Insulin resistance (18) The red line

Before I get on to the absolute treasure trove which is this paper from Tucker I would like to continue a little with this one:

α‐Tocopherol suppresses hepatic steatosis by increasing CPT‐1 expression in a mouse model of diet‐induced nonalcoholic fatty liver disease

In the last post I considered Fig 4 to show the role of α‐tocopherol in reducing the insulin resistance of high levels of ROS to allow a more effective insulin-like signal from those ROS in an insulin-free cell model system.

It's time to think about what is happening in intact mice. Which is different.

Here's the supplementary image again:

which we can simplify to this basic scheme with the measured levels of α‐tocopherol added in:

The red line is easy. I start from the premise that lipid storage in hepatocytes is mediated by insulin. Exactly as per adipocytes, resisting insulin resists hepatic lipid storage. We know that long chain saturated fats protect against fatty liver *because* their oxidation resists insulin's signal better than does the oxidation of linoleic acid. Going back to my old scheme of what I think is happening we have this effect from LA on insulin signalling. First is the normal resistance to insulin's signal limiting adipocyte size. Hepatocytes are not adipocytes but I consider this aspect still holds:

and if we allow extra insulin signalling by oxidising linoleic acid, a fat which fails to adequately resist insulin, we get this:

in which the peak ROS signal is the same, here an hypothetical equivalent to 0.3mM H2O2, but it needs extra caloric intake to achieve this "satiety" level of ROS. If we add in a couple of rising dose rates of α‐tocopherol we get hepatocytes which store even more fat than is the case for plain LA. We still have that peak 0.3mM equivalent of ROS but we need even more caloric ingress to achieve it. Some gets stored as fat in the liver:

This is pure Protons. ROS reduction means more signalling which means more intracellular lipid storage. Note that there is no suggestion of any increase in peak ROS hypothesised, the increase signalling action is mediated by α‐tocopherol limiting the "stop" signal, it's just that more signalling is allowed before that putative 0.3mM H2O2 is reached. So the ALT is not coming from ROS mediated direct damage.

If we push this process in adipocytes we end up with rising basal lipolysis, a process which is protective to individual adipocytes and cannot be suppressed by insulin.

If we push this process in hepatocytes there is no basal lipolysis. FFAs are absorbed by hepatocytes as metabolically active free acids and rendered inert by conversion to triglycerides by combining them with glycerol. These inert triglycerides are exported as VLDL under low insulin conditions. That's normal.

There is, undoubtedly, a "basal" VLDL secretion rate. The problem for hepatocytes is that VLDL secretion is not free from the control of insulin. Excess delivery of FFAs to hepatocytes in the presence of elevated insulin will trap triglycerides in hepatocytes.

Elevated basal lipolysis from adipocytes delivers excess FFAs and is fundamental to hyperinsulinaemia. Hyperinsulinaemia is fundamental to NAFLD.

Aside: The most effective management for NAFLD is caloric restriction. This drops adipocyte size which drops basal lipolysis which drops insulin which drops hepatic lipid storage. This simple management is complicated, in the presence of linoleic acid, by unremitting hunger. So it always fails. End aside.

So my view is that liver cells under normal physiology are insulin sensitive within the limits set by Protons, that this insulin sensitivity is still under the control of ROS and that linoleic acid, or α‐tocopherol, allows too much insulin signalling before the normal storage limiting signal of high ROS occurs. So why the damage?

I hope everyone recognises this image:

These are adipose tissue crown-like structures stained for macrophages in this study. If you want to see the same structures in liver tissue you need to go to a different study to find them. The black arrows are placed by the authors and are specifically denoting crown-like structures. They don't look as neat as in adipocytes because hepatocytes have lots of messy cytoplasm which gets in the way:

I discussed crown-like structures in a previous post or two but we can summarise by saying that, while triglycerides enclosed in perilipin proteins are inert, above a certain size the perilipin storage breaks down and all hell breaks lose on an inflammatory basis. In the soup of TNF-α and IL-6 surrounding the remains of a dead hepatocyte the still viable hepatocytes will, undoubtedly, become insulin resistant and share this disaster signal with the rest of the body.

Okay, okay. If you insist, here are crown-like structures in adipocytes stained for TNF-α and IL-6, because the images are so pretty. Given enough funding for these very expensive antibody stains you could show exactly the same in hepatocytes:

While the macrophages are what release the cytokines it is the dead hepatocytes which release the ALT. That is where the red line is coming from:

This red line process is pure Protons plus "pyroptosis", unlike the blue line.

I'll take a brief pause here because I have a ton of other stuff to do before I get to the blue line, which is much more interesting.

Peter