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.

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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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