions of human blood fractions from dietary intakes of both HUFAs and their precursors. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 136, 171–176. https://doi.org/10.1016/j.plefa.2017.03.005
Wikipedia. (2020). William E.M. Lands. In Wikipedia. https://en.wikipedia.org/w/index.php?title=William_E.M._Lands&oldid=994164694

Friday, December 11, 2020

Podcast Interview: "Linoleic Acid- Interview with Tucker Goodrich" with Dr. Joseph Mercola

Welcome to Dr. Mercola listeners and subscribers, if any of you make it here!

For existing readers, the Youtube version of this interview has been released. Here's the podcast version, on Apple Podcasts.

Here's Dr. Mercola's article on this topic:

How Linoleic Acid Wrecks Your Health
They did a transcript of the interview, also! (PDF, I'm impressed!)


For new visitors, here are a few of my key posts, some of which are mentioned in the interview.



Below are the extremely rough notes that Dr. Mercola and I worked off in the interview, including a bibliography.

Questions are welcome in the comments.

I'm on twitter here, and am active.



Why this is likely the major reason contributing to metabolic dysfunction and the epidemic of chronic disease

Criteria that I concluded had to be true for the cause (whatever it was) of chronic disease.

1.      Trans-Species
This is a problem that we see in all human populations, and the animal species that associate with them, which includes pets but also feral animals like rats, pigeons, and racoons.
This eliminates genetic causes, and many pathogens, which do not cross species lines easily.

2.      Diet-based
Several crucial books (Price, 1938; Stefansson, 1960; Trowell & Burkitt, 1981) looked at healthy, traditional cultures compared to sick ones, and made a clear suggestion that it was diet based T&B made it clear that it affected diseases seemingly unrelated to diet, like auto-immunity.
This eliminates other proposed mechanisms, like pollution (fattest country on earth is in the South Pacific: what is the pollution?).

3.      Novel
Must be a food that was recently introduced, contemporaneously with the emerging pandemics of T2DM and obesity. (Taubes, 2008) looked at diabetes emergence in the 1800s, (Lee et al., 1964) looked at emergence of ischaemic heart disease in the 20th century vs traditional cultures.

4.      Mechanistic confirmation
Too easy to be fooled by epidemiology without some mechanistic confirmation, as happened to Ancel Keys. (Ramsden et al., 2016)

5.      Contained in D12492
This is the diet used to induce chronic diseases in lab animals. It seems silly, but no-one went through this diet to figure out what ingredient actually had the measured effect until 2012!

How you figured this out so early

Jen’s explanation (more complimentary): "Always open-minded and not biased as to what other people were believing and the trends. Simply were assessing evidence-based research and making decisions according to that."

My version: "Dumb luck and stubborn."

Had dramatic personal experience that couldn’t be explained by physicians, so looked into why it had happened. Stuck with exploration even when mentor in topic abandoned it.

Some seminal studies that provide irrefutable evidence of the hypothesis

“Irrefutable” is hard, if such a study had been done you wouldn’t be talking to me, this would be old news. Must follow Bill Lands, a pioneer in PUFA research, and “connect the dots”.

(Alvheim et al., 2012) shows what induces obesity, explains mechanism behind human-approved drug that treated multiple aspects of chronic diseases. Compare to D12492.

“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 [HDL], reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in [HbA1c].” (Bronander & Bloch, 2007)


(Medina-Navarro et al., 2003) showing a physiological level of glucose and PUFA produced a poison in vitro. My tweet: “Etiology of metsym & chronic disease, in one chart. At physiologic lvls. God...”

(Singh et al., 2008) “Fat accumulation in Caenorhabditis elegans triggered by the electrophilic lipid peroxidation product 4-hydroxynonenal (4-HNE). Tweet: “N-6 metab 4-HNE induces obesity across species, "the process is conserved and thus likely to be universal."”

(Liu et al., 2011) “Formation Of 4-Hydroxynonenal From Cardiolipin Oxidation: Intramolecular Peroxyl Radical Addition And Decomposition”

(Witztum & Steinberg, 1991)

(Ghosh et al., 2004) “Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA” (Goodrich, 2018)

(Skulachev et al., 2009) “An attempt to prevent senescence: A mitochondrial approach”

(Bethancourt et al., 2019) “Household use of cooking oil increased and was positively associated with female BMI. Consumption of domesticated animal products did not change significantly but was positively associated with female BMI and male waist circumference. Conclusions Even small increases in energy-dense market-based foods can contribute to adiposity gains among a moderately active, subsistence-based population.”

(Maciejewska et al., 2015) “Following the six-month dietary intervention, hepatic steatosis resolved completely in all patients. This resulted in a significant decrease in the concentrations of all eicosanoids (LX4, 16-HETE, 13-HODE, 9-HODE, 15-HETE, 12-HETE, 5-oxoETE, 5-HETE) and key biochemical parameters (BMI, insulin, HOMA-IR, liver enzymes).”

(Goodrich, 2016) “The Cause of Metabolic Syndrome: Excess Omega-6 Fats (Linoleic Acid) in Your Mitochondria”

Will dive a bit into cardiolipin as I believe that is a major reason to explain the dilemma

Yes, covered in links above, plenty of material for discussion

Your best guess as to ideal LA consumption for optimal health and how to do that

LA is not essential, despite what was thought over last 90 years. Consumption should be minimal, discuss what should be avoided. (Alvheim et al., 2013; Blasbalg et al., 2011; Carlson et al., 2019)

Can tangent a bit to carnosine as a way to supply a sacrificial scavenger for reactive carbonyl species (RCS) or in LA context better known as OXLAMs or oxylipids

(Nègre-Salvayre et al., 2017) “A recent study by Colzani and colleagues analyzed and compared the ability of several classical carbonyl scavengers to prevent the carbonylation of proteins, and concluded that carnosine is the most effective scavenger for HNE...”
(Zhao et al., 2015) “Carnosic Acid as a Major Bioactive Component in Rosemary Extract Ameliorates High-Fat-Diet-Induced Obesity and Metabolic Syndrome in Mice”



References

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

Alvheim, A. R., Torstensen, B. E., Lin, Y. H., Lillefosse, H. H., Lock, E.-J., Madsen, L., Hibbeln, J. R., & Malde, M. K. (2013). Dietary linoleic acid elevates endogenous 2-arachidonoylglycerol and anandamide in Atlantic salmon (Salmo salar L.) and mice, and induces weight gain and inflammation in mice. The British Journal of Nutrition, 109(8), 1508–1517. https://doi.org/10.1017/S0007114512003364

Bethancourt, H. J., Leonard, W. R., Tanner, S., Schultz, A. F., & Rosinger, A. Y. (2019). Longitudinal Changes in Measures of Body Fat and Diet Among Adult Tsimane’ Forager-Horticulturalists of Bolivia, 2002-2010. Obesity, 27(8), 1347–1359. https://doi.org/10.1002/oby.22556

Blasbalg, T. L., Hibbeln, J. R., Ramsden, C. E., Majchrzak, S. F., & Rawlings, R. R. (2011). Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. The American Journal of Clinical Nutrition, 93(5), 950–962. https://doi.org/10.3945/ajcn.110.006643

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/

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

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

Goodrich, T. (2016, 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. (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

Lee, K. T., Nail, R., Sherman, L. A., Milano, M., Lee, K. T., Deden, C., Imai, H., Goodale, F., Nam, S. C., Lee, K. T., Goodale, F., Scott, R. F., Snell, E. S., Lee, K. T., Daoud, A. S., Jarmolych, J., Jakovic, L., & Florentin, R. (1964). Geographic Pathology of Myocardial Infarction: Part I. Myocardial infarction in orientals and whites in the United States; Part II. Myocardial infarction in orientals in Korea and Japan; Part III. Myocardial infarction in Africans in Africa and negroes and whites in the United States; Part IV. Measurement of amount of coronary arteriosclerosis in Africans, Koreans, Japanese and New Yorkers. The American Journal of Cardiology, 13(1), 30–40. https://doi.org/10.1016/0002-9149(64)90219-X

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

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

Medina-Navarro, R., Durán-Reyes, G., Díaz-Flores, M., Kumate Rodríguez, J., & Hicks, J. J. (2003). Glucose autoxidation produces acrolein from lipid peroxidation in vitro. Clinica Chimica Acta; International Journal of Clinical Chemistry, 337(1–2), 183–185. https://doi.org/10.1016/j.cccn.2003.07.005

Nègre-Salvayre, A., Garoby-Salom, S., Swiader, A., Rouahi, M., Pucelle, M., & Salvayre, R. (2017). Proatherogenic effects of 4-hydroxynonenal. Free Radical Biology and Medicine, 111, 127–139. https://doi.org/10.1016/j.freeradbiomed.2016.12.038

Price, W. (1938). Nutrition and Physical Degeneration. A Project Gutenberg of Australia EBook. http://gutenberg.net.au/ebooks02/0200251h.html

Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., Davis, J. M., Ringel, A., Suchindran, C. M., & Hibbeln, J. R. (2016). Re-evaluation of the traditional diet-heart hypothesis: Analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ, 353. https://doi.org/10.1136/bmj.i1246

Singh, S. P., Niemczyk, M., Zimniak, L., & Zimniak, P. (2008). Fat accumulation in Caenorhabditis elegans triggeredby the electrophilic lipid peroxidation product 4-Hydroxynonenal (4-HNE)—Full Text. Aging, 1(1), 68–80. https://doi.org/10.18632/aging.100005

Skulachev, V. P., Anisimov, V. N., Antonenko, Y. N., Bakeeva, L. E., Chernyak, B. V., Erichev, V. P., Filenko, O. F., Kalinina, N. I., Kapelko, V. I., Kolosova, N. G., Kopnin, B. P., Korshunova, G. A., Lichinitser, M. R., Obukhova, L. A., Pasyukova, E. G., Pisarenko, O. I., Roginsky, V. A., Ruuge, E. K., Senin, I. I., … Zorov, D. B. (2009). An attempt to prevent senescence: A mitochondrial approach. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1787(5), 437–461. https://doi.org/10.1016/j.bbabio.2008.12.008

Stefansson, V. (1960). Cancer: Disease of Civilization?: An Anthropological and Historical Study. Hill and Wang.

Taubes, G. (2008). Good Calories, Bad Calories. Penguin RandomHouse. https://www.penguinrandomhouse.com/books/176680/good-calories-bad-calories-by-gary-taubes/9781400033461

Trowell, H. C., & Burkitt, D. P. (1981). Western Diseases, Their Emergence and Prevention. Harvard University Press.

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

Zhao, Y., Sedighi, R., Wang, P., Chen, H., Zhu, Y., & Sang, S. (2015). Carnosic Acid as a Major Bioactive Component in Rosemary Extract Ameliorates High-Fat-Diet-Induced Obesity and Metabolic Syndrome in Mice. Journal of Agricultural and Food Chemistry, 63(19), 4843–4852. https://doi.org/10.1021/acs.jafc.5b01246

 

Podcast Interview: Linoleic Acid- Interview Preview with Tucker Goodrich with Dr. Joseph Mercola

 This is coming up this weekend. Not sure how it will be available, but I'll post an update.


Podcast Interview: Tucker Goodrich on Vegetable Oils Being at the Heart of Modern Disease with Brian Sanders at Peak Human

File this under better late than never, it's from 2018. The show notes are pretty extensive, so I won't go over it here, please follow the link and show Brian some love.

What makes this interview special is that afterward, Joe Kalb decided to do a fact check of what I said (horrors!).

Vegetable Oils are Bad: Tucker Goodrich, Peak Human podcast review (Part 1)
The Peak Human podcast with host Brian Sanders and guest Tucker Goodrich is my favorite health podcast episode of 2018. In the podcast, Goodrich makes a persuasive case as to what he believes is the primary cause of the diseases of civilization (diabetes, coronary heart disease, autoimmune disease, cancer, etc). In this 94 minute podcast, he strongly posits that one type of food is at the root of the health problems of our times.

What is the primary cause of these health issues? Vegetable oils. Or seed oils, as they are more accurately but less commonly known.

These seed oils are industrially-processed oils containing high levels of Omega-6 fatty acids, which break down into toxic products in our bodies. These vegetable oils (corn oil, sunflower oil, canola oil, soybean oil, safflower oil, etc.) are cheap and therefore ubiquitous in our modern food supply. Tucker Goodrich postulates that these oils, even more than refined carbohydrates, are driving the diseases that plague most of the civilized world. 
Goodrich makes the case by looking at the effects of consuming vegetable oils from several valid perspectives. In my view, he approaches the modern disease problem from all the correct angles. Some of the perspectives from which he approaches the problem are...

Joe put a lot of work into this (an amazing amount of work!) as you can tell by the fact that he broke the work into three parts! 

"Vegetable Oils are Bad: Tucker Goodrich, Peak Human podcast takeaways (Part 2)"

Most of the fact-check is in this post: 

"Vegetable Oils are Bad: Tucker Goodrich, Peak Human listening companion (Part 3)"

 Thanks a lot to Brian for doing the interview, and for Joe for fact-checking me. 

I must confess I was terrified when I heard he had done this!

Brian has a movie coming out now, also. Food Lies, there's a trailer at the link!



Sunday, November 22, 2020

Follow-up to "Does Consumption of Omega-6 Seed Oils Worsen ARDS and COVID-19?"

Two gentlemen were kind enough to send along the full text of a study I only referenced by abstract in that original post.

I've updated the post accordingly, and for those who'd rather not dig through it, here's the update:

PS: Thanks to Drs. Toshi Clark and Joseph Mercola for sending the full text of 1.02 to me.
Here's the summary of that paper:

"...This latter finding suggests that peroxidation of linoleic acid seen in the plasma of patients with ARDS probably occurs in the lung, since the lung is undergoing oxidative stress from sequestered neutrophils, and from ventilatory support with high FIO2.  
"The data further suggest that providing lipid substrates in the form of enteral or parenteral nutrition to patients experiencing severe oxidative stress may greatly exacerbate the underlying disease process. Specific and sensitive measurements of changes in the plasma polyunsaturated fatty acid linoleic acid, and one of its oxidation products, 4-hydroxy-2-nonenal, support the proposal that patients with established ARDS are under severe oxidative stress from their disease and from treatment with high FIO2 concentrations."

Emphasis mine.  The lipid substrate used was Intralipid, discussed above.

Here's the paper: 

1.02.
Quinlan GJ, Lamb NJ, Evans TW, Gutteridge JMC. Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. Read Online: Critical Care Medicine | Society of Critical Care Medicine. 1996;24(2):241–246. doi:10.1097/00003246-199602000-00010

Wednesday, November 4, 2020

New Interview: "Fundamental Health with Paul Saladino, MD: How Seed Oils Destroy Your Mitochondria and Lead To Chronic Disease, with Tucker Goodrich"

This was a very fun interview, and it was sort of a follow-up to an interview Paul Saladino did with Petro (Peter) Dobromylskyj of Hyperlipid a little while back.

We discuss the effect excess linoleic acid has on the mitochondria and the electron transport chain, and what effects some of the metabolites of linoleic acid produced during mitochondrial breakdown have on the body and chronic, "Western" diseases.






With a ridiculous number of references, including links to a bunch of other posts of mine that this builds upon (see below).

And here's the interview he did with Peter , which we discuss several times:



Enjoy!

Paul has a lot of good material and interviews, so do consider subscribing to his podcast. I have.





Selective bibliography for this podcast, referencing my other posts.


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

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)

 


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