Neurological Correlates

This post is an update on how brain cells grow and what can get messed up, so it’s wonky, and deceivingly so since the system has the whimsical name “Sonic Hedgehog.”  Basically, the cholesterol processing system seems to use the immune system to mediate growing the right cells in the right place.  And this is called the hedgehog signaling pathway .

Edit 12.15.09: More on hedgehog and pontine melinolysis, below the jump (scroll down).

The whole thing involves directing cells to grow or stop growing, and to migrate to certain places, and to develop into certain kinds of cells. Like most living systems, it’s a blessing and a curse.

On the one hand,  hedgehog signaling makes sure you grow the right cells, in the right place at the right time.  Cell growth, cell patterning = good. On the other hand, the system can go haywire, and wind up encouraging (if not outright causing) cancer. Drug companies are attacking cancer through the hedgehog pathway, for instance.

There are all sorts of backstops dialing down the hedgehog pathway, and all sorts of places in the pathway to intervene.  But, some inhibitors nuanced and indirect, indicating the cross-talk between systems.  For instance, there may be communication between the fat/cholesterol processing system, and the hedgehog/cell growth system, particularly in the brain.

It should be noted that for hedgehog to work properly, it is hooked to cholesterol, making a dual molecule. Where hedgehog is prevented from attaching to cholesterol during development, for example, birth defects can develop. Alcohol may be teratogenic, for example, because it reduces cholesterol-bound hedgehog . Birth defects were substantially amelioriated with extra hedgehog protein. (These were in animal models).  Hedgehog pathway may be involved in cases of holoprosencephaly, in both craniofacial as well as brain areas (and in general, neural crest development).

Because Hedgehog disruptions can cause any number of mild to serious musculo-skeletal-cranio-facial permutations,  how come no one ‘s looking at that in cases of developmental delay having the phenotypes?

Anyway. The liver X receptor (LXR) indirectly dials down the hedgehog pathway.  Liver X receptor is key in lipid homeostasis — there are tons and tons of papers on what this nuclear receptor does, as you can imagine when you think about all the lipids that live and work in your body.   Some oxysterols — involved in processing fats and cholesterols –  activate the liver X receptor (LXR) and inhibit  hedgehog.  The liver X receptor then somehow –  no one is sure how – communicates with the hedgehog pathway to dial it down.  There is a fair amount of research into liver X receptor agonists and partial agonists, that would activate the receptor only partially– just enough to dial down the hedgehog pathway, but not to do anything else.

Inflammation plays into this system.  LXR activation has a neuroprotective effect, and, after stroke, LXR agonists  are neuro-anti-inflammatory.  LXR also seems to cause immune clearing cells to home in to dead cells in the body, and clean up the debris – and mice lacking the LXR to do this became autoimmune against their own dead cell debris. Treatment with an LXR agonist ameliorated the lupus-like symptoms.

And what do oxysterols do? They cause cells to suicide;  the kind of “programmed” cell death that causes LXR activation and results macrophage homing to clean up the cell debris. And where there’s chronic oxysterol (like, in a high fat diet, perhaps, as a result of cholesterol processing) there is chronic LXR activation, and chronic pancreatic b-cell death — which may be why people get type 2 diabetes.

The hedgehog/oxysterol/liver X receptor loop looks like it is key in developing the part of the brain related to addiction, reward, and learning — the part of the brain having dopaminergic neurons. First,  oxysterols and LXR promote ventral midbrain neurogenesis in human embryos. The ventral midbrain is key in reward and learning behavior:  dopamine producing neurons in the ventral midbrain have axons that connect to other areas linked with the behavior.

And what makes the ventral midbrain dopaminergic axons grow in the right direction to connect to the right spots in the brain, so your reward or learning behavior isn’t messed up?

Hedgehog protein.  Hedgehog protein acts as a chemoattractant luring the axons to grow in the right direction. Smell — the olfactory axons — are also guided by hedgehog.  (Reward and smell — this is something the fragrance and flavors industry should look at.) Hedgehog is also involved in myelination and glia, and looks like it could relate to white matter integrity.

Taken together, where hedgehog is key in craniofacial and brain midline gestational development (see the teratogenic papers above), and where the very thing that inhibits hedgehog activity — oxysterol — promotes midbrain neurogenesis, it looks like there’s a serious sequence of events that has to happen gestationally so that the dopamine system functions properly. For instance, with an alcohol spike — which would, apparently, decouple the cholesterol from the hedgehog protein, thereby disabling the hedgehog protein, the ventral midbrain dopaminergic axons could be wired improperly. Combine that with oxysterols being not great for blood vessels, and you have a double whammy in utero: the placental arteries going bad, plus the blood that does get through has ethanol in it — so it decouples the hedgehog from cholesterol once it gets to the fetus. Bad news.

Oxysterols in the peripheral circulation may be a biomarker for early Alzheimers’, and LXR activation may improve memory in AD by correcting brain cholesterol processing (in a mouse model so far). Oxysterols are in cerebral spinal fluid, along with a bunch of other bioactive bile acids, and you could supercharge cerebral spinal fluid with an x-tra dose of LXR- activating oxysterol in the cerebral spinal fluid to amelioriate Alzheimers’, it would seem. (There are a number of well characterized partial agonists). Cerebral spinal fluid is Newtonian (in contrast to blood, which is non-Newtonian, see below) so the oxysterol would have have a similar amphilic profile.

The whole system is like playing 4 dimensional chess.

To add more complication – steroid chemistry:  Oxysterols and the persnickity lot of sterol/steroidal/bile acids are involved in fatty acid/cholesterol/metabolism; oxysterol itself is abundant in alcoholic fatty liver disease (hepatic steatosis) as well as steatohepatitis (fatty liver due to hepatitis). So if you smoke, drink, and get a tattoo in prison (with the astronomical hep c rate from prison tattoos), this is the molecule signaling system for you.

Being an observer and involuntary participant in steroid chemistry from time to time, the whole field (like I know what this is) strikes me as  a matter figuring out hydrophobicity, something to which I was supremely indifferent. That is, until I learned the word “non-Newtonian” and watched this video :

Via YouTube, “A pool filled with non-Newtonian fluid”

Blood, in fact, is non-Newtonian, I was told.  So it makes sense that non-Newtonian sterols would be blood-soluble, only seizing up when they are forced into a particular 3-d conformation, like, by a protein or  LXR receptor or something.  (Due apologies to the steroid chemists out there).

More, update re: pontine myelinolysis

Further researching the connection between LXR, hedgehog and white matter, there may be a connection with pontine myelinolysis. This myelin-stripping dysfunction happens in severe alcoholism, causing what used to be referred to as the “DT’s” or delerium tremors. There are also reports of pontine myelinolysis in liver transplants.

Liver is rich in the signals that downregulate hedgehog:  LXR receptors and sterols and oxysterols.  Hedgehog, on the other hand, promotes the formation of myelin.

Where a person needs a transplant, probably their LXRs aren’t working well — after all, their livers are damaged. No LXRs, and no backstop on the hedgehog pathway.  But, because hedgehog/LXR is a dynamic equilibrium, now it’s out of whack. Maybe then the hedgehog signals — having no backstop — just dial themselves down to low volume — as if they were being regulated by LXRs.   Then, when the new transplanted liver is put in –  all of a sudden there’s a burst of LXRs and the low volume hedgehog is shut down totally.

So now there is essentially no hedgehog, so perhaps there is no myelin formation. Reports sound like it’s an acute effect, and it’s not clear to me if hedgehog acutely stops making myelin or not. Regardless, it would seem that something preventing oxysterols or LXRs from downregulating hedgehog, or else some way to introduce hedgehog + cholesterol, would amelioriate pontine myelinolysis after liver transplant.

It’s just a shame to wait so long for a new liver, and then, when you get one, be put at risk because of pontine demyelination.  Not that Chinese liver transplants  are necessarily to be uninvestigated, particularly where there are credible reports that political prisoners are slaughtered for organ harvesting.