Posts Tagged ‘lipids’

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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Abstract dangers

Scientific journals aren’t for everyone. Journal articles use technical writing and can be rather dry. They can be long, they can be dull, they can show nothing new and exciting, or the research they describe can be so poorly thought out you wonder how a reviewer ever allowed the paper to go to the presses. Many good article are behind pay walls, so even if you want to read them, sometimes you can’t.


Fortunately an abstract of most papers can be found for free.  An abstract is a brief summation drawn up by the authors to get their point across.  Maybe it’s just me, but I sometimes think that abstracts can be a bit like movie trailers- they introduce the major players and they give you a general plot of the movie (and they try and hook you in by showing you all the good scenes).


Like a movie trailer, abstracts can be deceiving.  Take the trailer for The Matrix Reloaded– how excited were you when you first saw that trailer? How much did you wish the movie had never been made after you saw the actual feature?


Unfortunately, while in the cinematic world people are unlikely to act like they’ve seen the whole movie when all they’ve done is watch a trailer, in the world of scientific literature it often seems that people assume that reading the abstract is as good as reading the paper.


It is not.


The list of examples is endless, but this morning I stumbled across an example of this that finally pushed me to write about abstract abstraction.


It all started when I saw a tweet proclaiming “A high saturated fat mixed meal induces inflammation & insulin resistance & elevated glucose cf [compared to] other types of fats”.  Considering my interest in fats and my particular fondness for saturated fats you may not be surprised to hear that I decided to dig a little deeper.


The paper is from an open access journal. The full text is available here.


To be fair, the title of the paper is not quite as sensational as the tweet that led to it- The effect of two iso-caloric meals containing equal amounts of fats with a different fat composition on the inflammatory and metabolic markers in apparently healthy volunteers– but the “conclusions” offered in the abstract (the line that anyone who is just skimming the article will jump to) is rather dubious:


Metabolic and modest inflammatory changes occur within a few hours after the ingestion of a high SFA meal in apparently healthy adults.


I don’t have the time or the inclination to totally dismantle this paper (I really wonder how they did their statistics to show there was a significant difference), but I do want to point out how unwise it can be to draw conclusions from this abstract.


Let’s compare the methods sections. In the abstract, the authors say that healthy participants “were given two iso-caloric meals with similar amounts but different composition of fats: a meal high in monounsaturated fats (MUFA), and a meal high in saturated fat (SFA).”


The methods section in the paper reveals more detail:


The chosen meals represented two very popular meals habitually preferred by the general population: 1. Chicken sausages with fried potatoes, ketchup and mayonnaise (defined as SFA); 2. Pasta with olive oil, ketchup and nuts (defined as MUFA).




Two entirely different meals, and we’re supposed to believe that any differences in blood markers (of which I am skeptical) are due to the change in the type of fat- fat types that aren’t particularly well represented in at least one of the meals.  Chicken is not high in saturated fat.  Chicken fat is predominantly unsaturated, a combination of MUFA and polyunsaturated fats (PUFA), with less than a third of chicken fat being saturated.  What were the potatoes fried in? These days most things are fried in PUFA rich vegetable oils not SFA rich animal fats or coconut oil.  And mayonnaise? Mayonnaise contains very little saturated fat (because it’s usually made with PUFA-rich vegetable oils).  At least the second diet utilizes olive oil, which is rich in MUFA.


The authors state that they used the Israeli Food Database to calculate the breakdown of SFA:MUFA:PUFA in each diet and that the “SFA” and “MUFA” diets contained 24:33:17g and 8:51:14g respectively. Without knowing more about the ingredients (what fats and oils were used in the SFA diet and what nuts were used in the MUFA diet) it’s hard to know if the breakdown is accurate.  The meals are so different in every regard, it’s silly to quibble over the exact proportion of each fatty acid type.


The point of this post isn’t (or wasn’t) to pick this paper apart.  The purpose was to show that we should be cautious when drawing conclusions from abstracts.


The authors chose to say that any changes (that may or may not be real) occurred after “the ingestion of a high SFA meal”, but they could equally have said “after the consumption of mayonnaise (or potatoes)”… Likewise, they could have claimed that pasta (or nuts) “protects against metabolic changes induced by ketchup”. Of course, all of these claims would be ridiculous- though perhaps less ridiculous than suggesting any changes were due to ingestion of a high SFA meal (something they didn’t even test)!


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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.




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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Liver and lipids

My research background, at least as far as my PhD is concerned, is in pharmacology and physiology.  Specifically, I studied the effects of chronic alcohol consumption on signal transduction in the liver. Simply, I explored the ways in which chronic alcohol consumption affects how liver cells “talk” (both to each other, and how individual cells transmit a signal from an extracellular stimulus into an intracellular response).  If I were to go all “alphabet soup” on you, I would talk about my explorations into IP3-Ca2+ signaling, or my real area of expertise, cAMP-PKA signaling and CREB phosphorylation. Luckily (for all of us) that’s not what I want to write about.


What I want to write about is the role of various fats (aka lipids) in the development of fatty liver. Before I delve into the land of lipids, a bit of background is in order.


Fatty liver is the first phase of a process that in some people ends with cirrhosis and liver failure.  Most people associate this progression (from fatty liver, to fibrosis, and finally to cirrhosis) with chronic alcohol consumption, however recently the prevalence of nonalcoholic fatty liver disease (NAFLD) has grown. In fact, when I first started my PhD research, sources were saying that alcoholic fatty liver disease (AFLD) was the #1 cause of fatty liver. By the time I was writing my thesis (and I didn’t take THAT long), sources were claiming that AFLD had been overtaken by NAFLD. As the name suggests, fatty liver disease (aka liver steatosis) is the accumulation of fat in the liver. Microscopically this is evident as micro or macrovesicular fat accumulations within the cells of the liver (hepatocytes), while grossly a fatty liver appears enlarged, soft, oily, and pale (foie gras anyone?).


Fatty liver- both alcoholic and nonalcoholic – is generally asymptomatic, and requires a liver biopsy or radiology (such as CT, MRI, or ultrasonography) for diagnosis, though blood tests for liver markers are used to detect non-specific changes in liver health (you also might notice this while looking around someone’s insides during a surgical procedure, as I noted during a laparoscopic gallbladder removal during my surgery clerkship).  The prevalence of fatty liver is unclear, however the percentage of heavy drinkers that have fatty liver changes is probably quite high, with some studies showing that up to 90% of active drinkers have fatty changes [1]. Again, because of the relative “silent” nature of NAFLD, it’s hard to determine the prevalence of the condition, however it is strikingly (and increasingly) common, with sources suggesting that it may affect 20-30% of the US population [2]. Scarily, it is estimated that over 6 million CHILDREN in the US have this condition today, with this number continuing to grow [3].


Fat can accumulate in the liver in five different (though often simultaneous) ways. There can be (1) an increase in uptake and storage of dietary fats, (2) an increased uptake of free fatty acids (FFA) from other stores (from your fat tissue to your liver), (3) increased de novo lipogenesis (making lipids from scratch), (4) decreased consumption (b-oxidation to those in the trade) of fats, or (5) impaired export of triglycerides from the liver [4]. It is likely that a number of these mechanisms work in concert to produce fatty liver disease, but the precise reasons WHY they occur have not yet been determined, nor has the relative importance of each mechanism been teased out. Undoubtedly different mechanisms are of varying importance in different conditions and circumstances.  Indeed, relatively early studies of alcohol-induced liver disease showed that, depending on experimental conditions such as method and length of exposure, hepatic lipids could be derived from dietary, adipose, or de novo hepatic sources [5]. Teasing out what we already know (or think we know), and how each of these mechanisms interact to lead to fatty liver disease is beyond the scope of this blog post (it’s beyond the scope of most medical texts, really), but the role of dietary fats deserves some airtime in this discussion, and is what I wish to talk about here.


The research into the pathogenesis of alcoholic fatty liver is long and tortuous (or is that torturous, if you’re a graduate student trying to get a handle on past research?). Without going into too much depth, there has been controversy over the years as to whether alcohol itself causes fatty liver, or whether fatty liver occurs with alcohol consumption as a result of simultaneous nutrient deficiencies. Because chronic alcohol consumption is frequently accompanied by a very poor diet, it was postulated that liver disease occurred primarily as a result of nutrient deficiency, not alcohol consumption. This proved to be partially true in animal models, where a diet deficient in nutrients such as choline and methionine exacerbates the development of alcoholic liver disease.  Alas, nutritional supplementation only diminishes or slows, but does not prevent, alcoholic liver disease development and progression [6, 7]. Steatosis still occurs in the presence of an adequate diet, showing that nutritional deficiencies alone cannot account for the development of fatty liver.


Before I delve into the research, 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 which has one double bond is monounsaturated (MUFA) and a fatty acid with more than one double bond is called a polyunsaturated fatty acid (PUFA)*.


Most alcohol researchers rely on an isocaloric liquid diet containing 35% of the calories from alcohol in the treatment group with the alcohol replaced by a carbohydrate in the control group. It was discovered pretty early on (in the 1960s) that eliminating dietary fatty acids significantly reduced the amount of fat accumulated in the liver and that you needed at least 25% of calories from fat, and ideally around 40%, to get a good model of alcoholic fatty liver (granted this is in rats, not humans). It didn’t take long for researchers to realize that different types of fatty acids were better (or perhaps more interestingly, worse) at creating fatty liver than others. The first notable realization (at least as far as I’m aware) is that medium chain fatty acids (MCFA) caused much less steatosis than long chain fatty acids (LCFA). Indeed, as early as 1972 researchers were showing that alcoholic fatty liver in rats could be reversed by replacing corn oil (an excellent source of LCFA, especially polyunsaturated fatty acids (PUFAs)) with MCFA. Stunningly (to me at least), there was a more rapid regression of fatty liver when the corn oil was replaced with MCFA than when the alcohol was replaced with sucrose [8]!


Another fascinating and interesting piece to this puzzle came in the mid 80s when it was shown that beef fat prevents alcoholic liver disease in rats. This research was conducted after epidemiological studies showed that a high intake of saturated fat was relatively protective against ALD disease while a high intake of polyunsaturated fats promoted ALD.  Researchers took this epidemiological finding to the lab, and showed that rats that were fed an alcohol-containing diet with tallow (beef fat) developed none of the symptoms of alcoholic fatty liver disease, while those fed alcohol with corn oil developed severe pathology [9]. More recent research (which I will explore in an upcoming post) delves into the protective mechanisms of SAFAs.


Alas, a high fat model of ALD that doesn’t actually give you liver pathology is not particularly useful for studying fatty liver, so most ALD research uses a diet that combines olive oil, corn oil, and/or soy oil and produces significant fat accumulation in the liver (indeed, this is what my PhD research was based on).  But what can research that has used other sources of fats tell us about alcoholic liver disease, and perhaps more interestingly (as the NAFLD epidemic continues to sweep the nation and the world) what can this research tell us about fatty liver disease that has nothing to do with alcohol consumption?


During my time in the lab (and even more so while writing my dissertation), I came to recognize that there are many similarities between fatty liver diseases of apparently very different etiologies. From a cell signaling perspective (my specialty), I was surprised by the parallels of our ALD fatty liver model and the fatty liver caused by protein malnutrition (yes- protein malnutrition leads to fatty liver- bizarre, no?). I have had less time to focus on the parallels between ALD and NAFLD (not caused by protein-malnutrition), however most of the medical information on this topic suggests life-style modification that focuses on the importance of reducing fat, especially (*eye roll*) saturated fat. I have yet to see the smoking gun for saturated fats in the pathogenesis of NAFLD, and if the process is anything like that of alcoholic liver disease (as I much suspect to be the case), minimizing saturated fats for those with NAFLD will likely do more harm than good.


I will expound on this statement in an upcoming post.



*For the lipid lovers in the crowd… Yes- there are significant differences in the effects of various types of PUFAs when it comes to alcoholic liver disease, though there are some interesting complications with the Omega3s depending on what research you look at. For the sake of this post (and most research), when I say PUFA I am generally referring to linoleic acid, the main PUFA in the dietary models of ALD and the modern diet.



1.            Kondili, L.A., G. Taliani, G. Cerga, M.E. Tosti, A. Babameto, and B. Resuli, Correlation of alcohol consumption with liver histological features in non-cirrhotic patients. Eur J Gastroenterol Hepatol, 2005. 17(2): p. 155-9.

2.            Kim, C.H. and Z.M. Younossi, Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med, 2008. 75(10): p. 721-8.

3.            Jin, R., N.A. Le, S. Liu, M. Farkas Epperson, T.R. Ziegler, J.A. Welsh, D.P. Jones, C.J. McClain, and M.B. Vos, Children with NAFLD Are More Sensitive to the Adverse Metabolic Effects of Fructose Beverages than Children without NAFLD. J Clin Endocrinol Metab, 2012. 97(7): p. E1088-98.

4.            Lim, J.S., M. Mietus-Snyder, A. Valente, J.M. Schwarz, and R.H. Lustig, The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol, 2010. 7(5): p. 251-64.

5.            Lieber, C.S., N. Spritz, and L.M. DeCarli, Role of dietary, adipose, and endogenously synthesized fatty acids in the pathogenesis of the alcoholic fatty liver. J Clin Invest, 1966. 45(1): p. 51-62.

6.            Nieto, N. and M. Rojkind, Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet. J Hepatol, 2007. 46(2): p. 330-9.

7.            Kajikawa, S., K. Imada, T. Takeuchi, Y. Shimizu, A. Kawashima, T. Harada, and K. Mizuguchi, Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine- and choline-deficient diet. Dig Dis Sci, 2011. 56(4): p. 1065-74.

8.            Theuer, R.C., W.H. Martin, T.J. Friday, B.L. Zoumas, and H.P. Sarett, Regression of alcoholic fatty liver in the rat by medium-chain triglycerides. Am J Clin Nutr, 1972. 25(2): p. 175-81.

9.            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.



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