Friday, February 5, 2016

The Cause of Metabolic Syndrome: Excess Omega-6 Fats (Linoleic Acid) in Your Mitochondria

I've had the idea for this post rattling around in my head for a while, but Dr. Eades' excellent post summarizing some of Hyperlipid's posts on linoleic acid's [LA] effect on mitochondria has spurred me on.

Mitochondria, the engine of life

Your body's motor.
As an introduction, the mitochondria are the fundamental element of higher life forms such as ourselves.  They are the power plants of the cells, and are essential for life to continue.

(If you want more detail, see Nick Lane's website, or read his excellent book, Power, Sex, Suicide: Mitochondria and the Meaning of Life.)

One of the hallmarks of the metabolic syndrome is mitochondrial dysfunction, where the mitochondria fail to generate power correctly.  This review focuses on the heart, but does a good job of explaining some of the many symptoms, while not addressing the cause:
"The metabolic syndrome represents a cluster of abnormalities, including obesity, insulin resistance, dyslipidaemia and Type 2 diabetes, that increases the risk of developing cardiovascular diseases, such as coronary artery disease and heart failure. ... Recent findings suggest that myocardial mitochondrial dysfunction may play an important role in the pathogenesis of cardiac contractile dysfunction in obesity, insulin resistance and Type 2 diabetes."
They forgot cancer, but that's fine, we'll get to it.

Mitochondria are so essential to life that they control it.  Mitochondria control the life or death of individual cells, and can send a signal to a cell that causes it to commit suicide—known as apoptosis:
"Mitochondria are the bioenergetic and metabolic centers of eukaryotic cells. During apoptosis, mitochondria suffer specific damages that result in loss of their function.... 
"...The logical conclusion from studying mitochondria-initiated apoptosis is that the best way to prevent cell death is to block apoptotic signals before mitochondrial damage occurs." [My emphasis]
"The expanding role of mitochondria in apoptosis"
So, having established  established their importance both to life, and the initial hint that they may be fundamental to metabolic syndrome, let's look into why.


Cardiolipin (CL) is a component of the mitochondria, which, as Wikipedia explains:
" found almost exclusively in the inner mitochondrial membrane where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism."
It triggers apoptosis:
"Cardiolipin distribution to the outer mitochondrial membrane would lead to apoptosis of the cells, as evidenced by cytochrome c (cyt c) release... A cardiolipin-specific oxygenase produces CL hydroperoxides which can result in the conformation change of the lipid. The oxidized CL transfers from the inner membrane to the outer membrane, and then helps to form a permeable pore which releases cyt c."
Causing apoptosis.  So oxidized CL is something we'd like to avoid.  Unfortunately:
"Mitochondrial electron transport chain is a major intracellular source of ROS [Reactive Oxygen Species] (33). Therefore, the effect of these reactive species should be greatest at the level of mitochondrial constituents, given that they are a highly reactive and short-lived species. Cardiolipin, an inner mitochondrial membrane phospholipid component, appears particularly susceptible to ROS attack either because of its high content of unsaturated fatty acids (90% represented by linoleic acid) or because its location in the IMM, near to the site of ROS production." 
"Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria"
So cardiolipin is uniquely susceptible to oxidation because it's composed of easily-oxidized linoleic acid, and it's adjacent to the source of free oxygen in the mitochondria.  Cardiolipin appears doomed. Is there any hope?

Well, while one often reads that cardiolipin is composed of four linoleic acid molecules (tetralinoleoyl CL), this isn't entirely correct. This review, while making the same observation as above, notes an important distinction, which is the key to this entire post of mine:
"Cardiolipin molecules are particularly susceptible to ROS-induced oxidation, either for their fatty acyl composition or for their proximity to the ROS generating centers. In fact, CL molecules are rich in unsaturated fatty acids, particularly linoleic acid in heart and liver, or docosahexanoic [DHA] and arachidonic [AA] acids in brain tissue mitochondria. In addition, CL molecules are located near to the site of ROS production, mainly represented by complex I and complex III of the respiratory chain." 
"Functional role of cardiolipin in mitochondrial bioenergetics"
So cardiolipin isn't necessarily composed of linoleic acid.  And therein lies our hope.

Remodel Your Mitochondria

In fact, CL fatty-acid composition is directly, and immediately, dependent on dietary intake of fatty acids.

When the human fetus is developing, cardiolipin's structure changes.  LA goes from 45% to over 90%, but this study was published in 1974, decades after high-LA seed oils were invented and pushed as a healthy alternative to traditional animal fats.  And it is indeed possible to alter the CL composition, either increasing or decreasing the amount of LA:
"Different dietary fatty acid patterns leading to steatosis [NAFLD] were explored. With high-fat diet, moderate macrosteatosis was observed and the liver mitochondrial phospholipid class distribution and CL fatty acids composition were modified. Indeed, both CL content and its C18:2n-6 [the chemist's way of describing LA] content were increased with liver steatosis. Moreover, mitochondrial ATP synthase activity was positively correlated to the total CL content in liver phospholipid and to CL C18:2n-6 content while other complexes activity were negatively correlated to total CL content and/or CL C18:2n-6 content of liver mitochondria. The lard-rich diet increased liver CL synthase gene expression while the fish oil-rich diet increased the (n-3) polyunsaturated fatty acids content in CL. Thus, the diet may be a significant determinant of both the phospholipid class content and the fatty acid composition of liver mitochondrial membrane, and the activities of some of the respiratory chain complex enzymes may be influenced by dietary lipid amount in particular via modification of the CL content and fatty acid composition in phospholipid." 
"Dietary fatty acids modulate liver mitochondrial cardiolipin content and its fatty acid composition in rats with non alcoholic fatty liver [NAFLD] disease."
That association with a change in the LA content in the cardiolipin with NAFLD is an interesting one.

This study goes into a bit more detail:
"...The fatty acid compositions of the major mitochondrial membrane phospholipids, phosphatidylcholine, phosphatidylethanolamine and cardiolipin were modified according to the fatty acid composition of the diet. Each of these phospholipids had a distinct fatty acid composition and similar effects of dietary lipid manipulation on the fatty acid compositions were observed. Feeding the SO [safflower oil] diet resulted in fatty acid compositions which were most similar to those found after feeding the LF [low-fat] diet. Feeding the HCO [hydrogenated coconut oil] and OO [olive oil] diets increased the proportions of stearic and oleic acids, respectively, while decreasing the proportion of linoeic acid. Feeding the MO [menhaden (a fish) oil] diet resulted in increased proportions of palmitic [PA], palmitoleic [POA], eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids and decreased proportions of linoleic and arachidonic acids in each of the phospholipids." 
"The effect of dietary lipid manipulation on hepatic mitochondrial phospholipid fatty acid composition and carnitine palmitoyltransferase I activity."
(AA is produced from LA in the body, although it can also be consumed.  Tissue, but not serum, levels of AA are influenced by LA consumption.  I'm guessing that if this study was done today, they wouldn't be using a hydrogenated fat.)

A third study sheds even more light on the susceptibility of cardiolipin to dietary manipulation, this time in the rat brain.  Levels of brain cardiolipin fat content can be modified by adjusting the levels of omega-6/omega-3 in the diet, although the brain seems to limit the rate of LA uptake (the only place I've seen a rate-limiter on the incorporation of LA into tissues outside of cattle).
"Weanling rats were fed for three weeks on diets designed to separate the neural effects of the amount of dietary saturated, monounsaturated, and essential fatty acids (EFA). The results revealed that the level of 18:2n6 in neural CL was very strongly correlated (r2 = 0.851: P < 0.0001) with the amount of EFA in the diet. This relationship was linear (slope − 0.793,y-intercept = 6.53%) over a wide range of dietary EFA levels (4–15% wt/wt of diet) with the level of 18:2n6 [LA] in CL varying by two-fold. Neural 18:2n6 levels were not affected by the ratio of dietary EFA (18:2n6/18:3n3 [linolenic acid, ALA]) when the total amount of EFA was held constant. These results indicate that: 1) the amount of dietary EFA substantially alters the level of 18:2n6 in CL from the brain of the weanling rat in a relatively short time; and 2) this relationship is linear over a wide range of EFA levels that are well above the accepted EFA requirements for the rat and within levels that are typical of human diets." 
"The level of linoleic acid in neural cardiolipin is linearly correlated to the amount of essential fatty acids in the diet of the weanling rat"
The authors of an earlier paper, noting the same effect, dryly observe that:
"In the rat some protection of the brain against diets containing little fat or with high dietary ratios of 06:03 FA is afforded by the poor breeding performance of rats maintained on these diets (Tinoco, Williams, Hincenbergs & Lyman, 1971; Sinclair & Crawford, 1973)." 
"Long-chain polyunsaturated fatty acids in the mammalian brain" (PDF)
That's certainly one way to solve the problem of over-consumption of LA: poor breeding performance.

(They then note potential consequences for humans:
"In view of the important role of milk in the immediate postnatal nutrition of humans it is of interest to note that the PUFA content of six common brands of artificial milk (mg/g total FA) ranges from 27 to 352, compared with about IIO [sic] in human milk. Furthermore the ratio, 06:03 FA in these milks varies from 1.5:' up to 129:1, compared with a ratio of 2.8:1 in human milk. Therefore consideration of the foregoing observations may be relevant to human nutrition."
From 1975... Sigh.)

Impact on Mitochondria of High Levels of LA in Cardiolipin

So here's where we're entering the frontiers of science, and I'm going to have to walk across a narrow bridge to get to the other side of the link between LA and metabolic syndrome.

The following study (2014) looked at the formation of oxidized linoleic acid metabolites (OXLAMs) and their effects:
"Free radical-induced [free radical = ROS] lipid peroxidation has been linked to multiple human diseases including atherosclerosis [8]. Among the complicated oxidation products, lipid electrophiles, including 4-HNE, generated from lipid oxidation have attracted increased attention due to their potential roles in altering protein structures and functions through covalent modification of critical nucleophilic amino acid residues [10,21,22]. Overwhelming evidence indicates that mitochondria play an essential role in ROS generation, lipid peroxidation, and the pleiotropic effects of 4-HNE in various biological processes. In contrast to the well-studied biology of 4-HNE, the chemical mechanisms for 4-HNE formation and cellular locations remain poorly defined [23,24].  In a previous report we proposed a novel chemical mechanism for the formation of 4-HNE and other reactive lipid aldehydes from mitochondrial cardiolipin oxidation [17]. In our current study, we provide evidence that this mechanism operates both in vitro in t-Bid induced cyt c release and in vivo in mice liver of atherosclerosis [sic] after Western diet feeding."
They also found that CL that did not contain the typical four LA was much less susceptible to oxidation:
"Besides the major cardiolipin species L4CL, mouse liver tissue contains other minor cardiolipins such as L3OCL. The structure of L3OCL has one of the LA side chains replaced by an oleic acid. According to our chemical mechanism of 4-HNE formation from CL, cross-chain peroxyl radical reaction occurs between two adjacent side chains; thus the presence of an unreactive oleic acid side chain in L3OCL may disrupt this reaction and lead to less lipid electrophile production through this mechanism. As shown in Fig. 4, our data showed that the formation of similar electrophiles EAA-CL from L3OCL was indeed significantly suppressed compared to those from L4CL, highlighting the importance of this cross-chain reaction during the formation of reactive electrophiles. Interestingly, formation of other major oxidation products, such as HODE-CL, from L3OCL was decreased compared to L4CL but did not reach statistical significance." 
"Formation of electrophilic oxidation products from mitochondrial cardiolipin in vitro and in vivo in the context of apoptosis and atherosclerosis"
In the next study we find that, sure enough, if you feed mice an essential fatty acid (EFA) "deficient" diet (0.05% LA) their cardiolipin used OA (which the body can produce) in place of LA.  They shifted from 58% LA to 70% OA. The diet they were fed was also deficient in DHA, apparently.  (Whether or not LA is actually essential is an interesting question, although outside the scope of this discussion.)  Sadly, they didn't look at production of OXLAMs.
(PDF) "Paradoxical  Conservation of Cardiac  and Renal  Arachidonate Content in Essential Fatty Acid Deficiency"
But this study (2014) did, although not in a reduced-LA state, sadly:
"The central role of mitochondria in metabolic pathways and in cell death mechanisms requires sophisticated signaling systems. Essential in this signaling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin, are oxidized by the intermembrane space hemoprotein, cytochrome c. We show that an assortment of oxygenated cardiolipin species undergoes phospholipase A2-catalyzed hydrolysis thus generating multiple oxygenated fatty acids, including well known lipid mediators. This represents a new biosynthetic pathway for lipid mediators."
They looked in the mouse gut cells:
"...The major FAox [oxidized Fatty Acid] species – mostly mono-oxygenated LA-derivatives - were 9-HODE and 13-HODE (Fig 1d). In addition, 9-KODE, 13-KODE, 9-HpODE, 13-HpODE, 12-HETE, 15-KETE, 15-HETE were also detectable albeit in significantly smaller amounts (Supplementary Fig. S2, Supplementary Table S2)...."
and in the rat brains:
"...In addition, the oxygenated species of non-esterified LA and AA were produced (Fig. 2d, Supplementary Fig. S4), whereby several lipid mediators were identified such as 9-KODE, 13-KODE, 9-HODE, 13-HODE, 9,12,13,-KEpOME, 9-HpODE, 13-HpODE, 12-HETE, 15-HETE (Supplementary Table S2). Markedly smaller amounts of oxygenated DHA were also detected (Fig. 2d).... 
And once they cause apoptosis, they're loose in the body:
"Our studies reveal that not only CL and CLox but also CLox hydrolysis products – mCL and FFAox – may be released, along with mitochondria, from injured cells. Importantly, sufficient hydrophobicity of mCL retains its association with mitochondria. However, oxygenated mCLs may lose their association with the outer mitochondrial membrane and partition into the aqueous phase of extracellular compartments. Oxygenated FFAs also water-soluble, hence diffuse independently of mitochondrial surfaces. Release of CL44 and cyt c 45 from injured host cells into the extracellular space, have been shown. Thus lipid mediators may also be generated extracellularly from CL with the contribution of cyt c and subsequent hydrolysis of CLox by Lp-PLA2. Overall, CL-dependent lipid mediators may be represented by a diversified variety of membrane-associated and freely diffusible and circulating signaling molecules whose identification and quantitative analysis will represent an intriguing opportunity for the future studies."
"A mitochondrial pathway for biosynthesis of lipid mediators" and full-text PDF
Those OXLAMS are interesting, as they're bio-active.  Since the body can't produce LA itself, it can only be gotten through the diet, and therefore the OXLAMs can only be produced through the diet.

Now the hole in this argument, at the moment, is that I can't find a study that looks at OXLAM production and cell apoptosis in a LA-restricted diet. [P.S. This hole is plugged.  You might even call it a smoking gun.]

But we'll find some other evidence that plugs a bit of that hole.

Oxidized Linoleic Acid Metabolites and Fatty Liver

So there's a great deal of evidence that if you feed someone intravenously glucose and soybean oil (yes, they do this, it's called total parenteral nutrition (TPN), and is used for people with a serious intestinal problem) they will reliably get fatty liver, aka hepatic steatosis.  This leads to cirrhosis, perhaps liver cancer, and liver failure.  If you switch them to a fish-oil based TPN solution soon enough, it cures the fatty liver.

This is very similar, if not identical, to the non-alcoholic fatty liver disease (NAFLD) which is a hallmark of the metabolic syndrome:
"Nonalcoholic fatty liver disease (NAFLD) has become the most common form of liver disease, affecting 20% to 30% of the US population. Its clinical manifestations are usually absent or subtle, and it usually comes to medical attention incidentally when aminotransferase levels are found to be elevated or a radiographic study reveals that the liver is fatty. Primary NAFLD is now considered the hepatic manifestation of the metabolic syndrome. The pathogenesis is thought to be a multiple-hit process involving insulin resistance, oxidative stress, apoptosis, and adipokines. In general, the prognosis for simple steatosis is very good; however, nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatocellular carcinoma in 10% to 15% of patients. There is no established treatment for NAFLD except for weight loss and treating each component of the metabolic syndrome." 
"Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome."
Some people don't find the TPN evidence to be convincing, although it convinced me.  But now we also have another line of evidence.
"In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) [same as OXLAMs] with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). ...we show that only in subjects with hepatic steatosis, the OXFAs are associated... We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D." 
"Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents?"
OXLAM levels are correlated with both fatty liver and type 2 diabetes.  So let's go find a "novel therapeutic opportunity".  From 2013:
"These observations suggest novel therapeutic strategies. In fact, because LA cannot be synthesized de novo in humans, dietary LA is the sole source of LA for the human body, therefore also being the sole source for OXLAM synthesis. Lowering LA in the diet might help to reduce OXLAMs in the blood and other tissues such as the liver, leading to an improvement of liver histology. Recently, a study was designed to evaluate the effect of low dietary LA on plasma and erythrocyte fatty acids, and it has demonstrated that a 12-week diet low in n-6 PUFAs significantly reduced the plasma levels of OXLAMs and reduced the LA content of several circulating lipid fractions that may serve as precursors of endogenous OXLAM synthesis [54]. LA reductions were more pronounced in phospholipids and TGs, indicating that these fractions may be more responsive to dietary modifications [51]. These data clearly suggest that if the same reduction of LA and OXLAMs may be achieved in the liver, it may help to reduce or even cure NASH [NASH is when NAFLD gets worse]." 
"Oxidized metabolites of linoleic acid as biomarkers of liver injury in nonalcoholic steatohepatitis"
Yes, if OXLAM levels are correlated with NAFLD, and can be modified by the diet, reducing LA levels would seem to the the next thing to do.

Footnote 54 is to this study, from 2012:
"We report for the first time that lowering dietary LA reduces OXLAMs in humans, here among subjects with chronic headaches. This link between dietary LA and OXLAMs may have important implications for pathological conditions linked to increased activity or abundance of OXLAMs (e.g. chronic pain, Alzheimer’s dementia, cardiovascular disease, NASH) [,,,]. To our knowledge, this is the first demonstration that changes in dietary LA can alter the abundance of plasma OXLAMs in humans, or that lowering dietary LA reduces the abundance of OXLAMs in any tissue in a human or animal model. Our findings are consistent with a report [] that a 4-fold increase in dietary LA (from corn oil) produced a 5-fold increase in the 9- and 13-HODE content of mammary tissue in female mice. Collectively, these observations indicate that dietary LA may hold proximal control over the production and/or accumulation of OXLAMs in certain tissues. 
"Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans
So OXLAM levels are controlled by the diet in humans (rats are nice, but I'm more concerned with human health). And these radical Polish scientists in 2015 decided to—gasp—go test the hypothesis:
"Twenty-four patients, 12 in the first and 12 in the second stage of NAFLD, were prospectively enrolled in this study. Biochemical parameters and eicosanoids (HETE and HODE) were compared between the first and the second stage of hepatic steatosis and the effect of a 6-month dietary intervention on these parameters was evaluated." 
"RESULTS: Patients with stage I NAFLD had a significantly higher level of HDL cholesterol and a lower level of 5-HETE. Patients with grade II steatosis had higher concentrations of 9-HODE. Following the six-month dietary intervention, hepatic steatosis resolved completely in all patients. [Emphasis mine] 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)." 
"Metabolites of arachidonic acid and linoleic acid in early stages of non-alcoholic fatty liver disease-A pilot study."
So what, exactly, was that dietary intervention?  While they don't detail the before diet, the typical Western diet that induces metabolic syndrome contains north of 7% of energy as LA.
"The total omega-3 and omega-6 fatty acids consumption was approximately 0.5% E for omega-3 and 4% E [energy] for omega-6. Carbohydrate intake, differed depending on the needs of the patient, and ranged between 50 and 65%."
So this is a high-carb diet, with restricted LA*, and it cured NAFLD—in 100% of the people put on the diet.  And it reduced all the OXLAMs produced in the mitochrondria.

Which, from what we've seen above, makes perfect sense.

13-HODE levels strongly correlate with hepatic fat content.
Now what this doesn't show is the exact mechanism by which OXLAMs induce steatosis (13-HODE appears to most highly correlate with it in mice).  However, this is of little interest outside of the lab if you can effect a 100% cure rate with a mere dietary manipulation.

But as a confirmation that the hypothesis is validated—a similar, but less effective result, was demonstrated using a drug in 2012:
"...In summary, this study demonstrated that therapy with PTX in NASH results in decreased oxidized lipid products of LA and AA compared to placebo. These are novel findings. Furthermore, the oxidized lipid products modified by PTX have described associations with NASH and specifically with nonenzymatic oxidation of lipid precursors,10, 11supporting that the beneficial effects of PTX in NASH are likely partly mediated through decreasing free-radical-mediated lipid oxidation. In addition, to our knowledge, this is the first time that decreased levels of oxidized fatty acids are shown to correlate with histological improvement in the setting of a therapeutic trial in NASH. The correlation between decreased oxidized lipid products and improved liver fibrosis scores is particularly noteworthy.
"Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: New evidence on the potential therapeutic mechanism"

Two of the most-notable ingredients of the "Western diet" are refined carbohydrates and LA.  Others have shown that the obvious ill effects do not occur if LA is not included, or, if it is included, if the mitochondria are given a chance to rest, through use of a feeding window (food is not provided for 16 hours a day).

I think this post establishes that there is a clear cause-and-effect relationship between dietary consumption of excess linoleic acid and at least some aspects of the metabolic syndrome.  The excess qualifier is important since linoleic acid in small quantities is found in most natural foods.

The only way to get excess amounts in the diet are: eat oils made from seeds, eat animals that are fed on excessive amounts of grain that concentrate LA, or eat far too much grain yourself.  And don't makes nuts, avocados, or olive oil a staple part of your diet.

I think this also explains a few of the seeming contradictions of the Paleo diet.  The Kitavans eat a high-carb diet, but it's high in coconut fat and fish oil and low in seed oils, and therefore they're protected against metabolic syndrome.  The !Kung Bushmen eat the high-LA mongongo nut as a staple, and don't suffer from metabolic syndrome, I suspect because they eat them seasonally, and the nuts are low in carbohydrates—and it's the combination of the two that really seems to cause mitochondrial dysfunction.  And there's also good evidence that linoleic acid directly stimulates appetite and carbohydrate cravings via the hypothalamus.

As I said, I'd love to see some studies looking at the cardiolipin make-up of people eating an ancestral diet, or those following a low-LA Paleo diet.  I'd also like to see some better examination of the mitochondrial impact of a low-linoleic acid diet.**  Some of the research I've seen seems to indicate that LA makes the mitochondria better at burning glucose, and as in Dr. Eades' point at the beginning of the post, this may be why, in part, we are over-consuming carbohydrates.  Based on the results of some athletes who are following a low-carb, Paleo-style diet, I suspect that this hint that LA makes us better sugar burners and therefore able to produce more power is non-significant, if it even exists outside the lab.

And there's a lot more research going on on the connection between this novel staple food and metabolic syndrome:
"...we demonstrate that ABCA1 and ABCG1 protein levels are synchronously suppressed by high glucose levels and the ω6-unsaturated fatty acid linoleic acid. We conclude that metabolites associated with the metabolic syndrome enhance the formation of atherosclerotic lesions by diminishing the reverse cholesterol transport function of ABCA1 and ABCG1. 
"High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages"
P.S.  So after writing all of this, I found the following review:

"Oxidative Stress, Cardiolipin, and Mitochondrial Dysfunction In Nonalcoholic Fatty Liver Disease" (PDF) which comes the the same conclusions I did absent the final ones.  The authors, stating that PUFAs are "essential" in cardiolipin, suggest antioxidant therapy as a promising line of research.  Seems to me that stopping the oxidation in the first place is a better one...

P.P.S.  Yep.

"Roles of the Lipid Peroxidation Product 4-Hydroxynonenal [4-HNE] in Obesity, the Metabolic Syndrome, and Associated Vascular and Neurodegenerative Disorder."

I wish they wouldn't say "lipid peroxidation", thus blaming all fats, as it's only one particular lipid (basically) that's to blame...

( * See this study on how a high concentration of LA seems to be a requirement for oxidation in the mitochondria—for pigs)

P.S.  ** Here's one test of the necessity for LA in mitochondria: 
"Further, high levels of tetralinoleoyl [CL] were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs. 
"Improved mitochondrial function with diet-induced increase in either [DHA] or [AA] in membrane phospholipids."