Medical Hypotheses 85 (2015) 148–152

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Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease? – A mechanistic hypothesis Ivanildo Coutinho de Medeiros a,⇑, Josivan Gomes de Lima b a b

Universidade Federal do Rio Grande do Norte, Departamento de Medicina Clínica, Divisão de Gastroenterologia, Av. Nilo Peçanha, 620 - CEP 59012-300 Natal/RN, Brazil Universidade Federal do Rio Grande do Norte, Departamento de Medicina Clínica, Divisão de Endocrinologia, Av. Nilo Peçanha, 620 - CEP 59012-300 Natal/RN, Brazil

a r t i c l e

i n f o

Article history: Received 28 November 2014 Accepted 21 April 2015

a b s t r a c t Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are so similar that only a detailed history of alcohol intake can distinguish one from the other. Because subjects with NAFLD produce significantly more endogenous ethanol (EE) than controls, some researchers suspected that these similarities are not merely coincidental. For this reason, it was attempted to show that NAFLD is actually an endogenous alcoholic fatty liver disease (EAFLD). However, negligible blood-alcohol concentration (BAC) and the inability of gut microbiota to produce hepatotoxic concentrations of EE rejected this hypothesis. To clarify these conflicting results, we provide a mechanistic framework explaining how NAFLD may be an EAFLD. First of all, the key finding is that ethanol is a prodrug, enabling the idea that AFLD may develop with negligible/absent BAC. Second, extrahepatic acetaldehyde (ACD) alone recapitulates AFLD and is about 330-fold more hepatotoxic than that generated inside the liver. Third, gut microbiota can even produce much larger amounts of EE than those currently considered cirrhotogenic for man. Fourth, an extensive gut-liver axis first-pass metabolism of ethanol prevents the development of significant BAC in NAFLD. Fifth, all genes involved in EE metabolism are upregulated in the livers of patients with nonalcoholic steatohepatitis (NASH). Last, overexpression of the gene encoding alcohol dehydrogenase (ADH) 4 implicates liver exposure to high concentrations of EE. In conclusion, this work provides mechanistic explanation supporting the assumption that NAFLD may indeed be an EAFLD. If validated by further testing, the hypothesis may help develop novel therapeutic and preventive strategies against this ubiquitous condition. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction Nonalcoholic fatty liver disease (NAFLD) is a huge public health concern worldwide. Overall, it has been estimated that NAFLD affects about 20% of the world population [1]. The disease has two very distinct clinical presentations: the primary form or diet-induced NAFLD and secondary forms, which occur in patients with various apparently unrelated diseases [2]. It is known that NAFLD and alcoholic fatty liver disease (AFLD) share similar histopathological and molecular biological features, as well as identical polymorphism in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) [3–5]. Besides, the finding that patients with nonalcoholic steatohepatitis (NASH) produce more endogenous ethanol (EE) than control subjects further strengthens this connection [6–9]. As a result, it is suspected that ⇑ Corresponding author at: Rua Hist. Tobias Monteiro, 1863 – Lagoa Nova, NatalRN CEP 59056-120, Brazil. Tel.: +55 84 9984 3994; fax: +55 84 3342 9703. E-mail addresses: [email protected], [email protected] (I.C. de Medeiros). http://dx.doi.org/10.1016/j.mehy.2015.04.021 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.

NAFLD and AFLD have a common mechanistic background [3]. Thus, some researchers attempted to demonstrate that NAFLD is indeed an endogenous alcoholic fatty liver disease (EAFLD) [10– 12]. However, insignificant blood-alcohol concentration (BAC) and the inability of gut microbiota to produce hepatotoxic concentrations of EE rejected this hypothesis [10,11]. To reconcile these conflicting results, we developed a mechanistic hypothesis to explain how NAFLD may be an EAFLD.

The hypothesis (Fig. 1) Ethanol is a prodrug It is well known that inhibitors of oxidative and nonoxidative ethanol metabolism can counteract its harmful effects. This implicates that it is a prodrug and that it needs to be converted to ACD by alcohol dehydrogenase (ADH) or metabolized non-enzymatically to fatty acid ethyl esters (FAEE) to elicit tissue injury [13– 19]. This paves the way to understanding how EAFLD can occur

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at low BAC. In this context, the experimental induction of AFLD by ACD alone is consistent with this observation [20–22].

Gut microbiota produces ethanol and acetaldehyde Gut microbiota of healthy abstaining subjects produces trace amounts of EE from unabsorbed dietary sugars (Fig. 1) [23,24]. Then, EE is converted in the liver to ACD, which in turn is oxidized to non-toxic acetate [25]. The finding that dietary addition of baker’s yeast provokes a 4-fold increase in gastric EE concentration supports this notion. Additionally, pharmacological inhibition of ADH provokes a 130-fold rise in EE content in hepatic venous blood of rats [25]. Conversely, in small intestinal bacterial overgrowth (SIBO)-related conditions, body concentrations of EE are significantly higher than in control subjects [7,26–28]. In such instances, gut concentrations of EE may be proportionally higher than those found after moderate drinking [11,12,28,29].

Acetaldehyde by itself is a causative agent of alcoholic liver disease Unsurprisingly, ACD alone can produce liver damage ranging from fatty infiltration to inflammation and fibrosis [20,21]. However, the amount of extrahepatic ACD required to cause liver injury is quite surprising. For example, ACD at 500 mg/kg/day provoked AFLD in rats in an 11-week short-term experiment [20]. Interestingly, this dose of ACD is extremely low. It corresponds to only around 3% of ACD derived from hepatic oxidation of 15 g/ kg/day of ethanol according to an animal model of AFLD [20]. Even more interesting, a smaller dose of ACD (60 mg/kg/day) has also caused rat liver fibrosis in a 6-month long-term study [21]. Accordingly, extrahepatic ACD (generated outside the liver) is about 30–330-fold more hepatotoxic than that originated inside the liver. If these calculations are correct, they may profoundly change our understanding of the pathogenesis of NAFLD. Further details on this issue will be described in the following section.

Hepatic genes of alcohol-metabolizing enzymes are overexpressed A pioneering study revealed that hepatic genes involved in ethanol metabolism are up-regulated in NASH livers [9]. Particularly important was the finding of increased expression of the gene encoding ADH4 isoenzyme [9,30]. This implies not only liver exposure to EE, but, and more importantly, exposition to high concentrations of this compound [30,31].

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Estimating EE production and first-pass metabolism of ethanol To calculate the EE production we use a validated physiologically-based pharmacokinetic model of body alcohol metabolism [32] and demographic data taken from a published study [27]. According to this study, patients presented an average BAC of 7.14 mg/dL 12-h after an overnight fast [27]. We assume that the mean patient height was 1.74 m (68.8976 inches) and Watson’s equation was used for total-body water calculation (TBW) [32]. Equation 1: calculating TBW. RVd = 2.44 (0.09516  age) + [0.1074  (height in inches)  2.54)] + [0.3362  weight in pounds/2.2045)]. RVd is TBW or volume of distribution in which alcohol will be dispersed according to the age, weight, height, and patient gender [32]. Inserting the figures from Menezes et al.’s study [27] (age, 48 years, BMI, 35 kg/m2, and body weight, 107.20 kg [236.3355 lb]), we obtain: RVd = [2.44 (0.09516  48)] + [0.1074  (68.8976  2.54)] + [(0.3362  236.3355)/2.2045] = 52.70 liters. Then, we use the modified Widmark’s equation. Equation 2: calculating total alcohol consumed (TAC). TAC = RVd  (BACobj + b1n  t)/B‘H2O. Here, TAC means total alcohol endogenously produced; BACobj is the objective blood-alcohol concentration result; b1n is the range of the ethanol elimination rate (10–20 mg/dL/h for healthy individuals and 20–30 mg/dL/h for heavy drinkers); t is the time from the start of drinking (here meaning the start of carbohydrate intake) until the time of the BAC test, and B‘H2O is the constant (80.65) approximate percentage of water in blood. It follows that TAC = 52.70  (7.14 + 20  12)/80.65 = 161.49 g of ethanol [32]. This means each patient produces 161.49 g of EE after a12-h overnight fast. Hence, by extrapolation, the daily production of EE should reach 484 g after eating three equicaloric meals (3  161 g = 484 g). Once the patients’ BAC is consistently low, one concludes that EE has undergone extensive conversion to ACD in the gut-liver axis. The first-pass metabolism of EE in the gut-liver axis can also be accurately calculated. For this, we need initially to calculate the alcohol burden in the circulation utilizing some data we already described. Equation 3: calculating circulation alcohol burden (CAB). CAB = (BACobj  RVd)/80.65. Inserting the data into the equation, one obtains CAB = (7.14  52.70)/80.65 = 4.60 g of ethanol. First-pass metabolism of ethanol can be estimated subtracting circulating alcohol burden (4.60 g) from total alcohol produced (161.49 g). We obtain the amount of EE metabolized (156.80 g) [32]. This is consistent with the finding that blind-loop contents of a 0.3 kg rat oxidizes ethanol at a rate of 123 mg/h) [11]. If these

Fig. 1. The hypothesis NAFLD as an EAFLD – (1) Gut microbiota produces endogenous ethanol (EE) mostly from unabsorbed dietary carbohydrates; (2) EE is a prodrug and (3) originates extrahepatic (intraluminal) and intrahepatic acetaldehyde (ACD) toxic to liver; (4) genes of alcohol-metabolizing liver enzymes (ADH4, catalase, cytochrome P450 2E1 and ALDH (aldehyde dehydrogenase) are over-expressed in liver, increasing first-pass metabolism of ethanol and (5) keeping low systemic blood alcohol concentration.

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data could be extrapolated to a SIBO patient weighing 107.20 kg, EE first-pass metabolism should reach about 43.90 g/h.

Discussion The focus of this study was to mechanistically explain how NAFLD may be an EAFLD. To achieve this target, we refer to the concept that ethanol is a prodrug [13,14,33,34]. According to this, ethanol exerts its harmful effects through its oxidative and nonoxidative metabolites [13,19,33–35]. The finding that ACD and FAEEs themselves elicit tissue injury is consistent with this view [19–22]. Importantly, these observations support the idea that NAFLD can be an EAFLD with negligible BACs. Our calculations showed that EE production may exceed 480 g per day in patients with NAFLD. The rationale for this huge production of EE along with insignificant BACs is not completely clear. The length and mucosal surface area of a normal human’s small bowel are, respectively, 5-fold and 100-fold greater than those of the large intestine [36,37]. We postulate that the advent of SIBO functionally converts the small bowel into a huge colonic bioreactor for continuous production of EE. In such a scenario, the area for EE production should be quintuple, leading to formation of hepatotoxic quantities of EE. Additionally, in the relative aerobic environment of the small bowel the conversion of ethanol into ACD is about twice higher than in colonic anaerobiosis. This process is dose-dependent and does not achieve saturation at up to 920 mg/dL of ethanol [11]. This is in line with the observations that (i) SIBO and gut hyperpermeability are closely associated with the progression from simple steatosis to NASH [6,38–42], (ii) SIBO eradication with oral antibiotics prevents the development of both NAFLD and AFLD [43–47], (iii) germ-free mice are resistant to both diet-induced obesity and NAFLD [48,49], (iv) rats with experimentally-induced SIBO produce significantly more EE than controls, and (v) intragastric administration of sucrose in these animals elicits a 3fold increase in portal concentrations of ACD with only modest elevation of systemic BAC [11]. Interestingly, livers of rodents with experimental blind-loops were histologically normal despite production of hepatotoxic quantities of EE. This occurred despite a 3- and 10-fold increase in portal concentrations of ACD, respectively, after intragastric administration of sucrose and ethanol [11]. Most likely, the reason for this unexpected finding lies in the short-term (4-wk) duration of the study. It is known that Sprague-Dawley rats with experimental blind-loops only develop steatohepatitis and fibrosis 12– 14 weeks following the study onset [50]. Thus, if the study duration had been longer, certainly the researchers should have demonstrated for the first time a complete animal model of EAFLD. Hence, one concludes that these studies are not mutually exclusive; rather, they complement each other and provide a comprehensive rat model of EAFLD. The induction of EAFLD with cirrhotogenic quantities of EE along with negligible BACs indicates that it undergoes extensive first-pass metabolism in the gut-liver axis. This observation reconciles the high production of EE with the low BAC found in NAFLD individuals. The finding that breath ACD significantly differentiates children with NAFLD from healthy controls supports this view [51]. Additionally, blind-loop contents of rats dose-dependently convert ethanol to ACD, leading to substantial elevation of ACD in portal blood and modest systemic BACs [11]. Likewise, sucrose administration also provoked significant elevation of ACD in portal blood while ethanol increased only modestly [11]. An exception to this first-pass metabolic pattern is found in the auto-brewery syndrome. In it, dysbiotic microbiota can produce much higher quantities of EE than those of NASH patients. In this syndrome, the overproduction of EE overcomes the ability of gut-liver axis to

oxidize it. As a consequence, BAC can reach intoxicating peak levels of 250–350 mg/dL [52]. The gastrointestinal content of mammals is capable of converting large amounts of ethanol into ACD. This process is dose-dependent and does not reach saturation at up to 200 mM (920 mg/dL) of ethanol [11]. Consonant with this observation, the km (Michaelis constant) of bacterial ADH may be 30-fold higher than that of the liver [31,53]. The net result is that first-pass metabolism of EE in the gut-liver axis prevents the appearance of significant BAC [11]. Additionally, and importantly, extrahepatic ACD is approximately 30–330-fold more hepatotoxic than that formed inside the liver [20–22]. Hence, one infers that intraluminal metabolism of 0.18–2.0 g of EE provides ACD as cirrhotogenic as that provided by 60 g of exogenous ethanol [54]. The reasons for this marked hepatotoxicity of extrahepatic ACD are not entirely clear. It is well known that human hepatic detoxification of ACD almost totally happens within the mitochondria [55]. Very likely, the majority of ACD formed outside the liver in subjects with NAFLD escapes from the mitochondrial redox system. This is possible because of its large ability to covalently bind to proteins and cellular components [22,56]. Additionally, the reduction of the activity of liver cytosolic aldehyde dehydrogenase (ALDH) should facilitate this process [57–59]. Thus, ACD coming in direct contact with hepatocyte cytosol should form proinflammatory, immunogenic, profibrotic, and mutagenic adducts [60–63]. Importantly, nearly 8% of the world population and 15–40% of East Asians possess an inactive ALDH2, thereby allowing the build-up of large quantities of ACD after alcohol intake [31,64]. This leads to an increased risk of AFLD, hepatocellular carcinoma, pharynx, larynx and alimentary tract cancers [65][66]. We hypothesized that NAFLD patients carrying a defective ALDH2 also have a higher risk of developing the above-mentioned conditions. Although there are no studies directly linking NAFLD progression/carcinogenesis to an inactive ALDH2, there are some indirect evidences supporting this connection. In this regard, several studies have shown a significant rise in the incidence of hepatocellular carcinoma and other malignancies in NAFLD [67] as well as in its related disorders [68–70]. Recently, it has been shown that all genes involved in ethanol/ ACD metabolism are upregulated in NASH livers. Of particular interest was a 40-fold elevation in ADH4 gene expression [9,30]. The clear implication of this finding is that NASH livers consistently scavenge ethanol and ACD from portal circulation. More importantly, the upregulation of ADH4 suggests liver exposure to high concentrations of EE. Since the km for liver ADH4 is 34 mM, the enzyme works with only half of its catalytic power at alcohol concentration of 156 mg/dL [31]. Based on data presented herein, EE and ACD recapitulate the spectrum of abnormalities found in NAFLD. However, there is evidence suggesting that other endogenous factors might be involved in its pathogenesis. These include obstructive sleep apnea-induced hypoxia [71,72], by-products of both carbohydrate [73–77] and lipid metabolism [78–80], and gut-derived bacterial toxins [81,82]. Furthermore, nonoxidative metabolites of ethanol [19,83,84], methanol/formaldehyde [27,85,86], and nitrosative stressors [87,88] may also contribute to NAFLD pathogenesis. The EAFLD hypothesis can be tested in both human and animal models by well-established laboratory techniques. Survey designs should include time-course analysis of ethanol and ACD in breath and body fluids after a sugar-rich meal. The main weakness of the EAFLD hypothesis is that the most convincing evidence comes from uncontrolled studies. Notwithstanding, it provides a mechanistic framework on how NAFLD may be an EAFLD. In this context, it gives a logical explanation of how individuals may develop EAFLD despite low BAC. Additionally, it presents convincing evidence that gut microbiota can produce hepatotoxic amounts of EE. Lastly, the upregulation

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Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease? - A mechanistic hypothesis.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are so similar that only a detailed history of alcohol intake can di...
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