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Archive for the ‘Liver’ Category

I’ve written previously about the role of dietary fats in liver diseaseI’ve spoken on the subject as well.  It’s kind of my “thing”- lipids and liver- so I was kind of excited yesterday when I came across a relatively new paper while browsing PubMed.  I thought it was so interesting, and the final points so salient, that it deserved a post… I hope you think so too!

 

If this is something you're into, I suggest reading on!

If this is something you’re into, I suggest reading on!

 

I’ve written before about “Liver Saving Saturated Fats”.  By “hits” it’s one of my most popular posts to date, and it’s a good primer to this post, so if you haven’t read it I’d suggest you go back and give it a read.  The long and the short of it, however, is that when it comes to alcoholic (and non-alcoholic) fatty liver disease, saturated fat is not the enemy.  On the contrary, dietary saturated fats protect against liver disease while fat sources that are rich in polyunsaturated fatty acids (PUFAs), such as corn oil, soy oil, or just about any industrial “vegetable” oil, are closely associated with the development and progression of liver disease.

 

One of the great papers on this subject (at least in my opinion), was published by Kirpich et al in 2011.  In this paper they showed that diets that contain alcohol and are rich in PUFA lead to increased intestinal permeability, increased circulating endotoxin (from gut bacteria), and increased production of inflammatory cytokines [1]. These pathologies aren’t seen in the absence of alcohol, or in the presence of alcohol in the context of a diet high in saturated fat.  While I am very fond of the Kirpich paper, I was somewhat frustrated by their choice of dietary fat in the saturated fat group: a mixture of beef tallow and medium chain triglyceride (MCT) oil.  The result was a diet that had a high degree of saturation, but consisted of a variety of different kinds of saturated fats.

 

The problem is, not all saturated fats are created equal.  

 

There are a number of important differences between medium chain fatty acids (MCFA) and long chain fatty acids (LCFA).  First is the obvious difference: size. MCFA are between 6 and 12 carbons in length, while LCFA are greater than 12 carbons in length.  Shorter fats are easily absorbed across intestinal epithelial cells, and MCFAs rapidly make it to the liver where they are metabolized. On the other hand, long chain fatty acids are absorbed by a longer route, travelling via the lymphatics and making it to the liver in newly formed chylomicrons.  Once in the liver, MCFAs are short enough to be directly transported into mitochondria to be used for energy, while LCFA must be “shuttled” into mitochondria via a pathway that requires carnitine and various transferases.  These are just some of the basic metabolic differences.  Fatty acids are also used by the body for cell signaling purposes- both as second messengers and through modulation of gene transcription and translation- and they’re incorporated into cell membranes.  Various dietary fats are handled differently by the body, and it can be difficult to tease out the details with mixed dietary sources and in complex biological systems, but scientists persevere!!

 

On to the paper…

 

The paper I came across yesterday is a concerted effort to start to tease apart the difference in the effects of dietary MCFA and LCFA in the context of chronic alcohol consumption[2].  Previous papers (discussed in my previous post) have shown that MCFA and LCFA (or frequently a combination of the two) protect against liver injury associated with chronic alcohol consumption, and some have started to understand the mechanisms by which these dietary fats are “liver saving”, but to date I have not seen a paper that specifically tried to look at the differences between MCFA and LCFA in the context of alcoholic liver disease.

 

The diets:

 

In order to look at the differences between dietary MCFA and LCFA in the context of chronic alcohol consumption, two experimental diets were used in addition to the traditional control and alcohol “pair fed” diets.  The control and traditional alcohol-fed diets relied on corn oil for 30% of calories.  Corn oil is approximately 50% PUFA, predominantly the omega-6 linoleic acid.  The two treatment groups relied on medium chain triglycerides or cocoa butter (yes, the stuff in chocolate) for 30% of calories.  All the fatty acids in MCT have less than 12 carbons (it’s 67% C8:0), while all the fatty acids in cocoa butter have more than 16 carbons (C16:0 and C18:0 are predominant).  By creating “saturated fat” diets that were exclusively medium chain or long chain in nature, the researchers were able to draw conclusions on the importance of saturated-fat chain length in liver pathology.  As with the alcohol-fed corn oil diet, in the MCT and cocoa butter diets 38% of the calories came from alcohol.  All the experiments in this paper were done after 8 weeks of alcohol consumption.

 

First things first- both MCT and cocoa butter (CB) were able to prevent most of the alcohol induced pathology that was seen in the regular (corn oil) alcohol-fed animals.  There was significantly less fat accumulation and none of the inflammatory cell infiltrates that were seen in the corn oil and alcohol-fed animals.  The alcohol-fed animals on the corn oil diet also had more hepatic triglycerides, more hepatic cholesterol, and more hepatic free fatty acids.

 

The liver can be damaged in a number of ways with alcohol consumption, but one significant mechanism relies on the activation of Kuppfer cells (the macrophages of the liver).  In rats fed ethanol and corn oil, there was an increase in the number and size of macrophages. There were also increases in inflammatory cytokines that were prevented with MCT and CB feeding.

 

Previous research has shown that saturated fat consumption prevents an alcohol-induced increase in gut permeability (which allows endotoxin to make it into the circulation where it can lead to the activation of macrophages).  This previous research, however, was with a diet that combined medium chain and long chain fatty acids.  In the current paper, Zhong et al show that the MCT diet maintains the tight junctions between cells, normalizing serum endotoxin in the face of alcohol consumption.  This is not true for the animals fed the CB diet, where there was an increase in circulating endotoxin similar to the alcohol-fed animals on the corn oil diet.  However, the amount of endotoxin in the livers of the CB-fed animals were on par with the control and MCT-fed animals, and as mentioned before the levels of inflammatory cytokines were not elevated.  This appears to be due to an increase in the protein levels of ASS1, which binds endotoxin, inactivates it, and clears it.  Thus it seems that dietary MCTs work in a way that maintains the expression of gut tight junction proteins, preventing endotoxin from making it into the circulation, while long chain saturated fats work in a way that increases endotoxin-binding proteins in the liver.  Both prevent endotoxin-induced damage in the liver, but in very different and distinct ways.

 

So where does this leave us?*

 

This paper again shows that saturated fats are protective against alcohol-induced liver damage.  It digs deeper than past papers, separating out the effects of dietary medium chain fatty acids versus long chain fatty acids.  While both medium chain and short chain fats are protective, they appear to be so in very different ways.  Dietary MCT prevent alcohol-induced downregulation of tight junction genes in the intestinal eptithelium, preventing endotoxemia and hepatic inflammation.  On the other hand, dietary CB normalized hepatic endotoxin concentrations by increasing the amount of an endotoxin-binding protein (ASS1), thus increasing the elimination of endotoxin from the liver and preventing hepatic inflammation.

 

This raises the question (at least to me), of how much MCT is needed to preserve the integrity of the intestinal epithelium?  While preventing inflammatory damage by endotoxin in the liver is an admirable task (well done chocolate!), I’d personally prefer to keep endotoxin out of the circulatory system in the first place. We know from the Kirpich paper that a “saturated fat” diet that is 40% fat using an MCT:beef tallow ratio of 82:18 maintains gut integrity in the face of alcohol consumption and prevents an increase in circulating endotoxin, but how much MCT do you need to maintain gut integrity in the face of an intestinal insult**. This is also important because there are no natural sources of pure (or concentrated) MCTs (at least to my knowledge).  Coconut oil is approximately 50% MCTs, predominantly the C12:0 Lauric Acid.

 

This paper makes good strides in starting to understand how saturated fats of different types protect against the damage done by chronic alcohol consumption.  While it may encourage you to have a coconut chocolate with your next glass of wine (oh twist my arm!), I think this paper is also important because if confirms the destructive nature of diets high in polyunsaturated fatty acids.  Tis the season for overindulging, and this paper shows that it’s better to over indulge on chocolate and coconut (or steak and eggs), and not on anything bathed in vegetable oils!

 

Personally I like to get my fats separate from my booze, but I know some are fans of this seasons saturated fat/alcohol combo!

Personally I like to get my fats separate from my booze (and with less sugar), but I know some are fans of this seasonal saturated fat/alcohol combo!

 

* It’s worth noting that this paper also presents data from metabolite profiles in liver and serum samples from the different groups of animals.  The data is way over my head (they analyzed 220 metabolites from liver samples and 167 metabolites from serum samples), but I did find it interesting that regardless of dietary fat source, the three alcohol-fed groups were quite distinct from the control group.  Additionally, the CB and MCT groups distributed closely, obviously distinct from the alcohol-fed corn oil group.

 

**Interestingly, that paper also showed that the saturated fat diet caused an increase in the mRNA levels of a number of tight junction proteins in comparison to the control (i.e.- not alcohol-fed) corn oil diet.  The current paper showed dietary MCTs capable of maintaining Occludin at control levels, and capable of increasing ZO-1 in comparison to all other groups (control corn oil-fed included).

 

1.            Kirpich, I.A., W. Feng, Y. Wang, Y. Liu, D.F. Barker, S.S. Barve, and C.J. McClain, The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res, 2012. 36(5): p. 835-46.

2.            Zhong, W., Q. Li, G. Xie, X. Sun, X. Tan, W. Jia, and Z. Zhou, Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. Am J Physiol Gastrointest Liver Physiol, 2013. 305(12): p. G919-32.

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Just a quick post that my talk from the 2013 Ancestral Health Symposium is up.  Alas, there were some technical difficulties and the last few minutes weren’t recorded, but most of the meat of the talk is there.

 

**Apparently the video has been set to private.  I’ll update when it’s back!

***Update 11/4- It’s back!

 

Also, the slides are up on Slide Sharer here (there were a few reveals/animations that didn’t make the upload, but again the meat of the topic is there!).

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As my last post started to explore, different types of dietary fats have different effects on the progression of alcoholic liver disease. This post will further explore the protective effects of saturated fats in the liver.

 

For many, the phrase “heart healthy whole grains” rolls off the tongue just as easily as “artery clogging saturated fats”. Yet where is the evidence for these claims? In the past few decades saturated fats have been demonized, without significant evidence to suggest that natural saturated fats cause disease (outside of a few well touted epidemiological studies). Indeed, most of the hypothesis-driven science behind the demonization of saturated fats is flawed by the conflation of saturated fats with artificial trans fats (a la partially hydrogenated soybean oil).

 

In the face of a lack of any significant scientific evidence that clearly shows that unadulterated-saturated fats play a significant role in heart disease (and without a reasonable mechanism suggesting why they might), I think the fear-mongering “artery clogging” accusations against saturated fats should be dropped. On the contrary, there is significant evidence that saturated fats are actually a health promoting dietary agent- all be it in another (though incredibly important) organ.

 

Again (from my last post), here is a quick primer on lipids (skip it if you’re already a pro). For the purpose of this post, there are two important ways to classify fatty acids. The first is length. Here I will discuss both medium chain fatty acids (MCFA), which are 6-12 carbons long, and long chain fatty acids (LCFA), which are greater than 12 carbons in length (usually 14-22; most have 18). Secondly, fatty acids can have varying amounts of saturation (how many hydrogens are bound to the carbons). A fatty acid that has the maximal number of hydrogens is a saturated fatty acid (SAFA), while one lacking two of this full complement, has a single double bond and is called  monounsaturated (MUFA) while one lacking more (four, six, eight etc.) has more double bonds (two, three, four, etc.) and is called a polyunsaturated fatty acid (PUFA).

 

Next time you eat a good fatty (preferably grass-fed) steak, or relish something cooked in coconut or palm oil, I hope you will feel good about the benefits you are giving your liver, rather than some ill-placed guilt about what others say you are doing to your arteries. From now on, I hope you think of saturated fats as “liver saving (and also intestine preserving) lipids”. Here’s why:

 

In 1985, a multi-national study showed that increased SAFA consumption was inversely correlated with the development of liver cirrhosis, while PUFA consumption was positively correlated with cirrhosis [1].  You might think it is a bit rich that I blasted the epidemiological SAFA-heart disease connection and then embrace the SAFA-liver love connection, but the proof is in the pudding- or in this case the experiments that first recreated this phenomenon in the lab, and then offered evidence for a mechanism (or in this case many mechanisms) for the benefits of SAFA.

 

The first significant piece of support for SAFA consumption came in 1989, when it was shown in a rat model that animals fed an alcohol-containing diet with 25% of the calories from tallow (beef fat, which by their analysis is 78.9% SAFA, 20% MUFA, and 1% PUFA) developed none of the features of alcoholic liver disease, while those fed an alcohol-containing diet with 25% of the calories from corn oil (which by their analysis is 19.6% SAFA, 23.6% MUFA, and 56.9% PUFA) developed severe fatty liver disease [2].

 

More recent studies have somewhat complicated the picture by feeding a saturated fatty-acid diet that combines beef tallow with MCT (medium chain triglycerides- the triglyceride version of MCFAs). This creates a diet that is more highly saturated than a diet reliant on pure-tallow, but it complicates the picture as MCFA are significantly different from LCFA in how they are absorbed and metabolized. MCFA also lead to different cellular responses (such as altered gene transcription and protein translation). Nonetheless, these diets are useful for those further exploring the role of dietary SAFA in health and disease.

 

These more recent studies continue to show the protective effects of SAFA, as well as offer evidence for the mechanisms by which SAFA are protective.

 

Before we explore the mechanisms, here is a bit more evidence that SAFAs are ‘liver saving’.

 

 

A 2004 paper by Ronis et al confirmed that increased SAFA content in the diet decreased the pathology of fatty liver disease in rats, including decreased steatosis (fat accumulation), decreased inflammation, and decreased necrosis.  Increasing dietary SAFA also protected against increased serum ALT (alanine transaminase), an enzymatic marker of liver damage that is seen with alcohol consumption [3].  These findings were confirmed in a 2012 paper studying alcohol-fed mice. Furthermore, these researchers showed that SAFA consumption protected against an alcohol-induced increase in liver triglycerides [4].  Impressively, dietary SAFA (this time as MCT or palm-oil) can even reverse inflammatory and fibrotic changes in rat livers in the face of continued alcohol consumption [5].

 

But how does this all happen?

 

Before I can explain how SAFA protect against alcoholic liver disease, it is important to understand the pathogenesis of ALD. Alas, as I briefly discussed in my last post, there are a number of mechanisms by which disease occurs, and the relative importance of each mechanism varies based on factors such as the style of consumption (binge or chronic) and confounding dietary and environmental factors (and in animals models, the mechanism of dosing). SAFA is protective against a number of mechanisms of disease progression- I’ll expound on those that are currently known.

 

In my opinion, the most interesting (and perhaps most important) aspect of this story starts outside the liver, in the intestines.

 

In a perfect (healthy) world, the cells of the intestine are held together by a number of proteins that together make sure that what’s inside the intestines stays in the lumen of the intestine, with nutrients and minerals making their way into the blood by passing through the cells instead of around them. Unfortunately, this is not a perfect world, and many factors have been shown to cause a dysfunction of the proteins gluing the cells together, leading to the infamous “leaky gut”. (I feel it is only fair to admit that when I first heard about “leaky gut” my response was “hah- yeah right”. Needless to say, mountains of peer-reviewed evidence have made me believe this is a very real phenomenon).

 

Intestinal permeability can be assessed in a number of ways.  One way is to administer a pair of molecular probes (there are a number of types, but usually a monosaccharide and a disaccharide), one which is normally absorbed across the intestinal lining and one that is not. In a healthy gut, you would only see the urinary excretion of the absorbable probe, while in a leaky gut you would see both [6]. Alternatively, you can look in the blood for compounds such as lipopolysaccharide (LPS-a product of the bacteria that live in the intestine) in the blood. (Personally, I would love to see some test for intestinal permeation become a diagnostic test available to clinicians.)

 

Increased levels of LPS have been found in patients with different stages of alcoholic disease, and are also seen in animal models of alcoholic liver disease.  Increased levels of this compound have been associated with an increased inflammatory reaction that leads to disease progression.  Experimental models that combine alcohol consumption and PUFA show a marked increase in plasma LPS, while diets high in SAFA do not.

 

 

But why? (Warning- things get increasingly “sciencey” at this point. For those less interested in the nitty-gritty, please skip forward to my conclusions)

 

Cells from the small intestine of mice maintained on a diet high in SAFA, in comparison to those maintained on a diet high in PUFA, have significantly higher levels of mRNA coding for a number of the proteins that are important for intestinal integrity such as Tight Junction Protein ZO-1, Intestine Claudin 1, and Intestine Occludin.  Furthermore, alcohol consumption further decreases the mRNA levels of most of these genes in animals fed a high-PUFA containing diet, while alcohol has no effect on levels in SAFA-fed animals.  Changes in mRNA level do not necessarily mean changes in protein levels, however the same study showed an increase in intestinal permeability in mice fed PUFA and ethanol in comparison to control when measured by an ex-vivo fluorescent assay. This shows that PUFA alone can disturb the expression of proteins that maintain gut integrity, and that alcohol further diminishes integrity. In combination with a SAFA diet, however, alcohol does not affect intestinal permeability [4].

 

Improved gut integrity is no doubt a key aspect of the protective effects of SAFA. Increased gut integrity leads to decreased inflammatory compounds in the blood, which in turn means there will be decreased inflammatory interactions in the liver.  Indeed, in comparison to animals fed alcohol and PUFA, animals fed alcohol with a SAFA diet had significantly lower levels of the inflammatory cytokine TNF-a and the marker of macrophage infiltration MCP-1 [4].  Decreased inflammation, both systemically and in the liver, is undoubtedly a key element of the protective effects of dietary SAFA.

 

This post is already becoming dangerously long, so without going into too much detail, it is worth mentioning that there are other mechanisms by which SAFA appear to protect against alcoholic liver disease. Increased SAFA appear to increase liver membrane resistance to oxidative stress, and also reduces fatty acid synthesis while increasing fatty acid oxidation [3]. Also, a diet high in SAFA is associated with reduced lipid peroxidation, which in turn decreases a number of elements of inflammatory cascades [5]. Finally- and this is something I will expand on in a future post- MCFAs (which are also SAFA) have a number of unique protective elements.

 

I realize that this post has gotten rather lengthy and has brought up a number of complex mechanisms likely well beyond the level of interest of most of my readers…

 

If all else fails- please consider this:

 

The “evidence” that saturated fats are detrimental to cardiac health is largely based on epidemiological and experimental studies that combined saturated fats with truly-problematic artificial trans-fats. Despite the permeation of the phrase “artery clogging saturated fats”, I have yet to see the evidence nor be convinced of a proposed mechanism by which saturated fats could lead to decreased coronary health.

 

ON THE CONTRARY…

 

There is significant evidence, founded in epidemiological observations, confirmed in the lab, and explored in great detail that shows that saturated fats are protective for the liver. While I have focused here on the protective effects when SAFA are combined with alcohol, they offer protection to the liver under other circumstances, such as when combined with the particularly liver-toxic pain-killer Acetaminophen [7].

 

Next time you eat a steak, chow down on coconut oil, or perhaps most importantly turn up your nose at all things associated with “vegetable oils” (cottonseed? soybean? Those are “vegetables”?), know that your liver appreciates your efforts!

 

 

1.            Nanji, A.A. and S.W. French, Dietary factors and alcoholic cirrhosis. Alcohol Clin Exp Res, 1986. 10(3): p. 271-3.

2.            Nanji, A.A., C.L. Mendenhall, and S.W. French, Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res, 1989. 13(1): p. 15-9.

3.            Ronis, M.J., S. Korourian, M. Zipperman, R. Hakkak, and T.M. Badger, Dietary saturated fat reduces alcoholic hepatotoxicity in rats by altering fatty acid metabolism and membrane composition. J Nutr, 2004. 134(4): p. 904-12.

4.            Kirpich, I.A., W. Feng, Y. Wang, Y. Liu, D.F. Barker, S.S. Barve, and C.J. McClain, The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res, 2012. 36(5): p. 835-46.

5.            Nanji, A.A., K. Jokelainen, G.L. Tipoe, A. Rahemtulla, and A.J. Dannenberg, Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. J Pharmacol Exp Ther, 2001. 299(2): p. 638-44.

6.            DeMeo, M.T., E.A. Mutlu, A. Keshavarzian, and M.C. Tobin, Intestinal permeation and gastrointestinal disease. J Clin Gastroenterol, 2002. 34(4): p. 385-96.

7.            Hwang, J., Y.H. Chang, J.H. Park, S.Y. Kim, H. Chung, E. Shim, and H.J. Hwang, Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats. Lipids Health Dis, 2011. 10: p. 184.

What is “Fatty Liver”? Well here’s a slide from my research showing a slice of liver from a control-fed rat on the left and an alcohol-fed rat on the right. Arrows mark macrovesicular lipid accumulations (other models can show much more impressive lipid accumulations).

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