Biochemical aspects associated with an ethanol-induced fatty liver.
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ABSTRACT:
SUBMITTER: Walker JE
PROVIDER: S-EPMC1179381 | biostudies-other | 1970 Sep
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:?Hepatic steatosis (fatty liver), an early and reversible stage of alcoholic liver disease, is characterized by triglyceride deposition in hepatocytes, which can advance to steatohepatitis, fibrosis, cirrhosis, and ultimately to hepatocellular carcinoma. In the present work, we studied altered plasma and hepatic lipid metabolome (lipidome) to understand the mechanisms and lipid pattern of early-stage alcohol-induced-fatty liver. METHODS:?Male Fischer 344 rats were fed 5% alcohol in a Lieber-DeCarli diet. Control rats were pair-fed an equivalent amount of maltose-dextrin. After 1 month, animals were killed and plasma collected. Livers were excised for morphological, immunohistochemical, and biochemical studies. The lipids from plasma and livers were extracted with methyl-tert-butyl ether and analyzed by 750/800 MHz proton nuclear magnetic resonance (¹H NMR) and phosphorus (³¹P) NMR spectroscopy on a 600 MHz spectrometer. The NMR data were then subjected to multivariate statistical analysis. RESULTS:?Hematoxylin and Eosin and Oil Red O stained liver sections showed significant fatty infiltration. Immunohistochemical analysis of liver sections from ethanol-fed rats showed no inflammation (absence of CD3 positive cells) or oxidative stress (absence of malondialdehyde reactivity or 4-hydroxynonenal positive staining). Cluster analysis and principal component analysis of ¹H NMR data of lipid extracts of both plasma and livers showed a significant difference in the lipid metabolome of ethanol-fed versus control rats. ³¹P NMR data of liver lipid extracts showed significant changes in phospholipids similar to ¹H NMR data. ¹H NMR data of plasma and liver reflected several changes, while comparison of ¹H NMR and ³¹P NMR data offered a correlation among the phospholipids. CONCLUSIONS:?Our results show that alcohol consumption alters metabolism of cholesterol, triglycerides, and phospholipids that could contribute to the development of fatty liver. These studies also indicate that fatty liver precedes oxidative stress and inflammation. The similarities observed in plasma and liver lipid profiles offer a potential methodology for detecting early-stage alcohol-induced fatty liver disease by analyzing the plasma lipid profile.
| S-EPMC3095964 | biostudies-literature
Project description:Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5'-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5'-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver.
| S-EPMC2648683 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome (MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance (IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.
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Project description:Background & aimsAlcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease.MethodsWe used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse.ResultsAnalyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls.ConclusionsIn humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
| S-EPMC4274236 | biostudies-literature
Project description:OBJECTIVE:Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. METHODS:We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). RESULTS:Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber-DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. CONCLUSIONS:Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.
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Project description:Silkworm, Bombyx mori, contains high amounts of beneficial nutrients, including amino acids, proteins, essential minerals, and omega-3 fatty acids. We have previously reported a technique for producing steamed and freeze-dried mature silkworm larval powder (SMSP), which makes it easier to digest mature silkworm. In this study, we investigated the preventive effects of SMSP on alcoholic fatty liver disease and elucidated its mechanism of action. Male Sprague-Dawley rats treated with SMSP (50 mg/kg) or normal diet (AIN-76A) were administered 25% ethanol (3 g/kg body weight) by oral gavage for 4 weeks. SMSP administration for 4 weeks significantly decreased hepatic fat accumulation in ethanol-treated rats by modulating lipogenesis and fatty acid oxidation-related molecules such as sirtuin 1, AMP-activated protein kinase, and acetyl-CoA carboxylase 1. Moreover, SMSP administration significantly diminished the levels of triglyceride in liver tissues by as much as 35%, as well as lowering the serum levels of triglyceride, gamma glutamyl transpeptidase, alanine transaminase, and aspartate aminotransferase in ethanol-treated rats. SMSP supplementation also decreased the pro-inflammatory tumor necrosis factor-alpha and interleukin 1 beta levels and cytochrome P450 2E1 generating oxidative stress. These results suggest that SMSP administration may be possible for the prevention of alcoholic liver disease.
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Project description:Male rats developed fatty liver after being fed on an ethanol-containing diet for 31 days. Liver mitochondria from these animals catalysed ATP synthesis at a slower rate when compared with mitochondria from pair-fed control rats (control mitochondria), and demonstrated lowered respiratory control with succinate as substrate, owing to a decrease in the State-3 respiratory rate. Respiration in the presence of uncoupler was comparable in mitochondria from both groups of rats. Translocation of both ATP and ADP was decreased in mitochondria from ethanol-fed rats, with ADP uptake being lowered more dramatically by ethanol feeding. Parameters influencing adenine nucleotide translocation were investigated in mitochondria from ethanol-fed rats. Experiments performed suggested that lowered adenine nucleotide translocation in these mitochondria is not the result of inhibition of the translocase by either long-chain acyl-CoA derivatives or unesterified fatty acids. Analysis of endogenous adenine nucleotides in these mitochondria revealed lowered ATP concentrations, but no decrease in total adenine nucleotides. In experiments where the endogenous ATP in these mitochondria was shifted to higher concentrations by incubation with oxidizable substrates or defatted bovine serum albumin, the rate of ADP translocation was increased, with a linear correlation being observed between endogenous ATP concentrations and the rate of ADP translocation. The depressed ATP concentration in mitochondria from ethanol-fed rats suggests that the ATP synthetase complex is replenishing endogenous ATP at a slower rate. The lowered ATPase activity of the ATP synthetase observed in submitochondrial particles from ethanol-fed animals suggests a decrease in the function of the synthetase complex. A decrease in the rate of ATP synthesis in mitochondria from ethanol-fed rats is sufficient to explain the decreased ADP translocation and State-3 respiration.
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Project description:The rapid increase in fatty liver disease (FLD) incidence is attributed largely to genetic and lifestyle factors; however, environmental toxicants are a frequently overlooked factor that can modify the effects of more common causes of FLD. Chronic exposure to inorganic arsenic (iAs) is associated with liver disease in humans and animal models, but neither the mechanism of action nor the combinatorial interaction with other disease-causing factors has been fully investigated. Here, we examined the contribution of iAs to FLD using zebrafish and tested the interaction with ethanol to cause alcoholic liver disease (ALD). We report that zebrafish exposed to iAs throughout development developed specific phenotypes beginning at 4?days post-fertilization (dpf), including the development of FLD in over 50% of larvae by 5?dpf. Comparative transcriptomic analysis of livers from larvae exposed to either iAs or ethanol revealed the oxidative stress response and the unfolded protein response (UPR) caused by endoplasmic reticulum (ER) stress as common pathways in both these models of FLD, suggesting that they target similar cellular processes. This was confirmed by our finding that arsenic is synthetically lethal with both ethanol and a well-characterized ER-stress-inducing agent (tunicamycin), suggesting that these exposures work together through UPR activation to cause iAs toxicity. Most significantly, combined exposure to sub-toxic concentrations of iAs and ethanol potentiated the expression of UPR-associated genes, cooperated to induce FLD, reduced the expression of as3mt, which encodes an arsenic-metabolizing enzyme, and significantly increased the concentration of iAs in the liver. This demonstrates that iAs exposure is sufficient to cause FLD and that low doses of iAs can potentiate the effects of ethanol to cause liver disease.This article has an associated First Person interview with the first author of the paper.
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Project description:Metabolic-associated fatty liver disease (MAFLD) starts with hepatic triglyceride accumulation (steatosis) and can progress to more severe stages such as non-alcoholic steatohepatitis (NASH) and even cirrhosis. Butyrate, and butyrate-producing bacteria, have been suggested to reduce liver steatosis directly and systemically by increasing liver β-oxidation. This study aimed to examine the influence of butyrate directly on the liver in an ex vivo induced MAFLD model. To maintain essential intercellular interactions, precision-cut liver slices (PCLSs) were used. These PCLSs were prepared from male C57BL/6J mice and cultured in varying concentrations of fructose, insulin, palmitic acid and oleic acid, to mimic metabolic syndrome. Dose-dependent triglyceride accumulation was measured after 24 and 48 h of incubation with the different medium compositions. PCLSs viability, as indicated by ATP content, was not affected by medium composition or the butyrate concentration used. Under induced steatotic conditions, butyrate did not prevent triglyceride accumulation. Moreover, it lowered the expression of genes encoding for fatty acid oxidation and only increased C4 related carnitines, which indicate butyrate oxidation. Nevertheless, butyrate lowered the fibrotic response of PCLSs, as shown by reduced gene expression of fibronectin, alpha-smooth muscle actin and osteopontin, and protein levels of type I collagen. These results suggest that in the liver, butyrate alone does not increase lipid β-oxidation directly but might aid in the prevention of MAFLD progression to NASH and cirrhosis.
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Project description:Recent evidence has demonstrated a strong interplay and multifaceted relationship between non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). CVD is the major cause of death in patients with NAFLD. NAFLD also has strong associations with diabetes and metabolic syndrome. In this comprehensive review, we aimed to overview the primary environmental and genetic risk factors of NAFLD, and CVD and also focus on the genetic aspects of these two disorders. NAFLD and CVD are both heterogeneous diseases with common genetic and molecular pathways. We have searched for the latest published articles regarding this matter and tried to provide an overview of recent insights into the genetic aspects of NAFLD and CVD. The common genetic and molecular pathways involved in NAFLD and CVD are insulin resistance (IR), subclinical inflammation, oxidative stress, and atherogenic dyslipidemia. According to an investigation, the exact associations between genomic characteristics of NAFLD and CVD and casual relationships are not fully determined. Different gene polymorphisms have been identified as the genetic components of the NAFLDCVD association. Some of the most documented ones of these gene polymorphisms are patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), adiponectin-encoding gene (ADIPOQ), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), leptin receptor (LEPR), sterol regulatory element-binding proteins (SREBP), tumor necrosis factor-alpha (TNF-α), microsomal triglyceride transfer protein (MTTP), manganese superoxide dismutase (MnSOD), membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), and mutation in DYRK1B that substitutes cysteine for arginine at position 102 in kinase-like domain. Further cohort studies with a significant sample size using advanced genomic assessments and next-generation sequencing techniques are needed to shed more light on genetic associations between NAFLD and CVD.
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