Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease

Engstler, Anna Janina; Aumiller, Tobias; Degen, Christian; Dürr, Marion; Weiss, Eva; Maier, Ina B.; Schattenberg, Jörn M.; Wei, Huangzhao; Sellmann, Cathrin; Bergheim, Ina

doi:10.1136/gutjnl-2014-308379

Cited by 112 publications

(103 citation statements)

References 43 publications

(48 reference statements)

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“…While short-chain fatty acids enhance intestinal absorption by activating glucagon-like peptide-2, ethanol causes triglyceride accumulation in hepatocytes via production of reactive oxygen species and initiation of liver inflammation. This might provide a second hit to the liver that had already accumulated fat [81][82][83]. Furthermore, the gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), expressed on most hepatic cells, thus contributing to acute and chronic liver diseases via immune activation, i.e.…”

Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

The potential of silymarin for the treatment of hepatic disorders

et al. 2016

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Silymarin has long been used as a hepatoprotective remedy. Chronic toxicity studies in rodents have confirmed that silymarin has a very low toxicity. These data support its history as a safe medication in hepatic diseases. In the last years, several studies expanded our understanding of the pharmacology of silymarin and its molecular mechanisms of action. These new insights may affect the handling of silymarin in clinical studies and daily practice. Additionally, scientific knowledge in hepatology is constantly evolving with, particularly, an increase in the field of non-alcoholic fatty liver disease which is considered today as the most frequent liver disease worldwide. In this review, we will describe scientific evidence for the effectiveness of silymarin in hepatic disorders. We will focus on silymarin's pharmacological effects in non-alcoholic fatty liver disease and on its well described effects in alcoholic liver disease and acute intoxications, e.g. with Amanita species. We will discuss the relevance of pharmacological data as a function of doses or concentrations required for a given effect and of concentrations achieved in the target tissues. Many pharmacological effects of silymarin can be attributed to effects downstream or upstream of its antioxidative and membrane-stabilizing properties. However, despite promising new experimental and clinical data further clinical studies are required including long-term observations and the application of hard clinical endpoints such as survival rates, to further support silymarin's use for the treatment of hepatic diseases.

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Section: Non-alcoholic Fatty Liver Diseasementioning

confidence: 99%

The potential of silymarin for the treatment of hepatic disorders

et al. 2016

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“…Also, intragastric administration of ethanol (1 g/kg) to rats with SIBO evoked a 10-fold increase in the portal concentration of acetaldehyde, whereas portal and systemic BACs reached negligible values [70]. Another study showed similar portal venous concentrations of ethanol in obese and lean mice, suggesting intraluminal FPM of ethanol in the obese group [125]. In addition, host ADH3 present in the stomach, small bowel, and liver may play a significant role in FPM of ethanol.…”

Section: Equation (3): Calculating Circulation Alcohol Burden (Cab)mentioning

confidence: 67%

“…A plausible explanation is that chronic exposure to ethanol leads to hyperinsulinemia [125], which shifts energy supply from glucose to ketone bodies [65]. In turn, high ketone bodies alongside oxidized carbohydrates and iron overload shift ethanol metabolism from low Km ADH1 (that works in the millimolar range) to high Km alcohol-metabolizing enzymes (that work in the molar range) [65,141] such as cytochrome P450 2E1 (CYP2E1), ADH4, and ADH3 [28,30,66,69,126,142,143].…”

Section: Discussionmentioning

confidence: 99%

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Medeiros¹,

Lima²

2016

Gastroenterol Hepatol Endosc

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Nonalcoholic fatty pancreas disease (NAFPD) is closely linked to nonalcoholic steatohepatitis (NASH), suggesting that the two conditions share a common etiopathogenetic background. In Addition, growing evidence indicates that endogenous ethanol (EE) plays a fundamental role in NASH pathogenesis. Accordingly, it is intuitively appealing to assume that EE plays also a causative role in NAFPD development. This connection is further supported by the finding that NAFPD shares with alcoholic fatty pancreas disease (AFPD) similar metabolic signaling pathways and histopathological features. However, low blood alcohol concentrations (BAC) along with the alleged inability of gut microbiota to produce toxic amounts of ethanol are the main obstacles to validate the idea of an endogenous alcoholic fatty pancreas disease (EAFPD). Here, we provide a mechanistic explanation reconciling the EAFPD hypothesis with these apparently conflicting observations. The key conclusions of our investigation are as follows. First, ethanol is a prodrug, implicating that under extensive presystemic metabolism BACs can be low and/ or absent. Second, oro-gastrointestinal microbiota may produce higher amounts of ethanol than those required to cause AFPD. Last, livers of NASH/NAFPD individuals overexpress all genes encoding alcohol-metabolizing enzymes identically to livers of patients with alcoholic hepatitis. Even more importantly, the upregulation of these genes is higher in the early steatotic stage of nonalcoholic fatty liver disease than in alcoholic hepatitis. This suggests a greater exposure of the liver, and by extension, of the pancreas, to ethanol in the former than in the latter condition. In summary, this paper provides a mechanistic framework for how NAFPD indeed may be an EAFPD.

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“…"oth studies demonstrated that the gut microbiota proile in pediatric N"FLD is diferent from lean healthy children, with more ethanol-producing bacteria, suggesting that endogenous alcohol production by intestinal microbiota may play a role in N"FLD pathogenesis. Engstler et al also showed that fasting ethanol levels were positively associated with measures of insulin resistance and signiicantly higher in children with N"FLD than in controls [60]. Interestingly, with further animal experiments, they demonstrated that increased blood ethanol levels in children with N"FLD may result from insulin-dependent impairments of alcohol dehydrogenase activity in liver tissue rather than from an increased endogenous ethanol synthesis [60].…”

Section: Nafld In Children Gut Microbiota and Nafld In Childrenmentioning

confidence: 97%

“…Engstler et al also showed that fasting ethanol levels were positively associated with measures of insulin resistance and signiicantly higher in children with N"FLD than in controls [60]. Interestingly, with further animal experiments, they demonstrated that increased blood ethanol levels in children with N"FLD may result from insulin-dependent impairments of alcohol dehydrogenase activity in liver tissue rather than from an increased endogenous ethanol synthesis [60]. Taken together, human studies demonstrated signiicant diferences in gut microbiota between normal subjects and patients with N"FLD.…”

Section: Nafld In Children Gut Microbiota and Nafld In Childrenmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease in Children: Role of the Gut Microbiota

Li¹,

Yang²,

Gong³

et al. 2016

The Gut Microbiome - Implications for Human Disease

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Nonalcoholic faty liver disease N"FLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries due to increasing prevalence of obesity. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of N"FLD. Convincing evidences have shown that gut microbiota alteration is associated with N"FLD pathogenesis both in patients and animal models. "acterial overgrowth and increased intestinal permeability are evident in N"FLD patients and lead to increased delivery of gut-derived bacterial products, such as lipopolysaccharide and bacterial DN", to the liver through portal vein and then activation of toll-like receptors TLRs), mainly TLR4 and TLR9, and their downstream cytokines and chemokines, resulting in hepatic inlammation. Currently, the role of gut microbiota in the pathogenesis of N"FLD is still the focus of many active clinical/basic researches. Modulation of gut microbiota with probiotics or prebiotics has been targeted as a preventive or therapeutic strategy on this pathological condition. Their beneicial efects on the N"FLD have been demonstrated in animal models and limited human studies.

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Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease

Abstract: NCT01306396.

Cited by 112 publications

References 43 publications

The potential of silymarin for the treatment of hepatic disorders

The potential of silymarin for the treatment of hepatic disorders

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

Nonalcoholic Fatty Liver Disease in Children: Role of the Gut Microbiota

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