Metabolism of polyunsaturated fatty acids and ketogenesis: an emerging connection

https://doi.org/10.1016/j.plefa.2003.11.002Get rights and content

Abstract

This paper summarizes the emerging literature indicating that at least two polyunsaturated fatty acids (PUFA; linoleate, α-linolenate) are moderately ketogenic and that via ketone bodies significant amounts of carbon are recycled from these fatty acids into de novo synthesis of lipids including cholesterol, palmitate, stearate and oleate. This pathway (PUFA carbon recycling) is particularly active in several tissues during the suckling period when, depending on the tissue, >200 fold more carbon from α-linolenate can be recycled into newly synthesized lipids than is used to make docosahexaenoate. At least in rats, PUFA carbon recycling also occurs in adults and even during extreme linoleate deficiency. Hence, this pathway should be considered an obligatory component of PUFA metabolism. It is still speculative but part of the clinical benefit of the very high fat ketogenic diet in intractable seizures may be achieved by raising plasma levels of PUFA that have anti-seizure effects, especially arachidonate and docosahexaenoate. Hence, in addition to some PUFA being ketogenic substrates, the state of ketosis involves potentially beneficial changes in PUFA homeostasis. Both the molecular controls on these pathways and their clinical significance still need elucidation.

Section snippets

Essential fatty acids

Throughout this paper I will refer to fatty acids such as linoleate and α-linolenate as polyunsaturated fatty acids (PUFA). To most specialists in fatty acid metabolism, the term PUFA is equivalent to ‘essential fatty acid’. However, I feel that the term—essential fatty acid (EFA)—is flawed and should be abandoned because few people agree on which PUFA are EFA. Some adhere to a stricter definition limited to linoleate and α-linolenate; others include several long chain PUFA. Ultimately, many

Ketogenesis from linoleate and α-linolenate

Most of the evidence for linoleate and α-linolenate being ketogenic is still circumstantial. Several studies report that by comparison with other common dietary long chain fatty acids, linoleate and α-linolenate are relatively easily β-oxidized (reviewed elsewhere [2]). The figure summarizes these data, which represent experiments done both in vivo and in vitro in three species. Thus, regardless of the experimental design or the species studied, there is broad agreement that the rank order of

Dietary PUFA and ketosis

The foregoing studies make the point that under a variety of experimental conditions, carbon readily gets from linoleate and α-linolenate into newly synthesized lipids. This seems plausible given their active β-oxidation (see Fig. 1) and one study directly showing their greater ketogenic capacity compared to oleate [4]. We have evaluated whether a ketogenic diet enriched in linoleate and α-linolenate actually induces greater ketosis than one largely devoid of those two fatty acids [13]. Rats

Raised plasma PUFA during ketosis

As noted above, it was disappointing to observe that increased ketosis did not increase seizure protection in our animal model [13]. We attributed this to relatively weak seizure protection even in our most ketotic group on medium chain triglyceride, i.e. relatively poor ability to demonstrate a seizure protective effect, regardless of the dietary fat chosen. Seizure protection in children on a ketogenic diet has generally been thought to require a threshold level of ketosis [14], [15].

Biological role

Assuming that more rapid release from adipose tissue and more rapid β-oxidation indeed contribute to making linoleate and α-linolenate more ketogenic, one is left with the question of why; what biological outcome is served? Many in the field of PUFA adhere to the concept that linoleate and α-linolenate serve one major function and that is to provide precursor to their respective families of long chain PUFA (Fig. 2). An extension of that ‘structural’ role is their role in cell signaling,

References (31)

  • N. Emmison et al.

    Linoleic and α-linolenic acids are selectively secreted in triacylglycerol by hepatocytes from neonatal rats

    Am. J. Physiol.

    (1995)
  • G.J. Anderson et al.

    Uptake of fatty acids by the developing rat brain

    Lipids

    (1988)
  • C.R. Menard et al.

    Recycling of carbon into lipids synthesized de novo is a quantitatively important pathway of [U-13C]-α-linolenate utilization in the developing rat brain

    J. Neurochem.

    (1998)
  • A.J. Sinclair

    Incorporation of radioactive polyunsaturated fatty acids into liver and brain of the developing rat

    Lipids

    (1975)
  • G.A. Dhopeswarkar et al.

    Metabolism of α-linolenic acid in developing brain. II. Incorporation of radioactivity from [1-14C]-α-linolenic acid into brain lipids

    Lipids

    (1975)

    • Cited by (20)

    • Metabolism of linoleic and linolenic acids in hepatocytes of two freshwater fish with different n-3 or n-6 fatty acid requirements

      2020, Aquaculture
      Citation Excerpt :

      In fish hepatocytes, mitochondria and peroxisomes are the main organelles for FA β-oxidation (Hashimoto et al., 1999). Some mammalian studies have shown that LA and LNA are good substrates for β-oxidation (Cunnane, 2004), and that LNA has a higher β-oxidation efficiency than LA (Tran and Christophersen, 2002). However, in fish, such as Atlantic salmon, liver cells were found to have higher β-oxidation efficiency for LA compared to LNA, as was also observed in freshwater fish, such as, catfish and zebrafish (Almaida-Pagán et al., 2007; Bandyopadhyay et al., 1982; Lu et al., 2019).

    • An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy

      2017, Epilepsy and Behavior
      Citation Excerpt :

      In non-responsive individuals, a gradual increase to a maximum of 80–90% calories from fat determining whether a higher systemic acidity might be well tolerated and whether ketogenic ratio up to a 4:1 ratio of fat to combined protein and carbohydrate (90% fat) is more therapeutic for the individual. Intake of the higher amounts of ketogenic medium-chain triglycerides (MCTs) [59] and polyunsaturated fatty acids (PUFAs) [60] is controlled by selecting certain foods with a view to balancing the overall fatty acid profile of the diet. Caloric intake also affects the degree of ketosis.

    • Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats

      2013, Life Sciences
      Citation Excerpt :

      It has been proposed that ketone bodies partially replace glucose consumption as a fuel to maintain neuronal activity (Melo et al., 2006), but it is not clear whether these compounds are directly involved in the beneficial effects of this diet on the CNS. In addition to ketone bodies, the content and proportion of polyunsaturated fatty acids have been suggested to be mediators of the effects of KD on brain disorders (Cunnane, 2004; Borges, 2008). KD were originally proposed for epileptic disorders (Baranano and Hartman, 2008)and have a wide use today for treating brain disorders including Parkinson's disease (Vanitallie et al., 2005), Alzheimer's disease (Van der Auwera et al., 2005; Henderson, 2008), amyotrophic lateral sclerosis, depression (Zhao et al., 2006) brain ischemia (Tai and Truong, 2007), bipolar disease (El-Mallakh and Paskitti, 2001) and autism (Evangeliou et al., 2003).

    • Long-term monitoring of the ketogenic diet: Do's and Don'ts

      2012, Epilepsy Research
      Citation Excerpt :

      Eggs, bacon and protein sources high in saturated fats are often used to minimize the amount of fat added to each meal to keep the ratio unchanged. Such traditional or classic KD will cause hyperlipidemia, with elevation in triglycerides and cholesterol, LDL, VLDL and decrease in anti-athrogenic-HDL (Dekaban, 1966; Chesney et al., 1999; Sharman et al., 2002; Fraser et al., 2003; Kwiterovich et al., 2003; Cunnane, 2004; Kang et al., 2004; Groesbeck et al., 2006; Dahlin et al., 2007; Nizamuddin et al., 2008; Zupec-Kania and Zupanc, 2008; Fenton et al., 2009; Porta et al., 2009). Two studies have analyzed the specific fatty acids and phospholipids changes induced by the KD (Fraser et al., 2003; Dahlin et al., 2007).

    • A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet

      2007, Epilepsy and Behavior
      Citation Excerpt :

      Perhaps, in a manner similar to the improvement seen sometimes immediately with fasting [8], stricter carbohydrate restriction during the initial 3 months of the modified Atkins diet may be important for seizure control. Future studies, incorporating either a brief fasting period or ketotic supplements (e.g., omega-3 fatty acids [9], polyunsaturated fatty acids [10]) during the initial months of the modified Atkins diet, may further improve efficacy rates. Our results also demonstrate that after 3 months, an increase in daily carbohydrates not only was believed to be more tolerable, but also did not negatively impact efficacy.

    • Association of Fatty Acid Desaturase Genes with Attention-Deficit/Hyperactivity Disorder

      2006, Biological Psychiatry
    View all citing articles on Scopus
    View full text
    Copyright © 2003 Elsevier Ltd. All rights reserved.