Aqueous Extract of Pepino (Solanum muriactum Ait) Leaves Ameliorate Lipid Accumulation and Oxidative Stress in Alcoholic Fatty Liver Disease

Chronic alcohol intake leads to alcoholic fatty liver. The pathogenesis of alcoholic fatty liver is related to abnormal lipid accumulation, oxidative stress, endotoxins, and cytokines. Solanum muricatum Ait. (Pepino) is a plant food commonly cultivated in the Penghu island, Taiwan. Previous studies indicated that the aqueous extract of pepino was able to attenuate diabetic progression via its antioxidative and anti-inflammatory effects. However, the mechanisms of the antioxidative and anti-inflammatory effects of pepino leaf in preventing alcoholic fatty liver remain unknown. In this study, Lieber–DeCarli ethanol-containing liquid diet was used to induce alcoholic hepatic injury in C57BL/6 mice. The hepatoprotective effects and the related mechanisms of aqueous extract of pepino leaf (AEPL) were examined. Our results showed that 2% AEPL treatments protected the liver from ethanol-induced injury through reducing serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and triglyceride (TG) (all p < 0.05). AEPL had the effects in improving the ethanol-induced lipid accumulation in mice under histological examination. Molecular data indicated that the anti-lipid accumulation effect of AEPL might be mediated via inducing hepatic levels of phospho-adenosine monophosphate-activated kinase (p-AMPK) and peroxisome proliferator-activated receptor (PPAR)-α, and reducing the expressions of hepatic lipogenic enzymes, including sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) (all p < 0.05). AEPL also decreased hepatic levels of thiobarbituric acid relative substances (TBARS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, as well as the expression of nuclear factor kappa B (NF-κB) (all p < 0.05). Moreover, AEPL significantly elevated the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and glutathione (GSH) content compared to the ethanol-fed group (all p < 0.05). Our present study suggests that AEPL could protect the liver against ethanol-induced oxidative injury and lipid accumulation.

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Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

Current Drug Targets ◽

10.2174/1389450120666191007111712 ◽

2020 ◽

Vol 21 (6) ◽

pp. 599-609 ◽

Cited By ~ 3

Author(s):

Longxin Qiu ◽

Chang Guo

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Aldose Reductase ◽

Fatty Liver Disease ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Alcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

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Arazyme Suppresses Hepatic Steatosis and Steatohepatitis in Diet-Induced Non-Alcoholic Fatty Liver Disease-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20092325 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2325 ◽

Cited By ~ 2

Author(s):

Hua Li ◽

Wonbeak Yoo ◽

Hye-Mi Park ◽

Soo-Youn Lim ◽

Dong-Ha Shin ◽

...

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Diet Group ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Arazyme, a metalloprotease from the spider Nephila clavata, exerts hepatoprotective activity in CCL4-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (n = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (Srebf1), fatty acid synthase (Fas), acetyl-CoA carboxylase 1 (Acc1), stearoyl-CoA desaturase-1 (Scd1), Scd2, glycerol-3-phosphate acyltransferase (Gpam), diacylglycerol O-acyltransferase 1 (Dgat1), and Dgat2. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor α (Tnfa), interleukin-1β (Il1b), and chemokine-ligand-2 (Ccl2) expression in the liver, and inhibited secretion of TNFα and expression of inflammatory mediators, Tnfa, Il1b, Ccl2, Ccl3, Ccl4, and Ccl5, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.

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Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice

Cell & Bioscience ◽

10.1186/s13578-020-00477-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Chian-Jiun Liou ◽

Shu-Ju Wu ◽

Szu-Chuan Shen ◽

Li-Chen Chen ◽

Ya-Ling Chen ◽

...

Keyword(s):

Oleic Acid ◽

Fatty Acid ◽

Hepatic Steatosis ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Liver Lipid ◽

Obese Mice ◽

Alcoholic Fatty Liver

Abstract Background Phloretin is isolated from apple trees and could increase lipolysis in 3T3-L1 adipocytes. Previous studies have found that phloretin could prevent obesity in mice. In this study, we investigated whether phloretin ameliorates non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice, and evaluated the regulation of lipid metabolism in hepatocytes. Methods HepG2 cells were treated with 0.5 mM oleic acid to induce lipid accumulation, and then treated with phloretin to evaluate the molecular mechanism of lipogenesis. In another experiment, male C57BL/6 mice were fed normal diet or HFD (60% fat, w/w) for 16 weeks. After the fourth week, mice were treated with or without phloretin by intraperitoneal injection for 12 weeks. Results Phloretin significantly reduced excessive lipid accumulation and decreased sterol regulatory element-binding protein 1c, blocking the expression of fatty acid synthase in oleic acid-induced HepG2 cells. Phloretin increased Sirt1, and phosphorylation of AMP activated protein kinase to suppress acetyl-CoA carboxylase expression, reducing fatty acid synthesis in hepatocytes. Phloretin also reduced body weight and fat weight compared to untreated HFD-fed mice. Phloretin also reduced liver weight and liver lipid accumulation and improved hepatocyte steatosis in obese mice. In liver tissue from obese mice, phloretin suppressed transcription factors of lipogenesis and fatty acid synthase, and increased lipolysis and fatty acid β-oxidation. Furthermore, phloretin regulated serum leptin, adiponectin, triglyceride, low-density lipoprotein, and free fatty acid levels in obese mice. Conclusions These findings suggest that phloretin improves hepatic steatosis by regulating lipogenesis and the Sirt-1/AMPK pathway in the liver.

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Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Molecules ◽

10.3390/molecules24101848 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1848 ◽

Cited By ~ 10

Author(s):

Miey Park ◽

Anshul Sharma ◽

Hae-Jeung Lee

Keyword(s):

Fatty Acid Synthase ◽

Regulatory Element ◽

Adenosine Monophosphate ◽

Immunoblot Analysis ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocytes ◽

Health Promoting ◽

Treatment Of Obesity

Delphinidin-3-O-β-glucoside (D3G) is a health-promoting anthocyanin whose anti-obesity activity has not yet been thoroughly investigated. We examined the effects of D3G on adipogenesis and lipogenesis in 3T3-L1 adipocytes and primary white adipocytes using real-time RT-PCR and immunoblot analysis. D3G significantly inhibited the accumulation of lipids in a dose-dependent manner without displaying cytotoxicity. In the 3T3-L1 adipocytes, D3G downregulated the expression of key adipogenic and lipogenic markers, which are known as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBP1), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Moreover, the relative protein expression of silent mating type information regulation 2 homolog 1 (SIRT1) and carnitine palmitoyltransferase-1 (CPT-1) were increased, alongside reduced lipid levels and the presence of several small lipid droplets. Furthermore, D3G increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which suggests that D3G may play a role in AMPK and ACC activation in adipocytes. Our data indicate that D3G attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling, and, hence, could have a therapeutic role in the management and treatment of obesity.

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Polyphenol-Rich Extracts from Toona sinensis Bark and Fruit Ameliorate Free Fatty Acid-Induced Lipogenesis through AMPK and LC3 Pathways

Journal of Clinical Medicine ◽

10.3390/jcm8101664 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1664 ◽

Cited By ~ 3

Author(s):

Yung-Chia Chen ◽

Hsin-Ju Chen ◽

Bu-Miin Huang ◽

Yu-Chi Chen ◽

Chi-Fen Chang

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Free Fatty Acid ◽

Protein Expression ◽

Lipid Accumulation ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Autophagic Flux ◽

Alcoholic Fatty Liver ◽

Toona Sinensis

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease found worldwide. The present study aimed to evaluate the mechanisms of inhibiting lipid accumulation in free fatty acid (FFA)-treated HepG2 cells caused by bark and fruit extracts of Toona sinensis (TSB and TSF). FFA induced lipid and triglyceride (TG) accumulation, which was attenuated by TSB and TSF. TSB and/or TSF promoted phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coA carboxylase and peroxisome proliferator-activated receptor alpha upregulation. Furthermore, TSB and TSF suppressed FFA-induced liver X receptor, sterol regulatory element-binding transcription protein 1, fatty acid synthase, and stearoyl-CoA desaturase 1 protein expression. Moreover, TSB and/or TSF induced phosphorylation of Unc-51 like autophagy-activating kinase and microtubule-associated protein 1A/1B-light chain 3 expressions. Therefore, TSB and TSF relieve lipid accumulation by attenuating lipogenic protein expression, activating the AMPK pathway, and upregulating the autophagic flux to enhance lipid metabolism. Moreover, TSB and TSF reduced TG contents, implying the therapeutic use of TSB and TSF in NAFLD.

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Houttuynia cordata Attenuates Lipid Accumulation via Activation of AMP-Activated Protein Kinase Signaling Pathway in HepG2 Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x14500426 ◽

2014 ◽

Vol 42 (03) ◽

pp. 651-664 ◽

Cited By ~ 8

Author(s):

Hyun Kang ◽

Sushruta Koppula

Keyword(s):

Protein Kinase ◽

High Glucose ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Regulatory Element ◽

Adenosine Monophosphate ◽

Perennial Herb ◽

Houttuynia Cordata

Houttuynia cordata (H. cordata) from the family Saururaceae is a perennial herb native to Southeast Asia. It possesses a range of medicinal properties to treat several disease symptoms including allergic inflammation and anaphylaxis. In the present investigation, we provided the molecular mechanisms underlying the role of H. cordata extract (HCE) in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes. HepG2 cells were pre-treated with various concentrations of HCE (0, 10, 20, 40, and 80 μg/mL) and treated with serum-free medium with normal glucose (5 mM) for 1 h, followed by exposure to high glucose (25 mM D-glucose) for 24 h. HCE significantly and dose-dependently attenuated lipid accumulation in human HepG2 hepatocytes when exposed to high glucose (25 mM D-glucose) (p < 0.05, p < 0.01 and p < 0.001 at 20, 40, and 80 μg/mL concentrations, respectively). Further, HCE attenuated the expression of fatty acid synthase (FAS), sterol regulatory element-binding protein-1 and glycerol 3-phosphate acyltransferases (GPATs). The adenosine monophosphate-activated protein kinase (AMPK) was also activated by HCE treatment when exposed to high glucose (25 mM D-glucose) in human HepG2 hepatocytes. This study suggests the hypolipidemic effects of HCE by the inhibition of lipid biosynthesis mediated through AMPK signaling, which may play an active role and can be developed as an anti-obesity agent.

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Effective Food Ingredients for Fatty Liver: Soy Protein β-Conglycinin and Fish Oil

International Journal of Molecular Sciences ◽

10.3390/ijms19124107 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4107 ◽

Cited By ~ 5

Author(s):

Tomomi Yamazaki ◽

Dongyang Li ◽

Reina Ikaga

Keyword(s):

Fatty Liver ◽

Fish Oil ◽

Soy Protein ◽

De Novo ◽

Regulatory Element ◽

De Novo Lipogenesis ◽

Peroxisome Proliferator ◽

Experimental Conditions ◽

Alcoholic Fatty Liver ◽

Food Ingredients

Obesity is prevalent in modern society because of a lifestyle consisting of high dietary fat and sucrose consumption combined with little exercise. Among the consequences of obesity are the emerging epidemics of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor that stimulates gene expression related to de novo lipogenesis in the liver. In response to a high-fat diet, the expression of peroxisome proliferator-activated receptor (PPAR) γ2, another nuclear receptor, is increased, which leads to the development of NAFLD. β-Conglycinin, a soy protein, prevents NAFLD induced by diets high in sucrose/fructose or fat by decreasing the expression and function of these nuclear receptors. β-Conglycinin also improves NAFLD via the same mechanism as for prevention. Fish oil contains n-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Fish oil is more effective at preventing NAFLD induced by sucrose/fructose because SREBP-1c activity is inhibited. However, the effect of fish oil on NAFLD induced by fat is controversial because fish oil further increases PPARγ2 expression, depending upon the experimental conditions. Alcohol intake also causes an alcoholic fatty liver, which is induced by increased SREBP-1c and PPARγ2 expression and decreased PPARα expression. β-Conglycinin and fish oil are effective at preventing alcoholic fatty liver because β-conglycinin decreases the function of SREBP-1c and PPARγ2, and fish oil decreases the function of SREBP-1c and increases that of PPARα.

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Caffeoylquinic Acid-Rich Extract ofAster glehniF. Schmidt Ameliorates Nonalcoholic Fatty Liver through the Regulation of PPARδand Adiponectin in ApoE KO Mice

PPAR Research ◽

10.1155/2017/3912567 ◽

2017 ◽

Vol 2017 ◽

pp. 1-19 ◽

Cited By ~ 6

Author(s):

Yong-Jik Lee ◽

Yoo-Na Jang ◽

Yoon-Mi Han ◽

Hyun-Min Kim ◽

Jong-Min Jeong ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Liver ◽

Fatty Acid Synthase ◽

Serum Triglyceride ◽

Adenosine Monophosphate ◽

Serum Triglyceride Level ◽

Peroxisome Proliferator ◽

Atp Citrate Lyase ◽

Nonalcoholic Fatty Liver ◽

Protein Levels

Aster glehniis well known for its therapeutic properties. This study was performed to investigate the effects ofA. glehnion nonalcoholic fatty liver disease (NAFLD) in atherosclerotic condition, by determining the levels of biomarkers related to lipid metabolism and inflammation in serum, liver, and adipose tissue. Body and abdominal adipose tissue weights and serum triglyceride level decreased in all groups treated withA. glehni. Serum adiponectin concentration and protein levels of peroxisome proliferator-activated receptorδ, 5′ adenosine monophosphate-activated protein kinase, acetyl-CoA carboxylase, superoxide dismutase, and PPARγcoactivator 1-alpha in liver tissues increased in the groups treated withA. glehni. Conversely, protein levels of ATP citrate lyase, fatty acid synthase, tumor necrosis factorα, and 3-hydroxy-3-methylglutaryl-CoA reductase and the concentrations of interleukin 6 and reactive oxygen species decreased uponA. glehni. Triglyceride concentration in the liver was lower in mice treated withA. glehnithan in control mice. Lipid accumulation in HepG2 and 3T3-L1 cells decreased uponA. glehnitreatment; this effect was suppressed in the presence of the PPARδantagonist, GSK0660. Our findings suggest thatA. glehniextracts may ameliorate NAFLD through regulation of PPARδ, adiponectin, and the related subgenes.

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R. verniciflua and E. ulmoides Extract (ILF-RE) Protects against Chronic CCl4-Induced Liver Damage by Enhancing Antioxidation

Nutrients ◽

10.3390/nu11020382 ◽

2019 ◽

Vol 11 (2) ◽

pp. 382 ◽

Cited By ~ 4

Author(s):

Hwa-Young Lee ◽

Geum-Hwa Lee ◽

Young Yoon ◽

Han-Jung Chae

Keyword(s):

Oxidative Stress ◽

Er Stress ◽

Liver Damage ◽

Lipid Accumulation ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Protective Effects ◽

Gamma Glutamyl Transpeptidase ◽

Hepatic Lipid Accumulation ◽

Lipogenic Genes

This study aimed to characterize the protective effects of R. verniciflua extract (ILF-R) and E. ulmoides extract (ILF-E), the combination called ILF-RE, against chronic CCl4-induced liver oxidative injury in rats, as well as to investigate the mechanism underlying hepatoprotection by ILF-RE against CCl4-induced hepatic dysfunction. Chronic hepatic stress was induced via intraperitoneal (IP) administration of a mixture of CCl4 (0.2 mL/100 g body weight) and olive oil [1:1(v/v)] twice a week for 4 weeks to rats. ILF-RE was administered orally at 40, 80, and 120 mg/kg to rats for 4 weeks. Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transpeptidase (GGT), and lipid peroxidation assays were performed, and total triglyceride, cholesterol, and LDL-cholesterol levels were quantified. Furthermore, ER stress and lipogenesis-related gene expression including sterol regulatory element-binding transcription factor 1 (SREBP-1), fatty acid synthase (FAS), and P-AMPK were assessed. ILF-RE markedly protected against liver damage by inhibiting oxidative stress and increasing antioxidant enzyme activity including glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. Furthermore, hepatic dyslipidemia was regulated after ILF-RE administration. Moreover, hepatic lipid accumulation and its associated lipogenic genes, including those encoding SREBP-1 and FAS, were regulated after ILF-RE administration. This was accompanied by regulation of ER stress response signaling, suggesting a mechanism underlying ILF-RE-mediated hepatoprotection against lipid accumulation. The present results indicate that ILF-RE exerts hepatoprotective effects against chronic CCl4-induced dysfunction by suppressing hepatic oxidative stress and lipogenesis, suggesting that ILF-RE is a potential preventive/therapeutic natural product in treating hepatoxicity and associated dysfunction.

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