How Seed Oils Destroy Your Mitochondria and Lead To Chronic Disease, with Tucker Goodrich
Tucker Goodrich is a technology executive in the financial industry who designs, runs, and debugs complex systems in high-risk environments. Areas of expertise include risk management, systems management, and cyber-security.
After experiencing some personal health crises and realizing that the ‘solutions’ offered by medical professionals weren’t working or addressing causation he started applying the same approach in research and evaluation of data to his own health issues to determine root causes.
His interests have focused on dietary and environmental drivers of chronic disease, including carbohydrate, wheat, and various classes of fats. Specifically, he's attempting to understand and popularize understanding of the mechanisms driving the diet-derived explosion in so-called chronic diseases (or diseases of civilization). He is active on twitter (@tuckergoodrich, has a blog called Yelling Stop, is an Expert Advisor for the nutrition start-up Nutrita, and has been a guest on numerous podcasts.
0:09:38 0:03:21 Podcast Begins
0:11:12 0:04:55 What is Linoleic Acid?
0:16:44 0:10:27 How Linoleic acid caused disease
0:21:06 0:14:49 Understanding cardiolipin and the electron transport chain
0:23:28 0:17:11 Linoleic acid drives mitochondrial dysfunction, causes chronic illness
0:26:41 0:20:24 Maintenance of Cardiolipin and Crista Structure Requires Cooperative Functions of Mitochondrial Dynamics and Phospholipid Transport https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026740/
0:32:56 0:26:39 Linoleic acid is uniquely damaging
0:35:30 0:29:13 Myths surrounding linoleic acid
0:38:19 0:32:02 The supremacy of animal fats
0:41:05 0:34:48 Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA https://journals.physiology.org/doi/full/10.1152/ajpheart.00480.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
0:42:25 0:36:08 How seed oil consumption leads to necrosis and CVD
0:49:38 0:43:21 Mainstream understanding of PUFAs is built on faulty epidemiology
0:56:21 0:50:04 Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failurehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909262/
0:58:49 0:52:32 All about OxLAMs
1:03:32 0:57:15 Oxidized omega-6s are essential for atherosclerosis
1:13:33 1:07:16 Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467319/
1:14:30 1:08:13 Strong increase in hydroxy fatty acids derived from linoleic acid in human low density lipoproteins of atherosclerotic patients https://www.sciencedirect.com/science/article/abs/pii/S0009308497000959?via%3Dihub
1:15:38 1:09:21 The root cause of oxidative stress is linoleic acid
1:18:17 1:12:00 Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease—A pilot study https://www.sciencedirect.com/science/article/abs/pii/S1098882315300101
1:19:56 1:13:39 How Linoleic acid affects immunity
1:44:03 1:37:46 The linoleic acid-chronic illness hypothesis is air-tight
1:48:14 1:41:57 Calories In, Calories Out is the wrong paradigm
1:51:01 1:44:44 Role of Physiological Levels of 4-Hydroxynonenal on Adipocyte Biology: Implications for Obesity and Metabolic Syndrome https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038367/
1:51:53 1:45:36 Eating seed oils is about as smart as eating poison ivy
1:54:54 1:48:37 Tucker Goodrich radical paleo evangelism
1:58:19 1:52:02 Where to find Tucker Goodrich
Tucker's Blog Post:
Linoleic acid and its metabolites, a primer
Big topic, steadily getting bigger
Most studied metabolite is HNE (aka 4-HNE)
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:
But first, a little context and a caveat. Cardiolipin and Essential Fatty Acids
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. 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 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:
The first image shows a mitochondrion that has physically collapsed in the N-6+Hyperglycemia group, 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.
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)
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)
(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)
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)
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.
“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 oxidative stress (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).
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).
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.” (Perri 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)
"These reactive oxygen species readily attack the polyunsaturated fatty acids of the fatty acid membrane, initiating a self-propagating chain reaction." (Mylonas & Kouretas, 1999)
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)
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)
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