Wednesday, December 02, 2009

Cirrhosis and fructose

This is the paper for continued speculation about alcoholic and non alcoholic fatty liver disease. Rats again, to begin with!

I was looking at the endotoxin levels (from Table 3) in the blood of rats on various feeding protocols. The correct level of endotoxin in your blood is zero. Endotoxin (gram negative bacterial wall components) belongs in your gut, not in your bloodstream (if endotoxin is in your blood stream one function of LDL cholesterol to mop it up. Hmmm, rosuvastatin triggers diabetes, possibly termed hepatic failure to respond to insulin correctly! Is there a link here?). It's a reasonable marker of increased intestinal permeability and a serious toxin in its own right. Ethanol increases endotoxin blood level markedly in combination with fish oil but only moderately if combined with saturated fat. So, apart from ethanol, fish oil has some influence on the increased intestinal permeability induced by alcohol. That's not too surprising if you read this paper about the effects of DHA in its own right. Now I have no idea of what 100 microM DHA means in terms of drinking a slug of fish oil or how real this cell culture system is in terms of the human gut but I can see that people going the grass fed meat route have less to be concerned about that those of us using fish oil as a supplement. And I'm sure that Christian will love the taurine link! I would suspect that the best time to take DHA might be in association with your main meal of the day if you are looking to "mimic" grass fed meat...


Endotoxin in the blood appears to be one of the best agents to convert a fatty liver to an inflamed fatty liver. The switch from fish oil to saturated fat lowers endotoxin somewhat (about halves it) but markedly reduces the products of the genes controlled by NF-kappaB. I was particularly looking at Table 4 where mRNA for COX-2, the inducible pro inflammatory cyclo-oxygenase enzyme, is reduced to zero and that for TNFalpha is markedly reduced. The mRNA for the housekeeping enzyme COX-1 is unaffected, as you would expect. It's also worth noting that fish oil/dextrose produces a zero level of mRNA for COX-2, rehabilitation fish oil somewhat in the absence of ethanol (or fructose?).


Staying on endotoxin but switching to humans and fructose, we are all well aware that fructose is "associated" with fatty liver and that this association is probably causal.


What I find far more interesting is that fructose is "associated" with increased plasma endotoxin in humans. I haven't found the intervention study to confirm a causal role of fructose on endotoxin uptake but, with the known effects of fructose on clinical NAFLD in humans, I think it will turn out to be the case. Fructose does seem to be the perfect replacement for alcohol if you want a tea-total cirrhotic liver. And be labelled a secret drinker by your hepatologist!


To summarise, both alcohol and fructose cause fatty liver. Both alcohol and fructose allow endotoxin from the gut to the bloodstream. PUFA (certainly omega 3, probably omega 6) enhance intestinal permeability effects. Endotoxin and the lipid peroxides from PUFA activate NF-kappaB. There is a cascade of inflammation in the liver as a consequence of this.

I think it is also worth noting (from table 3 again) that non haem iron is elevated in the livers of those rats with maximum endotoxin absorption. This is another aspect of the common hepatopathy of iron overload which needs thinking about.

Peter

16 comments:

J said...

great post,
really enjoy your blog peter.

thanks again,

Byron said...

Fine liver backgrounds. A wine lover might have some serious trouble; fructose + alcohol? Maybe better to switch back to Cameron´s "Drinking man´s diet", he recommended fatty steaks + spirits like vodka etc.

mtflight said...

Peter, this is very interesting. As far as PUFA enhancing intestinal permeability--what does this mean for someone with autoimmune illness? Sounds like this increase in permeability is one in the same with gluten.

Warm Regards.
Alex

Gabriella Kadar said...

So is this possibly why taurine has anti-inflammatory effects? Decreases endotoxins in the blood that cause inflammation?

I'm probably late to this party. But....

Is it possible that taurine prevents endotoxins from entering the bloodstream alcohol or no alcohol?

Byron said...

There are indeed some experts advicing their fatty liver patients
low carb + n3.
http://translate.google.com/translate?js=y&prev=_t&hl=de&ie=UTF-8&layout=1&eotf=1&u=http%3A%2F%2Fwww.aerztezeitung.de%2Fmedizin%2Fkrankheiten%2Fmagen_darm%2Farticle%2F579532%2Ffett-schadet-leber-alkohol.html&sl=de&tl=en

donny said...

"A diet containing glycine improves survival in endotoxin shock in the rat"
---------------------------------
In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liver injury due to intravenous injection of endotoxin [Escherichia coli lipopolysaccharide (LPS)] in Sprague-Dawley rats in vivo. Fifty percent of the rats fed control diet died within 24 h after an intravenous injection of LPS (10 mg/kg), whereas feeding the rats glycine totally prevented mortality and markedly reduced an LPS-induced elevation of serum transaminase levels, hepatic necrosis, and lung injury. The elevation in serum tumor necrosis factor-alpha (TNF-alpha) due to LPS was also blunted and delayed significantly by glycine feeding. In a two-hit model (hepatic ischemia-reperfusion and injection of sublethal LPS), all rats fed control diet died, whereas 83% of glycine-fed animals survived with a significant reduction in transaminases and improved liver and lung histology. LPS elevated intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells, an effect blocked almost completely by glycine. Glycine most likely reduces injury and mortality by preventing the LPS-induced elevation of [Ca2+]i in Kupffer cells, thereby minimizing toxic eicosanoid and cytokine production
---------------------------------

I've seen studies where rats fed glycine had less visceral fat, lower blood pressure, etc., when fed a cruddy sucrose or fructose rich diet. There seems to be a lot of overlap between the benefits of taurine and glycine. (And resveratrol. Nobody's getting rich off of taurine or glycine anytime soon, though.)

Dr. Art Ayers said...

Peter,
Provocative post as always.

In this case, there is no direct measure of omega-3s altering gut permeability. Since it is already known that ethanol leads to leaky gut and migration of gut flora to the liver, it seems probable that the omega-3s provide a ready target for lipid peroxidation in the liver and increased liver inflammation leads to increased release of bacterial endotoxin from the liver to the serum.

This let's me sleep better after using fish oil capsules to compensate for any other minor inflammatory misbehavior. Alcohol in moderation still seems to be ok, as long as liver inflammation is avoided. Saturated fats seem to be a good form of insurance for liver health.

westie said...

Peter, I'm so glad you made this post. I started this year reading articles like these sited here and I still think that endotoxin derived inflammation may play major role in metabolic disorders.

Recently I noticed that zinc inhibits ethanol induced alterations in permeability. It's quite interesting. Do you have any idea how zinc may do that?

http://jpet.aspetjournals.org/content/305/3/880.abstract

One thing is that microbes and yeast may need zinc to use D-lactate efficiently for energy production.

http://www.biochemj.org/bj/082/0061/0820061.pdf

Thus zinc defiency may result in increased D-lactate concentration in the gut wall and that may lead to less energy to keep tight intestine since our cells doesn't manage well with high d-lactate or perhaps our cells need that zinc for conversion too; I don't know.

I don't have much refs to back this up but ATP deficiency sure is one way to increase permeability in the gut.

Here's enzyme for D-lactate oxidation:

http://www.ebi.ac.uk/intenz/query?cmd=SearchEC&ec=1.1.99.6

Ethanol oxidation is also zinc dependent:

http://www.ebi.ac.uk/interpro/IEntry?ac=IPR013149

westie said...

This article may shed some light to fructose effects on liver (and intestine?) cell metabolism:

http://jem.rupress.org/cgi/reprint/191/11/1975

Metabolic Depletion of Atp by Fructose Inversely Controls Cd95- and Tumor Necrosis Factor Receptor 1–Mediated Hepatic Apoptosis

In the gut short term ATP depletion/increased use of ATP may activate AMPK (like with butyrate) and theoretically thinking ATP consuming metabolism of moderate fructose/ethanol could activate energy production by AMPK activation and enhance intestinal barrier and as a result from that endotoxin will be kept on the right side of gut wall.

Except if you have a high fat meal but that's another story which is allready discussed earlier... :)

Peter said...

Hi J, glad you enjoy...

Byron, I do wonder if the fish oil research group got their initial leads from Cameron's diet...

Alex, it's interesting that many people who realise that gluten is the trigger for many auto immune diseases also realise that PUFA based diets are equally untenable... I would just reiterate that I see bulk fish oil (unlikely to be eaten) as a metaphor for bulk corn oil... The actual pharmacology of these fats in bulk are immunosuppressive, so you have quite a mix going on of effects. Of course if you remove the trigger you don't need the immunosupression...

Gabriella, It's possible taurine does a whole bunch of things! I wonder if it's effect on feline fatty liver syndrome might be gut and endotoxin related, without alcohol, and with relatively little fructose either.

Byron, Omega 3s seem to feature quite highly in fatty liver management. I think there is a world of difference in having a few DHA molecules each with an antioxidant radical attached as part of your phospholipid bilayers and drinking bulk fish oil. I still make sure I get some DHA somewhere along the line. I notice they are still using bariatric surgery when they have failed diet wise. Their diet uses restricted amounts of low GI carbs and some omega 3s. Should work (unless they still major on corn oil), but the people who end up with NAFLD are probably the least able to give up sucrose. They got there through sucrose (or HFCS), getting out would be hard. Like the German ketogenic cancer pilot study with the marked drop out rate. You are working with people on the upper ends of sugar intake. They'd be the hardest to help.

Donny, I've seen glycine as an effective management for arthritis in lab rat models too. It's interesting, but as you say, no profit there!

Westie, too much information, all of it interesting! Now there's more reading to do! That last full text paper makes some interesting points...

Peter

Peter said...

Art,

Yes, exactly where/how the endotoxin is getting in to the blood stream from is not clear. As you say, saturated fat seems to be a pretty good insurance policy, bulk PUFA is no one's idea of an anti inflammatory diet. Actually, it makes you think about what any of us means by an anti inflammatory diet... I'm for continuation of modest alcohol and modest fish oil!

Peter

Virginia said...

Peter,
Scary thought, if fructose causes fatty liver. So many foods are loaded with HFCS. The lesson is rather simple, stay away from processed foods. I was going to say junk food, but almost all processed foods are junk food.
Thank you,

mtflight said...

Peter,

once upon a time, I had TC a pinch above 200 and my then doc, wanted to statinate me. I thought I'd nip this in the bud and restarted low carb (lowers trigs to below 100), with the addition of about 8-10 g fish oil/day. Interestingly my triglycerides were unusually high for low carb... and it took months to lower them (inflammation?). never were my liver enzymes abnormal.

Confounding factors were a thyroid supplement (porcine extract pills T3+T4, armour) was being malabsorbed due to being taken alongside a whey and psyllum husk shake. The LDL receptor apparently needs T3, and my LDL went off the norm. At the same time I eliminated processed vegetable oils (which reduce LDL through PERPP).

So it was a mess. The interesting thing is my LDL levels never came back to what they once were (130 ish).. they remain above 200 for 2 years.

varg said...

A similar experiment with human subjects:

http://tinyurl.com/overfeedfastfood

donny said...

http://ajpgi.physiology.org/cgi/content/abstract/00088.2009v1
-------------------------------
Elevated dietary fructose intake, altered intestinal motility and barrier function may be involved in the development of non-alcoholic fatty liver disease (NAFLD). As intestinal motility and permeability are also regulated through the bioavailability of serotonin (5-HT) we assessed markers of hepatic injury in serotonin reuptake transporter knockout [SERT(-/-)] and wild-type mice chronically exposed to different monosaccharide solutions (30% glucose or fructose solution) or water for 8 weeks. The significant increase in hepatic triglyceride, tumor necrosis factor- (TNF) and 4-hydroxynonenal (4-HNE) adduct as well as portal endotoxin levels found in fructose fed mice was associated with a significant decrease of SERT and the tight junction occludin in the duodenum. Similar effects were not found in mice fed glucose. In contrast, in SERT(-/-) mice fed glucose portal endotoxin levels, concentration of occludin and indices of hepatic damage were similar to those found in wild-type and SERT(-/-) mice fed fructose. In fructose fed mice treated with a 5-HT3 receptor antagonist hepatic steatosis and the loss of SERT in the duodenum were significantly attenuated. Our data suggest that a loss of intestinal SERT is a critical factor in fructose-induced impairment of intestinal barrier function and subsequently the development of steatosis.
-----------------------------

I was looking at this today,
"A Serotonin-Dependent Mechanism Explains the Leptin Regulation of BoneMass,
Appetite, and Energy Expenditure"

http://cmbi.bjmu.edu.cn/news/report/2009/pdf/med09_09_1.pdf

and that got me to wondering about the fructose and leptin resistance connection; maybe that reliance on fructose for most of the calories early in life might cause some sort of exaggerated serotonin response once a starch and fat diet was introduced, or something like that. I think "something like that" probably comes closer to the truth than my original theory.:)

Maybe a cautionary tale in there for anyone who thinks glucose is automatically safe just because our ancestors ate lots of tubers, it might depend on whether the system has already been compromised or not.

This is suggestive;

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2098.html

"Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis"

Stephan at Whole Health Source just did a blog about corn oil causing osteoporosis. Maybe things that cause fatty liver also cause an increased need for gut-derived serotonin. Leaving less tryptophan available for transport into the brain. Which maybe means less brain serotonin, which according to the brain serotonin/leptin study guys, means less bone mass...

Jamila said...

Thank you Peter. Enjoyed reading it. I am desperate in finding some answers to the Constant Right Upper Quadrant pain that I have suffered for the last two years. I have visited the best clinics in the world in the US, Germany, Russia and have no answers from Drs whatsoever. All I know that eating fruits and carbs makes me very uncomfortable, itchy and triggers the pain. I have lost a lot of weight, but my liver enzymes, mri and ercp images seems to be normal. I wondered if going on no fructose and low carb diet might help... Would appreciate to hear from you. Thanks