Tue, Sep-22-15, 20:57
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Senior Member
Posts: 15,075
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Plan: mostly milkfat
Stats: 190/152.4/154
BF:
Progress: 104%
Location: Ontario
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https://en.wikipedia.org/wiki/Meval...hi_def_tiff.tif
https://en.wikipedia.org/wiki/Ketog...Ketogenesis.svg
Check out the ketogenesis and mevalonate pathways. Up to the point of HMG CoA, it's identical. At that point, HMG CoA lyase can produce an acetoacetate and an Acetyl-CoA, or HMG reductase produces mevalonate.
I first found the Hyperlipid blog when Peter commented on a Dr. Davis post about using niacin to reduce ldl and triglycerides, and raise hdl. Peter was commenting that beta-hydroxybutyrate was also a ligand for certain nicotinic acid receptors (and maybe they should have been named ketone receptors in the first place, for all we know).
Quote:
Nicotinic acid receptor subtypes and their ligands.
Soudijn W1, van Wijngaarden I, Ijzerman AP.
Author information
Abstract
Half a century ago, nicotinic acid (niacin) was introduced into the clinic as the first orally available drug to treat high cholesterol levels and to improve the balance between (V)low density lipoproteins (LDL) and high density lipoproteins (HDL). Remarkably, its putative mechanism of action has only been recently elucidated, particularly because of the cloning of a G protein-coupled receptor (HM74A or GPR109A). This receptor responds to both nicotinic acid and the ketone body beta-hydroxybutyrate, the latter thought to be the more probable endogenous ligand for HM74A. In this review, we will discuss the pharmacology and medicinal chemistry of this receptor subtype and a related one (HM74 or GPR109B). Although still in its infancy, the ligand repertoire is developing, and a number of compound classes have now been described, among which are both full and partial agonists. Antagonists, however, are still lacking, thus compromising thorough pharmacological studies. Mutagenesis experiments have provided clues regarding the ligand binding site; in particular, an arginine residue in transmembrane domain 3 of the receptor seems to recognize the acidic moiety present in nicotinic acid and related substances. HM74A has also been linked to one of the major side effects of nicotinic acid, that is, flushing, since this receptor subtype also occurs in skin immune cells. It is not known yet whether HM74 is also present on these cells. Since nicotinic acid is one of the few available medicines that raise HDL ("good cholesterol") levels, HM74A and HM74 appear promising targets for future pharmacotherapy.
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One thing nicotinic acid signalling does is reduce lipolysis, and this makes sense when ketones are high, usually--since, if they weren't already at an adequate level, then where did all those ketones come from?
That GPR109A receptor is found in the liver (at least in mouse livers), at much lower levels than in adipocytes. So there's at least one way for the liver to directly sense the ketones. But reduced lipolysis, leading to reduced beta oxidation and reduction in the Acetyl-CoA needed for cholesterol production in the liver also makes sense.
Okay, here's some full text, more detail on reduction of lipolysis through this receptor;
http://www.jbc.org/content/280/29/26649.full
Quote:
(D)-β-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G*
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Lowered triglycerides could be secondary to a reduction in lipolysis. Not necessarily as bad as it sounds, this might make for a more rapid depletion of glycogen stores between meals and especially during the longer fast of sleep. That might reduce blood glucose and insulin, but I might be stringing together too many mights here.
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