Why the Inuit Aren’t in Ketosis: The Redox Apocalypse

Video Summary

The Inuit live in the Arctic on the seal blubber. This would be considered a ketotic diet, yet they are not heavily in ketosis.

The reason is that they have a genetic deficiency in a gene called CPT1 that doesn’t allow them to import long chain fats – normal things such as stearic acid (chocolate) and oleic acid (olive oil) – into their mitochondria. This mutation has some serious disadvantages such as hypoketotic hypoglycaemia, seizers and sudden unexpected death in infancy. (Collins, 2010)

Despite theses serious drawbacks, the frequency of this mutant allele in the Inuit population suggests that there was strong selection pressure for this mutation. One of the effects of the mutation is a lack of ketosis. Ketones are produced in liver mitochondria and without the ability to directly import fat, there seems to be a lack of sufficient Acetyl-CoA to generate significant ketones.

It has been suggested that the reason this mutation was selected for is that being in ketosis long term is problematic. The argument is that in a cold environment, a combination of hypothermia with baseline ketosis could put you into ketoacidosis.

I am putting forth another hypothesis: highly unsaturated fat from seal blubber would put the liver into serious oxidative and reductive stress. Seal blubber is well over 20% long chain omega 3 fats (Kuhnlein, 1991), which are highly prone to oxidation. (Meydani, 1991) Compounding this problem, seal blubber is over 60% MUFA, which creates a high NADH/NAD+ ratio in the cell (AKA reductive stress)(Dziewulska, 2020), which drives the peroxidation of PUFA (Ogura, 2020; Yan, 2021).

Mice who lack the nuclear receptor PPAR alpha are killed via acute liver failure by a diet containing around 25% of calories as fish oil. (Luo, 2021) In normal circumstances, long chain PUFA are broken down in peroxisomes. PPAR alpha is activated by both the MUFA and PUFA in seal blubber. PPAR alpha controls peroxisomal activity, expression of CPT1, and detoxification of xenobiotics (Claudel, 2007). Humans have low peroxisomal activity. (Ammerschlager, 2004)

Clofibrate activates PPAR alpha. ACOX is an indicator or peroxisomal activity.

Seal blubber based diets would have provided at least twice the long chain PUFA as the diet that killed mice lacking the ability to increase peroxisomal liver activity.

I am suggesting that by losing CPT1 functionality, the Inuit were able to take advantage of the detoxification and peroxisomal amplifying effects of PPAR alpha activation while avoiding the increase in NADH/NAD+ ratio caused by an increase in CPT1 expression. Increased peroxisomal activity would have increased the rates of elimination of the long chain PUFA. The lower NADH/NAD+ ratios would have helped to maintain the PUFA as PUFA, rather than becoming peroxidized products such as malondialdehyde (MDA) – an indicator of oxidative stress.

Luo et al. recently demonstrated that mice and human liver cells with reduced CPT1a function have hugely reduced MDA levels. The human liver with reduced CPT1 function are a pretty reasonable approximation for what is happening in an Inuit liver. Knocking down CPT1a reduced MDA levels by two thirds.

Seal blubber’s ratio of Saturated/MUFA/PUFA is 10/64/26. (Kuhnlein, 1991) I don’t believe fat of this composition is a suitable staple food of humans. This amount of highly-peroxidizable PUFA with MUFA would have led to an apocalypse of liver failure among the earliest arctic inhabitants. Many would have perished just like the mice lacking PPAR alpha on a fish oil diet. Luo et al have demonstrated that dramatically reduced CPT1 function would have been key to surviving the redox apocalypse.

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