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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