Protons: SCD1 and the bomb

Our daughter has taken to watching DVDs. When we are not being tortured by Postman Pat (Special Delivery Serrrrrrviccccce, you know the tune) or the Mickey Mouse Clubhousssse we do at least get some amusement when she requests that blistering LC comedy "A Matter of Loaf and Death", by Nick Park.

Just how funny you can make a story about an obese cereal killer (no typo, the subtitles specify cereal killer, I said Park is funny!), murdering bakers as revenge for her obesity ("Are you ballooning?") has to be seen to be appreciated. It's a lot more amusing than Postman Pat.

One of the funniest scenes is where Gromit cannot get rid of Paella's bomb. It's a direct tribute to the 1960s Batman scene where "Some days you just can't get rid of a bomb".

You know, with the ducks

and the nuns. Park has kitten-enhanced the nuns



and included Yorkshire as the preferred site for bomb disposal. The Wars of the Roses are, apparently, over but not forgotten.

This post is about how physiology uses SCD1 to dispose of the metabolic bomb of hyperglycaemia in the presence elevated levels of palmitic acid.

It was pancreatic beta cells in culture which produced this picture:



I love this group because not only do they tell you in the methods section EXACTLY what glucose concentration they used in culture (5mmol/l vs 11-25mmol/l) without making you go back through three layers of references (to bury the 25mmol/l most groups use, but never discuss), but they also describe 11mmol/l as hyperglycaemia. That is, pathology.

This is Figure 4 from the same paper showing markers of apoptosis, superb:




Note the increase from palmitate to stearate. Note the complete protective effect of oleic acid and very modest toxic effect of linoleic acid. Aside: Note also the complete and total protection provided by limiting glucose to 5mmol/l, with any fatty acid, at any concentration. You have adipocytes leaking FFAs? Your best hope of keeping a functional pancreas is to limit your glucose to 5mmol/l. How? Answers on a postage stamp to...

It's also worth noting that stearic acid had to be reduced from the original 0.4mmol/l to 0.25mmol/l because at the higher concentration with high glucose they found exactly the same thing as Dave Lister did in Red Dwarf when Holly brought him out of stasis. Everyone is dead Dave. Everyone. Is. Dead. Dave. You have to U-tube the clip. Stearic acid at 0.4mmol/l with glucose at 25mmol/l, in cell culture, is utterly lethal to beta cells. If you pharmacologically block apoptosis the cells simply undergo the rather messy collapse of necrosis. This is a non survival insult.

Okay, okay, here's the clip:



The group went on to do quite intersting things with blockade of acyl-CoA synthetase and also with inhibition of fatty acid oxidation, which leads to all sorts of other threads which are, in part, where I have been wandering for the last few weeks. Far too much for this post.

So let's look at SCD1 knockout mice which have been rendered obese by also knocking out their leptin gene. Here we have rapid onset obesity due to adipocyte fat storage, free fatty acid leakage due to adipocyte insulin resistance and a complete inability to place a double bond in to palmitic acid or stearic acid. They have elevated FFAs and these are almost all saturated. This paper describes the study. It has to be noted that to obtain the FFA levels you have to reverse engineer Fig4 part A:



A ruler and calculator gives FFAs for the normal ob/ob mice as 0.32mmol/l and for the SCD1 k/o ob/ob mice as 0.56mmol/l. Any group which makes you reverse engineer in this way to get something as simple as FFA levels is, in my book, highly suspect. Does anyone think that 0.32mmol/l is quite low? Despite the greater obesity. Partly due to maintained insulin sensitivity in adipocytes (that's why they distend) while ever de novo lipogenesis produces palmitoleate using SCD1 and partly due to the higher levels of insulin production (normal beta cell mass) working on those insulin sensitive adipocytes... These mice are still in a slightly privileged position, metabolically, as they have yet to become obese enough for their SD1 equipped adipocytes to become seriously insulin resistant, they are still only six weeks old.

And here is the % of types of FFAs.



The column on the left is the one which represents about 0.32mmol/l of total FFAs and the column on the right is around 0.56mmol/l, as above. Glucose varies but fasting levels can be as high a 700mg/dl. So what happens to beta cells?

They divide up in to two types. The health ones and the dying ones.

The basic finding is that young ob/ob mice need either oleic or palmitoleic acid to maintain a functional beta cell mass. Exposure to high levels of glucose combined with palmitic and/or stearic acids induces apoptosis plus some necrosis in beta cells. Most non pancreatic tissues in the SCD1 knock out mice appear to be able to upregulate beta oxidation, especially in peroxisomes, of fatty acids which minimises both obesity and insulin resistance.

The beta cells of the pancreas do not appear to have this luxury.

They need to lower that F:N ratio with palmitoleate or oleate, otherwise they are left holding the bomb.

Peter