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BACKGROUND ON HISTONE ACETYLATION
Histones are proteins around which long strands of DNA are packaged tightly in a cell nucleus, producing what are called nucleosomes, which aggregate into the chromatin DNA and protein complexes. Histones can be modified at certain positions by methylation, phosphorylation, ubiquitination, SUMOylation, citrullination, and acetylation. Histones 3 and 4 have long tails which are frequently modified, while histones 2A and 2B are often modified at their cores. For example, lysine acetylation of a histone produces more accessible chromatin and is associated with more active transcription.
Histone acetylation is thus part of epigenetic modification. Histone acetyltransferases (HAT) are a family of enzyme that transfer a histone from one molecule (e.g. acetyl coenzyme A) to another (e.g. a lysine residue on the N-terminal tail of a histone). On the other hand, histone deacetylases (HDAC) do the opposite. Generally, acetylation of histones produces a more relaxed chromatin (called a euchromatin) that is associated with greater gene transcription.
There are four classes of HDACs. The first class includes the closely related HDAC1 and HDAC2 and the related HDAC3 and HDAC 8. Class IIA includes HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb includes the similar HDAC6 and HDAC10. Class III’s members are the seven mammalian sirtuins. Class IV includes HDAC11.
HDACs are overexpressed in cancerous tumors. Since 2006, the HDAC inhibitor (HDACi) Vorinostat has been FDA approved for the treatment of a kind of lymphoma. HDACis are being researched to attenuate the pathologic epigenetic modifications that accompany cocaine addiction, amphetamine addiction, and alcohol addiction.
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1. Short-chain fatty acids are a major metabolite of microbial anaerobic fermentation in the human gut. The major metabolites are acetate (C2), propionate (C3), and butyrate (C4), (at a ratio of 60:20:20 in the colon) though there are also branched short-chain fatty acids such as iso-butyrate, valerate, and iso-valerate.
a. Butyrate, whose name is derived from the Greek word for butter, smells like butter and is generated when triglycerides in milk fat experience lipase-catalyzed hydrolysis.
b. Apparently, it responsible for the smell of humans, including their vomit and sweat.
c. It has two isoforms: n-butyric acid and iso-butyric acid, with the former being more plentiful in humans. Both are produced by two different processes in the gut.
d. Under normal conditions, butyrate is only produced from fiber in the gut and circulates the blood in micromolar concentrations. The concentration in blood appears to mostly be low due to metabolism both in the gut and in the liver. Concentration may vary widely across time, with higher peaks.
e. Butyrate is produced by several unrelated species of bacteria, indicating that the process for its metabolism likely developed several times in history.
f. Butyrate content in human feces varies by a factor of 10x.
2. Gut expression of the transporters of butyrate, MCT1 and SMCT1, is governed by NFkB signaling. These transporters are also found in the brain.
3. High dosed supplemental sodium butyrate improves gut microbiome structure to the benefit of the host.
1. Butyrate is metabolized quickly, though the prodrug tributyrin delays the metabolism.
2. Butyrate may increase expression of the structurally similar D-beta-hydroxybutyrate (DHB).
1. Butyrate has been shown to bind to the FFAR2, FFAR3 (both activated by all major SCFAs), HCA2 (also activated by monomethyl fumarate and niacin), and OR51E1 (activated by valeric acids and nonanoic acid) receptors. The OR51E1 receptor may be involved in SCFAs’ influence on the release of serotonin from enterochromaffin cells in the gut.
a. FFAR3 and HCA2 expression is regulated by DNA methylation. FFAR3 expression is increased in the obese.
HISTONE DEACETYLASE INHIBITION
1. Butyrate inhibits histone deacetylation, which can influence up to 2% of the expression of mammalian genes. It preferentially inhibits classes I and IIa, and it is the strongest endogenous inhibitor.
2. Beta hydroxybutyrate is also an HDACi, and it upregulates BDNF due to inhibition of HDAC2 and HDAC3.
1. An early study found that elevating histone acetylation using butyrate improved both long-term potentiation (LTP) and contextual fear memory in rodents.
2. Butyrate has been shown to enhance LTP in several studies.
3. Butyrate is neuroprotective in models of Huntington’s disease, ALS (with human trials), Parkinson’s disease (and dopaminergic toxins), and vascular dementia.
4. Butyrate improves cognitive function in rodent models of Alzheimer’s disease and may reduce beta amyloid plaque levels.
5. Butyrate produces neurogenesis in the ischemic rodent brain and is neuroprotective in models of ischemic stroke.
6. In a rodent model of lipopolysaccharide-induced depression, sodium butyrate reduced activation of the miroglia and improved behavioral symptoms.
7. Butyrate increases the neurological effects due to cocaine and amphetamines. It also increases their drug-induced neuroplasticity.
8. Butyrate’s plasticity-inducing epigenetic effects on the brain are comparable to that of exercise.
9. Sodium butyrate’s effect on neurological disorders appears to be partially mediated by an increased transcription of BDNF due to HDAC inhibition. It appears that HDAC2 and HDAC3 (of Class I) are most relevant to the increased expression of BDNF, whereas HDAC1 is unrelated.
1. Butyrate insufficiency appears to produce a more permeable blood-brain barrier.
2. Butyrate is neuroprotective in rodent models of traumatic brain injury by improving blood-brain barrier quality.
1. Electroconvulsive shock therapy increases histone H3 acetylation. Deacetylation of hippocampal histones inhibits the antidepressant effect of imipramine in rodents exposed to chronic stress. Sodium butyrate produces an anti-depressant effect on its own and enhances the antidepressant effect of fluoxetine in rodents, likely due to HDAC inhibition and changes in BDNF expression. Similar findings are reported elsewhere, though evidence that HDACi is insufficient to produce an antidepressant phenotype has also been produced.
2. Butyrate alters epigenetic information on the BDNF gene, causing its overexpression.
METABOLIC SYNDROME, LIVER, & T2D
1. Sodium butyrate attenuates hepatic steatosis due to a high-fat diet in rodents and due to a high fat and fructose diet.
2. Sodium butyrate improves the inflammatory state in rodent models of T2D.
3. Sodium butyrate attenuates diabetic nephropathy by activating Nrf2.
4. It improves glycogen metabolism in the livers of diabetic rodents.
5. Fortuitously, butyrate protects livers from valproate-induced damage.
6. Sodium butyrate improved symptoms of T2D comparably to metformin.
7. Sodium butyrate upregulates PPAR gamma in obese rodents.
1. In a rodent model of kidney disease, butyrate improved renal condition and insulin resistance.
1. Butyrate reduces oxidative stress at atherosclerotic sites.
2. In animal models of high-fat diet-induced atherosclerosis, butyrate reduced plaque development.
1. Sodium butyrate has been shown to improve symptoms of colitis in animals, potentially because of improved mucosal synthesis or improvement to gut barrier quality.
2. Sodium butyrate may improve symptoms of autoimmune skin disorders.
3. In a rodent model of colitis, sodium butyrate improved symptoms by inhibiting NFkB.
1. Sodium butyrate induces apoptosis in colon, rectal, and colorectal cancer cell lines. It also does this in breast cancer cells
2. Given sodium butyrate, colorectal cancer cells experience enhanced autophagy due to AMPK (and LKB1) signaling.
3. There is a US patent held by Chinese on a method of treating cancer with metformin and sodium butyrate.
1. Butyrate may increase Foxo3a expression.
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