Foie Gras (1) Peroxisomes

Jaromir posted this link on Twitter/X. It's excellent groundwork for further discussions relating to the study cited by Tucker in rats and the hepatic lipidosis in mice mentioned by Bill Lagakos.

Fasting induces hepatic lipid accumulation by stimulating peroxisomal dicarboxylic acid oxidation

which can be summarised in this picture, modified very sightly to remove their drug manipulations. Each step was validated by a set of experiments, it looks to have been a large part of several people's lives over several years:

This looks very, very much like a protective mechanism, put in place within hepatocytes (which are the final port of call for FFAs when the system is overloaded from excess lipolysis, think of ethanol or fructose acting on adipocytes) to protect them from potentially lethal damage from excess beta oxidation derived ROS.

It's executed by peroxisomes. Anyone who is still shamefully unaware of Dave Speijer's ideas of the role of peroxisomes in the protection of LECA (last eukaryote common ancestor) from ROS damage should go and read     

How to deal with oxygen radicals stemming from mitochondrial fatty acid oxidation

Ultimately, when the liver cells are flooded with FFAs the peroxisomes respond* by producing DCAs, di-carboxylic acids. This is basically taking a FFA such as palmitic acid and sticking, by a specific process, a second carboxyl group on to the omega end. This is used a signal to increase peroxisomal oxidation to offload calories without generating the high delta psi which would damage mitochondria. Shortening DCAs ends up with the dicarboxylic acid succinate (HOOC.CH₂.CH₂.COOH) which is exported to mitochondria where it increases the NADH:NAD+ ratio resulting in the generation of inhibitory metabolites which divert FFAs from beta oxidation to stored triglycerides, fatty liver.

All that is missing from the story is the role of ROS.

*I have absolutely no data on this but, if you expect the signal for peroxisomes to generate dicarboxylic acids by omega oxidation is going to be anything other than mitochondrial derived ROS, then I cannot help you.

Peroxisomal beta oxidation generates hydrogen peroxide (well duh). And we can guesstimate how much H₂O₂ is being produced in hepatocytes under these circumstances. Enough to replace the missing insulin when a rat is being fasted. Never forget that insulin is merely a superficial overlay over the ROS signal. If you want to get damaging levels of FFAs out of the vicinity of mitochondria you need to divert them to be stored as inactive triglycerides. That requires activation of the "insulin" signalling pathway, mediated by H₂O₂. Without insulin all you need are the ROS. You can buy hydrogen peroxide in a bottle (here working on adipocytes) which, at an extracellular concentration of ~1mmol, will act to provide what we describe as peak insulin signalling:

Equally, you can evolutionarily generate these insulin equivalent levels of H₂O₂ from peroxisomes whenever FFAs are too high and insulin is too low. It's a safety net.

Which can go wrong.

It does go wrong, spectacularly so, in cats.

Just imagine a slightly more obese than normal domestic moggy, fed on chicken fat and starch (better known as Crapinabag). It never goes without eating for more than a few hours because a) there is dry "kibble" available at all times and b) the cat is hungry all the time c) whenever it eats, a proportion of its food is lost in to its adipocytes, keeping it hungry. That's why it's fat.

Now drop its level of insulin to basal fasting levels for three days. Maybe a road traffic accident, getting shut in a garden shed, having an acute infection, anything which stops it eating. It becomes hypoinsulinaemic. You can even do it by being too aggressive when putting your porky cat on a weight loss diet, without needing complete fasting.

It will do lipolysis. It has a huge fat mass. It will *really* do lipolysis. The hepatocytes are going to get massively overloaded with FFAs. The peroxisomes will kick in and protect the liver by signalling conversion of dangerous FFAs to harmless inactivated triglycerides. Fatty liver. There are limits to this protection. Evolution has not anticipated a cat with a body condition score of 9/10. The liver becomes so overloaded with lipid that cellular damage takes over and we are in to hepatic lipidosis. You can get the flavour of it here

Feline Hepatic Lipidosis

Basically, after years of continuous enhanced insulin signalling from a largely carbohydrate and LA diet  insulin is suddenly withdrawn and basal lipolysis can take over. With a vengeance. FFAs cannot be recycled to adipocytes because there is too little insulin. Hepatocytes have to take over. They use peroxisomal ROS to signal lipid sequestration in the absence of insulin.

There can be so much hepatic lipid sequestration that severe hepatocellular damage occurs and then it's up to the ICU clinician to try to save the cat's life. This is done by oesophageal tube feeding for anything up to a month. If the cat survives, recovery can be complete. The current advice is to feed protein based foods, the worry being insulogenic carbohydrate food might worsen hepatic lipid storage. Quite why no one has considered acipimox is beyond me, or peripheral low dose insulin infusion to target adipocytes rather than hepatocytes as an anti-lipolytic... But then I'm totally out of ICU work nowadays.

Anyhoo.

I hope people get the concept that fasting can trigger hepatic lipidosis. Bill Lagakos commented that he has seen chow fed mice develop the mouse equivalent of hepatic lipidosis by extended fasting. I completely believe him.

It puts us in a better position to understand what is happening in Tucker's cited study of safflower oil inducing fatty liver, which I was not expecting. I had been edging towards these concepts for weeks but the information from Jaromir and Bill have been extraordinarily helpful.

Peter