Random musings on uncoupling (7) DNP and metformin

NAFLD, NASH, ALD and alcoholic steatohepatitis (ASH?) are all associated with the accumulation of lipid within liver cells. The two primary culprits are fructose and alcohol. Both undergo rapid metabolism to acetyl CoA (+/- lactate) with the potential to generate lipid within hepatocytes as a result.

Sadly life is never quite that simple. Certainly some of the liver lipid does indeed come from the metabolism of fructose or ethanol, but back in this post there are the papers which suggest fructose acts systemically to induce acute insulin resistance in adipocytes and so releases fatty acids which transfer to the liver (and visceral fat) stores:

Fructose and lipolysis

and this post points out the same about ethanol:

Alcohol and weight loss

Hepatic lipid delivery should trigger hepatic insulin resistance and the resultant persistence of metabolic substrate in the blood should signal to the hypothalamus that there are plenty of calories available, ie it's not time to eat yet. You have only to look at the hepatic response of FGF21 production, which increases thermogenesis, in response to both alcohol or fructose to see this in action. FGF21, when not produced in response to starvation (which it is), signifies that the liver sees enough calories to stimulate thermogenesis in excess of obligate needs.

So what goes wrong in fatty liver disease?

The action of insulin on hepatocytes is to suppress glucose release, facilitate lipogenesis and facilitate triglyceride formation. You just have to ask yourself, is there any dietary component which facilitates the excessive action of insulin? Which might make a perfectly reasonable process into a lipid-storage overload pathology?

Could that be linoleic acid? Which induces a failure to resist caloric ingress at times when that would be appropriate.

Fatty liver disease, from fructose or ethanol, looks to me very much like the result of excess insulin action on hepatocytes. The same linoleic acid which produces this accumulation of lipid in adipocytes  will also facilitate accumulation in hepatocytes and facilitate the conversion of benign fatty liver into inflamed hepatitis though its lipoxide derivatives.

We've known for years that a high saturated fat diet protects against NASH: 

Long term highly saturated fat diet does not induce NASH in Wistar rats

provided it is very low in PUFA. In fact the low PUFA is probably more important than the high saturated fat content.

If we accept this chain of thought, fatty liver represents an accumulation of lipid in response to linoleic acid facilitated excessive action of insulin. It happens because while the oxidation of linoleic acid generates enough ROS to allow insulin signalling to occur, it does not allow the generation of enough ROS to limit insulin's actions when the hepatocytes are full. Exactly as for adipocytes.

So hepatic lipid accumulation is a consequence of excess insulin signalling, and only once the ability to accumulate any more intrahepatic lipid has been exceeded does the generation of ROS become adequate to resist insulin's caloric ingress/retain signal. After that, hepatic insulin resistance will occur, glucose will no longer be retained and the liver will no longer be a sump for absorbing FFAs.

Systemic levels of FFAs and glucose will rise and the rest of the body will have to go in to anti-oxidant defence mode, AKA whole body insulin resistance. Hunger will plateau and weight will stabilise.

So. The primary problem is the excess storage of (largely adipocyte derived) FFAs as intra hepatocellular triglyceride, beyond the point where this is adaptive.

It cannot happen without the LA facilitated augmentation of insulin signalling. This does not happen if the lipids being oxidised within the liver are predominantly saturated, as in the NASH prevention paper above.

Looking at hepatic lipid accumulation in these terms suggests that blunting insulin signalling might he a simple solution. Hence the efficacy of 2,4-dinitrophenol. You could view DNP as acting as a caloric sump for hepatocytes, burning off the fat and introducing a caloric deficit. Or you could speculate that all that is needed is a small drop in mitochondrial membrane potential, to produce a reduction of insulin signalling to approximately offset the augmentation induced by LA, and the problem would self correct.

I tend to favour the latter option. But then I would.

My personal view is that this is what low dose DNP does. It blunts insulin signalling in hepatocytes. Blunted insulin signalling blunts lipid accumulation and the liver never accumulates enough lipid intermediates to generate insulin resistance. Without the enhanced insulin signalling sequestering calories into lipid stores the liver will allow more glucose and FFAs in the systemic circulation which will reduce hunger. This might not be enough to generate detectable weight loss in a few weeks of a rodent study but it just might over a few years.

The parallel with metformin is that I consider metformin's core action at therapeutic dose rates is the inhibition of the mitochondrial component of the glycerophosphate shuttle, limiting FADH2 input to the CoQ couple and so limiting the ROS generation which is needed to maintain insulin signalling (and to markedly reduce insulin-induced insulin resistance, but that's another story). It does this at micromolar concentrations in the cytoplasm, where it can easily access mtG3Pdh.

Metformin and DNP both reduce the generation of ROS needed to maintain insulin signalling, all be it by different mechanism. Insulin signalling is blunted. Excess lipid (and glucose) storage is inhibited. There might be a trivial loss of weight due to reduced hunger.

ASIDE Obviously as metformin/DNP reduce ROS and insulin signalling they allow increased fat oxidation, largely via AMPK, and some "new" ROS will be generated to replace those suppressed by metformin/DNP. But the "cost" of these "new" ROS is fat loss. Which is a win overall for metformin/DNP/obesity END ASIDE.

Interestingly both metformin and vintage DNP increase lactate formation systemically, presumably because glycolysis is still on going, especially when glucose levels are raised post prandially, and the activation of the pyruvate dehydrogenase complex is blunted in proportion to the blunting of insulin signalling. Hence pyruvate to lactate becomes the preferred route to continue glycolysis.

Also both are longevity drugs, even using old fashioned plain DNP in rodent drinking water

Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity

Blunting insulin signalling certainly does interesting things.

I have tried to resist insulin for decades. So far, so good...

Peter