Creatine supplementation protects against diet-induced non-alcoholic fatty liver but exacerbates alcoholic fatty liver.

AIMS: This work investigated the effects of creatine supplementation on different pathways related to the pathogenesis of non-alcoholic fatty liver disease and alcoholic liver disease. MAIN METHODS: To induce alcoholic liver disease, male Swiss mice were divided into three groups: control, ethanol and ethanol supplemented with creatine. To induce non-alcoholic fatty liver disease, mice were divided into three groups: control, high-fat diet and high-fat diet supplemented with creatine. Each group consisted of eight animals. In both cases, creatine monohydrate was added to the diets (1 %; weight/vol). KEY FINDINGS: Creatine supplementation prevented high-fat diet-induced non-alcoholic fatty liver disease progression, demonstrated by attenuated liver fat accumulation and liver damage. On the other hand, when combined with ethanol, creatine supplementation up-regulated key genes related to ethanol metabolism, oxidative stress, inflammation and lipid synthesis, and exacerbated ethanol-induced liver steatosis and damage, demonstrated by increased liver fat accumulation and histopathological score, as well as elevated oxidative damage markers and inflammatory mediators. SIGNIFICANCE: Our results clearly demonstrated creatine supplementation exerts different outcomes in relation to non-alcoholic fatty liver disease and alcoholic liver disease, namely it protects against high-fat diet-induced non-alcoholic fatty liver disease but exacerbates ethanol-induced alcoholic liver disease. The exacerbating effects of the creatine and ethanol combination appear to be related to oxidative stress and inflammation-mediated up-regulation of ethanol metabolism.

Protective effects of E Se tea extracts against alcoholic fatty liver disease induced by high fat/alcohol diet: In vivo biological evaluation and molecular docking study.

BACKGROUND: With the development of economy and increased workload, chronic a high-fat/alcohol diet intake may lead to alcoholic fatty liver disease (AFLD), which is considered as a crucial health problem worldwide. E Se tea is produced of the leaves and leaf buds of Malus toringoides (Rehd.) Hughes in Tibet and has human health benefits with anti-hyperglycemia, hypertension, and hyperlipidemia effects. PURPOSE: The objective of this work was to investigate the protective effect of aqueous-ethanol and hot-water extracts of E Se tea against chronic high-fat/alcohol diet induced AFLD rats. METHODS: Firstly, to determine the chemical profiling of E Se tea extracts, UHPLC-ESI-HRMS analysis was conducted. Secondly, Sprague-Dawley male rats were used to establish the AFLD animal model by feeding with high-fat/alcohol diet. The animals were treated with E Se tea extracts for 12 weeks. Serum parameters were determined, histologic sections were prepared, and activities of enzymes related to inflammatory response and lipid metabolism imbalance were analyzed. The underlying mechanisms of E Se tea extracts alleviating AFLD were analyzed by immunofluorescence staining and Western blotting analysis. Lastly, key targets of 11-MT against AFLD were verified through molecular docking. RESULTS: In this study, seven main compounds were confirmed or tentatively identified in E Se tea extracts by UHPLC-ESI-HRMS. The results revealed that both the extracts could reverse histopathological steatotic alternation of the liver and reduced the activity of liver damage markers (ALT, AST). E Se tea extracts mitigated oxidative stress by inhibiting CYP2E1 protein and lipid peroxidation parameters (MDA), but enhancing the endogenous antioxidants (CAT, GSH, SOD). Moreover, E Se tea extracts ameliorated inflammation by restraining the activation of NF-κB, consequently releasing the expression of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, COX-2 and iNOS). Subsequently, E Se tea extracts reduced hepatocyte apoptosis by increasing capase-9, caspase-3 and Bax protein expression but decreasing Bcl-2 protein expression. Furthermore, E Se tea extracts improved metabolism imbalance by stimulating AMPK/SREBP1/FAS and PPAR-α/CPT1 signaling pathway by regulating lipid metabolism parameters (TC, TG, HDL-C, LHD-C). Furthermore, molecular docking results indicated that 7 chemical constituents of E Se tea extracts had strong docking affinity with 4 key target proteins (AMPK, PPAR-α, NF-кB and Caspase-9). CONCLUSION: E Se tea ameliorated AFLD through ameliorating inflammatory response, apoptosis, and lipid metabolism imbalance.

Stearic acid prevent alcohol-induced liver damage by regulating the gut microbiota.

The pathological characteristics of alcohol-associated liver damage (ALD) mainly include liver lipid accumulation, which subsequently leads to alcohol-associated steatohepatitis, fibrosis and cirrhosis. Dietary factors such as alcohol and fat may contribute to the development of ALD. A chronic alcohol-fed mouse model was used to investigate the effect of fatty acids in Jinhua ham on ALD. The fatty acids in Jinhua ham could prevent the occurrence of ALD from chronic alcohol consumption. In addition, the fatty acids in Jinhua ham with liver protective activity were long-chain saturated fatty acids (LCSFAs), including palmitic acid and stearic acid. In contrast, long-chain polyunsaturated fatty acids aggravated the pathogenesis of ALD. Furthermore, the mechanism underlying the prevention of ALD by fatty acids in Jinhua ham was ascribed to increasing relative abundances of Akkermansia muciniphila and Lactobacillus in the gut, which were beneficial to regulating intestinal homeostasis, ameliorating intestinal barrier dysfunction and reducing alcohol-associated hepatitis and oxidative stress damage. This study demonstrated that dietary supplementation with saturated fatty acids could prevent or mitigate ALD by regulating the gut microbiota (GM) and improving the intestinal barrier, while provided a more affordable dietary intervention strategy for the prevention of ALD.

Fermented Curcuma longa L. Prevents Alcoholic Fatty Liver Disease in Mice by Regulating CYP2E1, SREBP-1c, and PPAR-α.

We examined the efficacy of fermented Curcuma longa L. (FT) on the development of alcoholic fatty liver in mice and investigated the underlying mechanism. The protective potential of FT against ethanol-induced fatty liver was determined using C57BL/6 male mice allocated into four groups (8 mice/group). Control groups received either distilled water or 5 g/kg body weight (b.w.) per day ethanol for 8 days. Treatment groups were administered either 300 mg/kg b.w. per day of milk thistle or FT before receiving ethanol. FT contained a higher amount of caffeic acid and tetrahydrocurcumin than C. longa. FT pretreatment significantly suppressed the elevated hepatic lipid droplets associated with ethanol ingestion. In comparison with ethanol-treated control, FT pretreated mice showed inhibited cytochrome P4502E1 (CYP2E1), sterol regulatory element-binding protein-1 (SREBP-1c), and acetyl-CoA carboxylase production but elevated AMP-activated protein kinase, peroxisome proliferator-activated receptor-alpha (PPAR-α), and carnitine palmitoyltransferase 1 (CPT-1) levels. Taken together, FT is a promising hepatoprotectant for preventing of alcoholic fatty liver through modulating fatty acid synthesis and oxidation.

Red Quinoa Bran Extract Prevented Alcoholic Fatty Liver Disease via Increasing Antioxidative System and Repressing Fatty Acid Synthesis Factors in Mice Fed Alcohol Liquid Diet.

Alcohol is metabolized in liver. Chronic alcohol abuse results in alcohol-induced fatty liver and liver injury. Red quinoa (Chenopodium formosanum) was a traditional staple food for Taiwanese aborigines. Red quinoa bran (RQB) included strong anti-oxidative and anti-inflammatory polyphenolic compounds, but it was usually regarded as the agricultural waste. Therefore, this study is to investigate the effect of water and ethanol extraction products of RQB on the prevention of liquid alcoholic diet-induced acute liver injury in mice. The mice were given whole grain powder of red quinoa (RQ-P), RQB ethanol extract (RQB-E), RQB water extract (RQB-W), and rutin orally for 6 weeks, respectively. The results indicated that RQB-E, RQB-W, and rutin decreased alcoholic diet-induced activities of aspartate aminotransferase and alanine aminotransferase, and the levels of serum triglyceride, total cholesterol, and hepatic triglyceride. Hematoxylin and eosin staining of liver tissues showed that RQB-E and RQB-W reduced lipid droplet accumulation and liver injury. However, ethanol extraction process can gain high rutin and antioxidative agents contents from red quinoa, that showed strong effects in preventing alcoholic fatty liver disease and liver injury via increasing superoxide dismutase/catalase antioxidative system and repressing the expressions of fatty acid synthesis enzyme acetyl-CoA carboxylase.

Puerariae Lobatae radix flavonoids and puerarin alleviate alcoholic liver injury in zebrafish by regulating alcohol and lipid metabolism.

Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1ß, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.

Dihydromyricetin Protects the Liver via Changes in Lipid Metabolism and Enhanced Ethanol Metabolism.

BACKGROUND: Excess alcohol (ethanol, EtOH) consumption is a significant cause of chronic liver disease, accounting for nearly half of the cirrhosis-associated deaths in the United States. EtOH-induced liver toxicity is linked to EtOH metabolism and its associated increase in proinflammatory cytokines, oxidative stress, and the subsequent activation of Kupffer cells. Dihydromyricetin (DHM), a bioflavonoid isolated from Hovenia dulcis, can reduce EtOH intoxication and potentially protect against chemical-induced liver injuries. But there remains a paucity of information regarding the effects of DHM on EtOH metabolism and liver protection. As such, the current study tests the hypothesis that DHM supplementation enhances EtOH metabolism and reduces EtOH-mediated lipid dysregulation, thus promoting hepatocellular health. METHODS: The hepatoprotective effect of DHM (5 and 10 mg/kg; intraperitoneal injection) was evaluated using male C57BL/6J mice and a forced drinking ad libitum EtOH feeding model and HepG2/VL-17A hepatoblastoma cell models. EtOH-mediated lipid accumulation and DHM effects against lipid deposits were determined via H&E stains, triglyceride measurements, and intracellular lipid dyes. Protein expression of phosphorylated/total proteins and serum and hepatic cytokines was determined via Western blot and protein array. Total NAD+ /NADH Assay of liver homogenates was used to detect NAD + levels. RESULTS: DHM reduced liver steatosis, liver triglycerides, and liver injury markers in mice chronically fed EtOH. DHM treatment resulted in increased activation of AMPK and downstream targets, carnitine palmitoyltransferase (CPT)-1a, and acetyl CoA carboxylase (ACC)-1. DHM induced expression of EtOH-metabolizing enzymes and reduced EtOH and acetaldehyde concentrations, effects that may be partly explained by changes in NAD+ . Furthermore, DHM reduced the expression of proinflammatory cytokines and chemokines in sera and cell models. CONCLUSION: In total, these findings support the utility of DHM as a dietary supplement to reduce EtOH-induced liver injury via changes in lipid metabolism, enhancement of EtOH metabolism, and suppressing inflammation responses to promote liver health.

Proteomic Investigations of Transcription Factors Critical in Geniposide-Mediated Suppression of Alcoholic Steatosis and in Overdose-Induced Hepatotoxicity on Liver in Rats.

Alcoholic steatosis is one of the most prevalent forms of liver disease, and appropriate insight and application of anti-steatosis drugs must be considered. Geniposide, the major active constituent of the Gardenia jasminoides (Ellis) fruit, has been commonly used as a traditional herbal medicine for the treatment of liver diseases. However, its hepatoprotective effect on alcoholic steatosis has not been reported. Moreover, geniposide overdose-induced hepatotoxicity was demonstrated. Hence, its therapeutic effects and overdose-induced hepatotoxicity in rat models along with corresponding targets, especially the targets of transcription factors (TFs), were systematically investigated in this study by using a concatenated tandem array of consensus TF response elements. The results indicate that geniposide can attenuate alcoholic steatosis and liver injury by enhancing the transcriptional activities of peroxisome proliferator-activated receptor-α and hepatocyte nuclear factors 1α and 4α, while geniposide overdose perturbs other TFs. In addition, therapeutic doses and overdoses of geniposide have differentiated target TFs. This study is the first to provide a systematic insight into the difference of critical transcription factors between the actions of therapeutic doses and overdoses of geniposide, as well as much-needed attention to the important topic of alcoholic liver disease therapy.

Carvacrol inhibits cytochrome P450 and protects against binge alcohol-induced liver toxicity.

Alcoholism is a serious addiction that can lead to various health complications such as liver fibrosis, steatosis, and cirrhosis. Carvacrol is present in many plant-based essential oils and used as a preservative in the food industry. In this study, we have investigated the hepatoprotective role of carvacrol against ethanol-induced liver toxicity in mice. To determine the effect of carvacrol on liver injury parameters, 5 doses of 50% ethanol (10 mL/kg body weight) were orally administered every 12 h for inducing the hepatotoxicity in experimental mice. Interestingly, carvacrol pre-treatment (50 and 100 mg/kg) reversed the ethanol-induced effects on liver function, antioxidant markers, matrix metalloproteinases activities, and histological changes. Moreover, carvacrol binds to the active pocket of cytochrome P450 (Cyt P450) and inhibits its expression. Thus, our finding suggests carvacrol can be used as an adjuvant for the amelioration of alcohol-induced hepatotoxicity.

Metabonomics Study on the Hepatoprotective Effect of Panax notoginseng Leaf Saponins Using UPLC/Q-TOF-MS Analysis.

Alcohol liver disease is a major public health problem associated with lifestyle. Our recent study demonstrated that the roots of Panax notoginseng saponins (PNS) exert hepatoprotective effects against alcohol consumption. Considering that the leaves of Panax notoginseng saponins (LPNS) have similar chemical ingredients with PNS, increased attention should be given to the hepatoprotective effects of LPNS. In this study, a metabonomic approach based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS) was developed to evaluate the hepatoprotective effect of LPNS on alcoholic fatty liver and elucidate the interaction mechanisms. Results showed that the ethanol-induced metabolic perturbations were restored after treatment with LPNS. Furthermore, 12 potential biomarkers (11 upregulated and 1 downregulated) were identified by V-plot and orthogonal partial least square discriminant analysis. Changes in the levels of these metabolites indicated that glycerophospholipid and fatty acid metabolism were disturbed in alcoholic fatty liver mouse. Our findings demonstrated that the UHPLC-QTOF/MS-based metabonomic method may provide a useful means for exploring biomarkers involved in alcoholic fatty liver and elucidating the therapeutic effects of LPNS. This work also showed that the metabonomic approach is a powerful and promising tool for the evaluation of the efficacy of traditional Chinese medicine and elucidation of related mechanisms.

A combination of Pueraria lobata and Silybum marianum protects against alcoholic liver disease in mice.

BACKGROUND: Excess alcohol exposure leads to alcoholic liver disease (ALD). Pueraria lobata (PUE) and Silybum marianum (SIL) are two well-known hepatoprotective herbal remedies with various activities. The possible effect of combination of PUE and SIL on ALD has not been elucidated yet. PURPOSE: We aimed to demonstrate that the combination of PUE and SIL prevents against alcoholic liver injury in mice using a model of chronic-plus-single-binge ethanol feeding. STUDY DESIGN: Male C57BL/6 mice were randomly divided into five groups (n = 8-10), namely the control group (CON), ethanol-induced liver injury group (ETH), 150 mg/kg PUE treated group (PUE), 60 mg/kg SIL treated group (SIL), 210 mg/kg PUE+SIL treatment group (PUE+SIL). Except control group, all animals were fed a modified Lieber-DeCarli ethanol liquid diet for 10 days. While, control group received Lieber-DeCarli control diet containing isocaloric maltose dextrin substituted for ethanol. On day 11, the mice orally received a single dose of 31.5% (v/v) ethanol (5 g/kg BW) or an isocaloric maltose solution. RESULTS: Ethanol exposure caused liver injury, as demonstrated by remarkably increased plasma parameters, histopathological changes, the increased lipid accumulation, oxidative stress and inflammation in liver. These alterations were ameliorated by the treatments of PUE, SIL and PUE+SIL. While, the PUE+SIL treatment showed the most effective protection, which was associated with reducing alcohol-induced hepatic steatosis via upregulating LKB1/AMPK/ACC signaling, and inhibiting hepatic inflammation via LPS-triggered TLR4-mediated NF-κB signaling pathway. Our results also indicated that the hepatoprotective effects of SIL+PUE might mainly attribute to the protection of SIL and PUE alone in alcohol-induced hepatic steatosis and hepatic inflammation, respectively. CONCLUSION: These findings also suggest that the combination of PUE and SIL has a potential to be developed as a functional food for the management of ALD.

Gut Microbiota's Relationship with Liver Disease and Role in Hepatoprotection by Dietary Natural Products and Probiotics.

A variety of dietary natural products have shown hepatoprotective effects. Increasing evidence has also demonstrated that gut microorganisms play an important role in the hepatoprotection contributed by natural products. Gut dysbiosis could increase permeability of the gut barrier, resulting in translocated bacteria and leaked gut-derived products, which can reach the liver through the portal vein and might lead to increased oxidative stress and inflammation, thereby threatening liver health. Targeting gut microbiota modulation represents a promising strategy for hepatoprotection. Many natural products could protect the liver from various injuries or mitigate hepatic disorders by reverting gut dysbiosis, improving intestinal permeability, altering the primary bile acid, and inhibiting hepatic fatty acid accumulation. The mechanisms underlying their beneficial effects also include reducing oxidative stress, suppressing inflammation, attenuating fibrosis, and decreasing apoptosis. This review discusses the hepatoprotective effects of dietary natural products via modulating the gut microbiota, mainly focusing on the mechanisms of action.

Maternal Consumption of Low-Isoflavone Soy Protein Isolate Confers the Increased Predisposition to Alcoholic Liver Injury in Adult Rat Offspring.

Offspring of female rats fed either a casein (CAS) diet or a low-isoflavone soy protein isolate (SPI) diet were compared in an animal model of chronic ethanol consumption to investigate whether maternal diet regulates the adaptive responses of offspring to postnatal ethanol exposure and potentially affects the development of liver disease in later life. Female rats were fed either a CAS or an SPI diet before mating, and during pregnancy and lactation. Male offspring from the same litter were pair-fed either a control or ethanol diet for six weeks (CAS/CON, CAS/EtOH, SPI/CON, and SPI/EtOH groups). Serum aminotransferase activities and hepatic inflammatory indicators were higher in the SPI/EtOH group than in the CAS/EtOH group. Ethanol consumption increased serum homocysteine levels, hepatic S-adenosylmethionine:S-adenosylhomocysteine ratio, and hepatic endoplasmic reticulum stress only in offspring of SPI-fed female rats. Total and high-density lipoprotein (HDL) cholesterol levels and mRNA levels of hepatic genes involved in HDL cholesterol assembly were reduced in the SPI group in response to ethanol consumption. In conclusion, offspring of SPI-fed female rats were more susceptible to the later development of alcoholic liver disease than offspring of CAS-fed female rats. Furthermore, maternal SPI consumption altered one-carbon metabolism and cholesterol metabolism of offspring fed an ethanol diet.

Supplementation of all trans retinoic acid ameliorates ethanol-induced endoplasmic reticulum stress.

CONTEXT: Molecular pathogenesis of chronic alcoholism is linked to increased endoplasmic reticulum stress. Ethanol is a competitive inhibitor of vitamin A metabolism and vitamin A supplementation aggravates existing liver problems. Hence, we probed into the impact of supplementation of all trans retinoic acid (ATRA), the active metabolite of vitamin A on ethanol-induced endoplasmic reticulcum stress. METHODS: Male Sprague-Dawley rats were divided into four groups - I: Control; II: Ethanol; III: ATRA; IV: ATRA + Ethanol. After 90 days the animals were sacrificed to study markers of lipid peroxidation in hepatic microsomal fraction and expression of ER stress proteins and apoptosis in liver. RESULTS AND CONCLUSION: Ethanol caused hepatic hyperlipidemia, enhanced microsomal lipid peroxidation, upregulated expression of unfolded protein response associated proteins and that of apoptosis. Ethanol also led to downregulation of retinoid receptors. ATRA supplementation reversed all these alterations indicating the decrease in ethanol-induced endoplasmic reticulum stress.

Hepatoprotective Effect of Albumin Peptides from Corn Germ Meal on Chronic Alcohol-Induced Liver Injury in Mice.

Despite the fact that chronic and excessive alcohol consumption is a risk factor for many chronic diseases, such as a fatty liver disease, the addictive power of alcohol is strong worldwide. Corn germ meal albumin peptides (CGMAPs), by-products in corn germ oil industry have often been considered as wastes disposal in food processing. The aim of this study was to investigate the hepatoprotective effect of CGMAPs on chronic alcohol-induced liver injury in a mouse model. The corn germ meal-derived albumin was enzymatically hydrolysed, and the albumin peptides fractions (APFs) with Mw < 1 kDa (APF4) was collected. APF4 was an oligopeptide with a high Fischer's ratio (F > 3), rich in glutamic, alanine, leucine and proline. The hydrophobic Q value was 5.1, indicating the property of high enrichment in hydrophobic amino acids. Alcohol administration significantly increased the activities and levels of hepatic aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), and triglycerides (TG) (P < 0.01), and significantly reduced the activities of superoxide dismutase (SOD) and catalase (CAT) and levels of glutathione (GSH) (P < 0.01) compared to the control group. Those changes were significantly reversed by the application of APF4 at 800 mg/kg bw. Thus, APF4 of CGMAPs had a significant protective effect against chronic alcohol-induced liver injury through enhancement of in vivo antioxidant ability as a possible mechanism of action, which therefore suggested that APF4 might be useful as natural sources to protect liver from alcoholic damage. PRACTICAL APPLICATION: Corn germ meal albumin peptides (CGMAPs) of Mw < 1 kDa, a kind of bioactive peptides which could effectively improve alcohol metabolism and protect against the hepatic damage induced by alcohol, might be useful as natural sources to protect liver from alcoholic damage.

Omega-3 polyunsaturated fatty acids ameliorate ethanol-induced adipose hyperlipolysis: A mechanism for hepatoprotective effect against alcoholic liver disease.

Alcohol exposure induces adipose hyperlipolysis and causes excess fatty acid influx into the liver, leading to alcoholic steatosis. The impacts of omega-3 polyunsaturated fatty acids (n-3 PUFA) on ethanol-induced fatty liver are well documented. However, the role of n-3 PUFA in ethanol-induced adipose lipolysis has not been sufficiently addressed. In this study, the fat-1 transgenic mice that synthesizes endogenous n-3 from n-6 PUFA and their wild type littermates with an exogenous n-3 PUFA enriched diet were subjected to a chronic ethanol feeding plus a single binge as model to induce liver injury with adipose lipolysis. Additionally, the differentiated adipocytes from 3T3-L1 cells were treated with docosahexaenoic acid or eicosapentaenoic acid for mechanism studies. Our results demonstrated that endogenous and exogenous n-3 PUFA enrichment ameliorates ethanol-stimulated adipose lipolysis by increasing PDE3B activity and reducing cAMP accumulation in adipocyte, which was associated with activation of GPR120 and regulation of Ca2+/CaMKKß/AMPK signaling, resultantly blocking fatty acid trafficking from adipose tissue to the liver, which contributing to ameliorating ethanol-induced adipose dysfunction and liver injury. Our findings identify that endogenous and exogenous n-3 PUFA enrichment ameliorated alcoholic liver injury by activation of GPR120 to suppress ethanol-stimulated adipose lipolysis, which provides the new insight to the hepatoprotective effect of n-3 PUFA against alcoholic liver disease.

Investigation of the Hepatoprotective Effect of Prunus mume Sieb. et Zucc Extract in a Mouse Model of Alcoholic Liver Injury Through High-Resolution Metabolomics.

This study aimed to identify the changes in the metabolomics profile of liver damage caused by alcohol consumption and verify the beneficial effect of Prunus mume Sieb. et Zucc extract (PME) in protection of alcohol-induced injury by attenuating the level of identified metabolites. Mice were treated with PME and saline or untreated once daily for 5 days, followed by alcohol injection. The plasma samples were analyzed using liquid chromatography-mass spectrometry-based high-resolution metabolomics followed by a multivariate statistical analysis using MetaboAnalyst 3.0 to obtain significantly expressed metabolites, using a false discovery rate threshold of q = 0.05. Metabolites were annotated using Metlin database and mapped through Kyoto Encyclopedia of Genes and Genomes (KEGG). Among 4999 total features, 101 features were significant among alcohol- and PME-treated mice groups. All the samples cluster showed a clear separation in the heat map, and the scores plot of orthogonal partial least squares-discriminant analysis (OPLS-DA) model discriminated the three groups. Phosphatidylcholine, Saikosaponin BK1, Ganoderiol I, and N-2-[4-(3,3-dimethylallyloxy) phenyl] ethylcinnamide were among the significant compounds with a low intensity in alcohol group compared to PME group, suggesting that these compounds have a relation in the development of PME's protective effect. The study confirms the hepatoprotective, antioxidant, and anti-inflammatory effects of PME against alcohol-induced liver steatosis, inflammation, and apoptosis.

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice.

BACKGROUND AND AIMS: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis.

BACKGROUND: Alcohol-induced reduction in the hepatocellular S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio impairs the activities of many SAM-dependent methyltransferases. These impairments ultimately lead to the generation of several hallmark features of alcoholic liver injury including steatosis. Guanidinoacetate methyltransferase (GAMT) is an important enzyme that catalyzes the final reaction in the creatine biosynthetic process. The liver is a major site for creatine synthesis which places a substantial methylation burden on this organ as GAMT-mediated reactions consume as much as 40% of all the SAM-derived methyl groups. We hypothesized that dietary creatine supplementation could potentially spare SAM, preserve the hepatocellular SAM:SAH ratio, and thereby prevent the development of alcoholic steatosis and other consequences of impaired methylation reactions. METHODS: For these studies, male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol (EtOH) diet with or without 1% creatine supplementation. At the end of 4 to 5 weeks of feeding, relevant biochemical and histological analyses were performed. RESULTS: We observed that creatine supplementation neither prevented alcoholic steatosis nor attenuated the alcohol-induced impairments in proteasome activity. The lower hepatocellular SAM:SAH ratio seen in the EtOH-fed rats was also not normalized or SAM levels spared when these rats were fed the creatine-supplemented EtOH diet. However, a >10-fold increased level of creatine was observed in the liver, serum, and hearts of rats fed the creatine-supplemented diets. CONCLUSIONS: Overall, dietary creatine supplementation did not prevent alcoholic liver injury despite its known efficacy in preventing high-fat-diet-induced steatosis. Betaine, a promethylating agent that maintains the hepatocellular SAM:SAH, still remains our best option for treating alcoholic steatosis.

Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response.

It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF)-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH) level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol.