Choosing the right fat for keto diets: Fish oil's significant role in cancer prevention

By Hugo Francisco de SouzaMar 11 2024Reviewed by Lily Ramsey, LLM

In a recent study published in Scientific Reports, researchers used murine (A/J mice) models to evaluate the anti-cancer efficacy of different oils consumed as a part of ketogenic diets (KDs).

Specifically, they compared seven commonly consumed, fat-enriched KDs with Western-style diets and a 15% carbohydrate diet as controls.

Their results revealed that all ketonic diets proved better than Western-style and 15% carbohydrate diets at preventing nicotine-derived nitrosamine ketone (NNK)-induced lung cancer in mice.

Study: A ketogenic diet rich in fish oil is superior to other fats in preventing NNK-induced lung cancer in A/J mice. Image Credit: Natalia Klenova/Shutterstock.com

Background

This study highlights the anti-lung cancer potential of fish oils (FOs), which were found to increase plasma β-hydroxybutyrate (β-HB), reduce blood glucose, and attenuate fatty acid synthase (FAS) expression, thereby metabolically arresting lung tumor nodule formation.

Notably, to address KD-induced high plasma triglyceride (TG) and cholesterol levels, researchers further characterized the impacts of long-term ketogenic diets on lipid profiles and liver health and found that, not only did standard KDs not induce liver damage, FO-enhanced KDs were even less harmless to liver and lipid profiles, attesting to their safety.

What are ketogenic diets, and what makes them useful against cancers?

Ketogenic diets (KDs) are diets that were initially developed to treat intractable epilepsy in the 1920s. They are characterized by very high-fat contents and low carbohydrates (CHO), forcing the body to metabolize lipids for energy.

Most KDs are designed to supply 90% of total calories from fats, while only 2% are acquired from CHO. KDs acclimatize the body to depend on KD-derived ketone bodies instead of glucose.

Ketone bodies, in turn, have been the source of recent scientific excitement due to the inability of most cancerous tumors to utilize ketones as fuel sources.

Surprisingly, the systematic evaluation of KD-associated fats remains lacking. Still, scientists hypothesize that the differences in the fatty acid contents of these fats may result in vastly differing tumor cell proliferation profiles.

Previous work by the present research team has established that reductions in easily digestible CHO from 50% (typical CHO content of Western-style diets) to 15% significantly reduce nicotine-derived nitrosamine ketone (NNK)-induced tumor nodules in A/J mice, further supporting the need for an investigation of the benefits of alternative fat-rich, CHO-poor diets as preventive interventions against cancer.

“…saturated fatty acids like palmitic acid, the most common dietary fatty acid, are potent activators of Toll like receptor 4 (TLR4) signaling in macrophages, making them pro-inflammatory. As well, omega 6 fatty acids like arachidonic acid (AA) are known to be metabolized to prostaglandin E₂ (PGE₂), a prostanoid shown to help tumors grow, both directly and via suppression of anti-tumor immunity. Omega 3 fatty acids, on the other hand, have been shown to be anti-inflammatory, at least in part by inhibiting AA conversion to PGE_2.”

About the study

In the present study, researchers compared the anti-NKK-induced lung cancer efficacies of three different dietary regimes – the Western-style diet (50% CHO), the 15% amylose diet (developed in-house; 50% fat-based), and KDs (seven types, each with a different fat source).

The seven KDs comprised Western-type fats (standard KD), medium chain fatty acids (MCT-KD), milk fat (MF-KD), palm oil (PO-KD), olive oil (OO-KD), corn oil (CO-KD), and fish oil (FO-KD).

All experiments were conducted on 12-week-old female A/J mice. Data collection included blood glucose levels (measured during nocturnal feeding), biochemical blood and plasma analyses (Plasma β-hydroxybutyrate [β-HB], cholesterol, and alanine aminotransferase levels), and immunohistochemistry of excised and preserved lung and liver tissue.

Since the prolonged dependence on KDs has been hypothesized to alter lipid profiles and potentially damage the liver, researchers further investigated the liver health scores (via proxies and biomarkers) of the various KDs compared to Western and 15% amylose diets.

For liver health evaluations, the thiobarbituric acid substances (TBARS) assay was used to determine liver TBARS levels, enzyme-linked immunosorbent assays (ELISAs) were used for liver 8-OHdG determination, and whole liver sections were scored for non-alcoholic fatty liver disease (NAFLD).

Finally, in an attempt to unravel the mechanistic underpinnings of KDs’ (specifically, fats’) anti-cancer ability, mice fecal samples were used for microbiome analysis.

Study findings

The results of the five-month-long dietary interventions following NNK injections revealed that Western diets were the worst (mean nodule number = 18). In contrast, 15% of amylose diets only depicted ten nodules on average.

KDs (even the standard KD containing common Western diet fats) performed much better than both diets. FO-enriched KDs, in particular, were found to perform the best and were the only KD cohort to differ significantly in nodule number from standard KD.

Investigations into the mechanisms underpinning these observations revealed that FO-KD produced substantially more ketone bodies than other KD cohorts.

In parallel, KD was shown to downregulate, attenuate fatty acid synthase (FAS) expression, and increase CPT1a levels within the liver. Notably, fish oil enrichment further exuberated these results.

This suggests that ketosis improvements may contribute to FO-KD’s anti-cancer properties. FO-KDs were additionally observed to reduce the levels of inflammatory cytokines, including interleukin-6 (IL-6) and PGE₂, in mouse lungs.

“Interestingly, palm oil and corn oil-enriched KDs further lowered IL-6 levels, potentially challenging the long-held notion that palm oil and corn oil are pro-inflammatory. On the other hand, the PO-KD and CO-KD resulted in the highest levels of IFNγ and the lowest levels of IL-5 and IL-10 amongst the different KDs. Unexpectedly, even though the FO-KD was the most effective in preventing lung nodule formation, this diet had no unique impact on the pro-inflammatory cytokines/chemokines tested, other than a trend towards high IL-1β levels.”

Immunohistochemistry results validate these assays and suggest that FAS, substantially lower in KDs (and lowest in FO-KD) than Western diets, may play the most crucial role in NNK-induced lung pathology.

Encouragingly, liver health assays debunked previously hypothesized concerns, revealing that not only did KDs do no more damage than standard Western diets or the 15% amylose diet, but FO-KD and MCT-KD were found to cause even less liver damage than these.

In contrast, while standard KD did not significantly alter lipid profiles compared to Western and amylose diets, FO-KD and MCT-KD substantially increased low- (LDL) and very low-density lipoprotein (VLDL) levels in mice plasma.

Conclusions

The present study validates the long-term safety of KDs on liver health and validates their anti-lung cancer properties in A/J mice.

Fish oil was found to be the most effective of all tested KD fats and is assumed to confer anti-cancer protection through metabolic alterations, especially by reducing FAS levels.

These findings highlight FO-KD as a future intervention against lung cancer, but its cardiovascular safety must first be confirmed before these interventions can be implemented.