Category Archives: wine

Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:




More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).


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Fasting, circadian biology, and epigenetics

From the best I can gather, one of the more immediate players in circadian biology is the coenzyme nicotinamide adenine dinucleotide (NAD), which participates in a variety of redox reactions.  Fasting increases the intracellular NAD/NADH ratio, setting off a cascade of events involving epigenetics and the regulation of metabolism.  HT to Jack Kruse for really cracking into this nut.

NAD activates sirtuins, a family of deacetylase enzymes.  This is epigenetics.



SIRT1 regulates the activity of BMAL1 and CLOCK, two circadian transcription factors, which target NAMPT, an enzyme that synthesizes NAD.  And in a curious feed-forward mechanism, CLOCK and BMAL1 enhance SIRT1 expression… genetic deletion of any of these players induces insulin resistance (Zhou et al., 2014), and this can be recapitulated with constant darkness: reduced BMAL1 and SIRT1, hepatic insulin resistance; the latter can be reversed with resveratrol (which may or may not be acting through SIRT1; this is controversial).  While alcohol does no great favors for circadian biology, if you’re going to imbibe, perhaps a resveratrol-rich Argentinian malbec served, and this might be the important part, at night, when all of this stuff is going on… coincidentally [fortunately], that’s precisely when most choose to imbibe.

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Pharmaceutical-grade circadian manipulation.

BMAL1 and CLOCK, ‘positive’ regulators of circadian gene expression, activate transcription of the negative regulators Per, Cry, and Rev-erb.  PER and CRY inhibit BMAL1 and CLOCK, whereas Rev-erb inhibits Bmal1.  It is said that Rev-erb is “an important link between the positive and negative loops of the circadian clock.”  You don’t really need to know any of that to follow this blog post.

circadian genes

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Fish, dark chocolate, and red wine.

Fish oil fatty acids: EPA & DHA.

I’ve read that EPA tends to show slightly better results in outcomes related to mood, whereas DHA tends to be slightly better for cognition.  Not mutually exclusive; probably a lot of overlap.  This meta-analysis by Martins showed EPA fared better than DHA for depressive symptoms (2009); another one here, stressing the high %EPA relative to %DHA necessary for improvements (Sublette et al., 2011).  Whereas the reverse is true for certain cognitive outcomes in this study by Sinn and colleagues (2012).  Very few studies test EPA vs. DHA directly, and their effects on metabolism are relatively similar.  They’re the ball bearings of fatty acids.epa dpa dha

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Circadian biology: jet lag, mood, & potential role of BP regulatory peptides

There are enough connections here to suggest it’s an interesting rabbit hole.  Besides the effects of ARBs & desmopressin on mood and cognition, blood pressure regulation is not interesting <– fact.  But if it ties into fertility, circadian biology, and seasonal changes in how we should be doing things…

Way back in 1998 when I was graduating high school, Murphy and colleagues were screwing with “light-entrainable” and “food-entrainable” oscillators of circadian rhythmicity (1998).  They did this in two lines of rats, one with intact vasopressin signaling and one without.  With little mechanistic work, they showed vasopressin mediates circadian effects driven by light; and rats without vasopressin were more entrainable by meal timing.  N.B. in addition to the posterior pituitary, vasopressin is also found in the famous circadian light-regulated SCN neurons (Rosving 2010).

While it is speculated to play a role in social behaviors and sexual motivation, vasopressin is primarily known for its anti-hypotensive effects.  When plasma volume drops, vasopressin is secreted to decrease urinary water loss and increase blood pressure.  This is antagonized by alcohol, which is thought to be one reason why alcohol can dehydrate you.

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Alcohol-proof your liver. SFAs.

it probably has other benefits, too. 

Tissue lipid turnover, adipose vs. liver.

Can the saturated fat & MCTs in dark chocolate & coconut oil protect liver against the ravages of alcohol?  Tonight?

The studies discussed in “The liver is evil but need not be punished.  SFAs”  entailed chronic alcohol feeding in combination with a high saturated fat/MCT diet – the animals were given a liquid diet of complete nutrition and a LOT of booze.   Not very applicable to humans, imo [hopefully].  Which brings up the question: how long does it take for coconut oil & dark chocolate to flex their hepato-protective muscles?

wine and dark chocolate

Fortunately, [if tissue fat composition is in fact the relevant protective factor], unlike adipose fat which hangs around for years (Beynen et al., 1980 & Katan et al., 1997), liver fat appears to turn over quite rapidly.

For example, a single shot of radiolabeled oleate is cleared out of the liver within a few days, whereas it lingers significantly longer in adipose of rats (Iritani et al., 2005).  And this is actually enhanced in rats fed a higher fat diet.fat-free diet

Similarly, a study on diet-induced changes in liver fat in humans showed that after only 3 days of low carb dieting, liver fat significantly declined in 5/10 patients, and in all of them by day 10 (Hollingsworth et al., 2006):liver fat time course

Shoutout to Mike Eades for directing me to this study.  Whatever happens after 3-10 days, I suspect, will reflect the new dietary pattern – you are what you eat?  :/

I don’t put too much stock in generic nutrition textbooks, but those data are rather close to estimates put forth by Frayn, Arner, and Yki-Jarvinen (2006, free full text):Frayn

Translation: while a single meal of dark chocolate and coconut oil may not acutely protect the liver from alcohol [tonight], a few days’ worth just might.


Red meat.   While the saturated fat content of red meat is expected to similarly bolster liver resistance to oxidative stress, another component – carnitine (of the recent TMAO infamy) – may also provide some benefit by enhancing liver fat turnover (Kepka et al., 2011 sorry no full text, so only in theory).  Taurine, also found in red meat, also prevents some alcohol-induced liver pathologies [in rats] (Kerai et al., 1998 & Pushpakiran et al., 2005).

Coffee, too (Gallus et al., 2002Tverdal et al., 2003; Klatsky et al., 2006; Lopez-Garcia et al., 2008Sugiyama et al., 2010).  Probably has more to do with prevention of lipid peroxidation via antioxidant polyphenols.  just sayin’     …compared to the SFA’ers, would those on a high PUFA diet benefit more from coffee in this regard?

The culprit isn’t red meat or TMAO, its cigarettes & sedentary obese HFCS PUFA empty calories – the bona fide confounding factors in most anti-nutrition propaganda.

calories proper