scholarly journals l-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers

2019 ◽  
Vol 43 (4) ◽  
pp. 493-503 ◽  
Author(s):  
A. Montesano ◽  
P. Senesi ◽  
F. Vacante ◽  
G. Mollica ◽  
S. Benedini ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Lipid Accumulation ◽  
Liver Diseases ◽  
Liver Steatosis ◽  
Ampk Activation ◽  
Nonalcoholic Fatty Liver ◽  
Oxidative Damages ◽  
Compound C ◽  
Human Hepatoma Hepg2 Cells

Abstract Purpose Nonalcoholic fatty liver disease (NAFLD) is defined by excessive lipid accumulation in the liver and involves an ample spectrum of liver diseases, ranging from simple uncomplicated steatosis to cirrhosis and hepatocellular carcinoma. Accumulating evidence demonstrates that high fructose intake enhances NAFLD development and progression promoting inhibition of mitochondrial β-oxidation of long-chain fatty acids and oxidative damages. l-Carnitine (LC), involved in β-oxidation, has been used to reduce obesity caused by high-fat diet, which is beneficial to ameliorating fatty liver diseases. Moreover, in the recent years, various studies have established LC anti-oxidative proprieties. The objective of this study was to elucidate primarily the underlying anti-oxidative mechanisms of LC in an in vitro model of fructose-induced liver steatosis. Methods Human hepatoma HepG2 cells were maintained in medium supplemented with LC (5 mM LC) with or without 5 mM fructose (F) for 48 h and 72 h. In control cells, LC or F was not added to medium. Fat deposition, anti-oxidative, and mitochondrial homeostasis were investigated. Results LC supplementation decreased the intracellular lipid deposition enhancing AMPK activation. However, compound C (AMPK inhibitor-10 μM), significantly abolished LC benefits in F condition. Moreover, LC, increasing PGC1 α expression, ameliorates mitochondrial damage-F induced. Above all, LC reduced ROS production and simultaneously increased protein content of antioxidant factors, SOD2 and Nrf2. Conclusion Our data seemed to show that LC attenuate fructose-mediated lipid accumulation through AMPK activation. Moreover, LC counteracts mitochondrial damages and reactive oxygen species production restoring antioxidant cellular machine. These findings provide new insights into LC role as an AMPK activator and anti-oxidative molecule in NAFLD.

scholarly journals Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Ting Li ◽  
Ting Fang ◽  
Linxin Xu ◽  
Xiangyang Liu ◽  
Xiaoyu Li ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Liver Steatosis ◽  
Fatty Degeneration ◽  
Hepatic Lipid Accumulation ◽  
Compound C ◽  
Hepatocyte Steatosis ◽  
Autophagy Pathway

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

Preventive Effects of Total Flavonoid C-Glycosides from Abrus mollis on Nonalcoholic Fatty Liver Disease through Activating the PPARα Signaling Pathway

Planta Medica ◽  
2019 ◽  
Vol 85 (08) ◽  
pp. 678-688 ◽  
Author(s):  
Xiao-Long Hu ◽  
Ya-Jun Niu ◽  
Mi Chen ◽  
Jia-Hao Feng ◽  
Wei Shen ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Total Flavonoid ◽  
Edible Plant ◽  
Nonalcoholic Fatty Liver

Abstract Abrus pulchellus subsp. mollis (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1), isoschaftoside (2), schaftoside (3), and their enrichment fraction, total flavonoid C-glycosides, derived from the extracts of A. mollis, were firstly found to prevent nonalcoholic fatty liver disease both in vitro and in vivo. In the in vitro study, total flavonoid C-glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid C-glycosides are involved in the regulation of peroxisome proliferator-activated receptor α and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid C-glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid C-glycosides also increased the activities of the antioxidant enzyme system in vivo. In conclusion, total flavonoid C-glycosides are active components of A. mollis on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.

scholarly journals Qushi Huayu Decoction Inhibits Hepatic Lipid Accumulation by Activating AMP-Activated Protein KinaseIn VivoandIn Vitro

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Qin Feng ◽  
Xiao-jun Gou ◽  
Sheng-xi Meng ◽  
Cheng Huang ◽  
Yu-quan Zhang ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Lipid Accumulation ◽  
Nuclear Protein ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Element Binding Protein ◽  
L02 Cells

Qushi Huayu Decoction (QHD), a Chinese herbal formula, has been proven effective on alleviating nonalcoholic fatty liver disease (NAFLD) in human and rats. The present study was conducted to investigate whether QHD could inhibit hepatic lipid accumulation by activating AMP-activated protein kinase (AMPK)in vivoandin vitro. Nonalcoholic fatty liver (NAFL) model was duplicated with high-fat diet in rats and with free fatty acid (FFA) in L02 cells. Inin vivoexperimental condition, QHD significantly decreased the accumulation of fatty droplets in livers, lowered low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in serum. Moreover, QHD supplementation reversed the HFD-induced decrease in the phosphorylation levels of AMPK and acetyl-CoA carboxylase (ACC) and decreased hepatic nuclear protein expression of sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-responsive element-binding protein (ChREBP) in the liver. Inin vitro, QHD-containing serum decreased the cellular TG content and alleviated the accumulation of fatty droplets in L02 cells. QHD supplementation reversed the FFA-induced decrease in the phosphorylation levels of AMPK and ACC and decreased the hepatic nuclear protein expression of SREBP-1 and ChREBP. Overall results suggest that QHD has significant effect on inhibiting hepatic lipid accumulation via AMPK pathwayin vivoandin vitro.

Ginsenoside CK ameliorates hepatic lipid accumulation via activating LKB1/AMPK pathway in vitro and in vivo

2022 ◽  
Author(s):  
Jingjing Zhang ◽  
Xiaoxuan Ma ◽  
Daidi Fan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid Accumulation

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with complex etiology, which is considered as one of the main causes of hepatocellular carcinoma (HCC). The incidence of NAFLD...

scholarly journals Metformin inhibits both oleic acid-induced and CB1R receptor agonist-induced lipid accumulation in Hep3B cells: The preliminary report

2019 ◽  
Vol 33 ◽  
pp. 205873841983271
Author(s):  
Agnieszka Szuster-Ciesielska ◽  
Agnieszka Zwolak ◽  
Jadwiga Daniluk ◽  
Martyna Kandefer-Szerszeń
Keyword(s):  
Oleic Acid ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Cannabinoid Receptors ◽  
In Vitro Study ◽  
Negative Control ◽  
Protein Kinase Activity ◽  
Nonalcoholic Fatty Liver ◽  
Hep3b Cells

Fatty liver is characterized by excessive accumulation of triglycerides within hepatocytes. Recent findings indicate that natural history of nonalcoholic fatty liver is regulated, in part, by endogenous cannabinoids. Metformin is an oral hypoglycemic medication which inhibits gluconeogenesis and glycogenolysis in hepatocytes and limits lipid storage in the liver through the inhibition of free fatty acid formation via induction of activated protein kinase activity (AMPK). Both endocannabinoids and metformin may modulate hepatosteatosis; therefore, it was interesting to examine whether metformin may affect lipid accumulation in hepatocytes by acting on cannabinoid receptors, CB1 and CB2, in in vitro study. Hep3B cells were incubated with or without metformin (Met), phosphatidylcholine (PC), and oleic acid (OA). Cells without any of the examined substances served as negative control. Cells treated only with OA served as positive control. The quantity of intracellular lipids was assessed using Oil-Red-O staining. Selective CB1R agonist, arachidonyl-2-chloromethylamide (ACEA), and CB2R agonist, AM1241 (2-iodo-5-nitrophenyl)-[1-(methylpiperidin-2-ylmethyl)-1 H-indol-3-yl]methanone, were also used to treat Hep3B cells. In some experiments, antagonist for CB1R, AM6545, or SR144528 as selective antagonist of CB2R were used. In the study, Met decreased lipid accumulation in cells treated with OA and inhibited CB1R agonist–induced lipid accumulation in hepatocytes. The CB2R agonist–induced hepatic lipid accumulation was not inhibited by metformin. The results indicate that metformin may interact with endocannabinoid system in the liver by inhibiting CB1R agonist–stimulated fat accumulation in hepatocytes.

scholarly journals Herbicide Widespread: The Effects of Pethoxamid on Nonalcoholic Fatty Liver Steatosis In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Anna Virginia Adriana Pirozzi ◽  
Antonietta Stellavato ◽  
Chiara Schiraldi ◽  
Mariateresa Giuliano
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Cell Model ◽  
Human Subjects ◽  
Liver Steatosis ◽  
Nonalcoholic Fatty Liver ◽  
Fatty Acid Accumulation ◽  
Impaired Liver ◽  
Postemergence Herbicides

Pethoxamid is a widespread herbicidal product, presenting itself as an extremely flexible active substance and with a high potential for use as an herbicide for preemergence. The emergence of multiple resistance in crops has been addressed using combinations of preemergence and postemergence herbicides in the same seeding-harvest cycle. A winning combination of pethoxamid and glyphosate mainly affected the acidobacteria population. Glyphosate scientific literature has demonstrated an observational link between herbicide exposure and liver disease in human subjects. Identifying and ranking the risk to the public that pethoxamid could exert on target organs has not been evaluated so far. Due to similarities to glyphosate, we did look at the effect of pethoxamid on impaired liver cells HepG2, using a nonalcoholic fatty liver disease (NAFLD) cell model in vitro. Pethoxamid was cytotoxic starting at 1 ppm. Fatty acid accumulation (FA) was enhanced while low doses of pethoxamid slightly decreased LDH protein expression compared to FA-treated HepG2. The same trend was observed for cytochrome c. Based on our data, we can argue that NAFLD hepatic cells react to pethoxamid trying detoxifying strategies, ready to undergo cell death to avoid further degeneration. Downregulation of cytochrome can lead to the hypothesis that pethoxamid should not induce herbicide resistance.

scholarly journals Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2α/PPARα pathway

2019 ◽  
Vol 317 (4) ◽  
pp. E710-E722 ◽  
Author(s):  
Jiandi Chen ◽  
Jianxu Chen ◽  
Huirong Fu ◽  
Yun Li ◽  
Lingling Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Intermittent Hypoxia ◽  
Peroxisome Proliferator ◽  
Nonalcoholic Fatty Liver

This study aimed to investigate whether hypoxia can affect nonalcoholic fatty liver disease (NAFLD) progression and the associated mechanisms, specifically regarding the hypoxia-inducible factor (HIF)-2α/peroxisome proliferator-activated receptor (PPAR)α pathway in vitro and in vivo. Recent studies have reported that, compared with HIF-1α, HIF-2α has different effects on lipid metabolism. We propose hypoxia may exacerbate NAFLD by the HIF-2α upregulation-induced suppression of PPARα in the liver. To verify this hypothesis, a steatotic human hepatocyte (L02) cell line treated with free fatty acids and a mouse model of NAFLD fed a high-fat diet were used. Steatotic hepatocytes were treated with hypoxia, HIF-2α siRNA, PPARα agonists, and inhibitors, respectively. Meanwhile, the NAFLD mice were exposed to intermittent hypoxia or intermittent hypoxia with PPARα agonists. The relative gene expression levels of HIF-1α, HIF-2α, mitochondrial function, fatty acid β-oxidation and lipogenesis were examined. Evidence of lipid accumulation was observed, which demonstrated that, compared with normal hepatocytes, steatotic hepatocytes exhibited higher sensitivity to hypoxia. This phenomenon was closely associated with HIF-2α. Moreover, lipid accumulation in hepatocytes was ameliorated by HIF-2α silencing or a PPARα agonist, despite the hypoxia treatment. HIF-2α overexpression under hypoxic conditions suppressed PPARα, leading to PGC-1α, NRF-1, ESRRα downregulation, and mitochondrial impairment. Additionally, β-oxidation genes such as CPT1α, CPT2α, ACOX1, and ACOX2 were downregulated and lipogenesis genes including LXRα, FAS, and SCD1 were upregulated by hypoxia. Therefore, we concluded that HIF-2α overexpression induced by hypoxia aggravated NAFLD progression by suppressing fatty acid β-oxidation and inducing lipogenesis in the liver via PPARα.

scholarly journals TMAO Stimulate Inflammation and Lipid Accumulation via NF-κB Signaling Pathway in Nonalcoholic Fatty Liver Disease

2021 ◽  
Author(s):  
zhijun chen ◽  
Jiale Zhang ◽  
Qian Cheng ◽  
Xiangsheng Cai ◽  
RuiTian Xie ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Intestinal Flora ◽  
Common Disease ◽  
Nonalcoholic Fatty Liver

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a common disease and it is commonly associated with obesity. Trimethylamine N-oxide (TMAO) is a metabolite of intestinal flora generated in liver by flavin-containing monooxygenase 3 (FMO3), which has been widely studied in cardiovascular diseases and obesity. However, the mechanism of TMAO reacted on liver remains unclear. This study aimed to determine TMAO activated hepatitis inflammation and lipid accumulation which was associated with nuclear factor kappa B (NF-κB) signaling pathway in vitro. ResultsThe present study showed that TMAO in 50μM markedly increased the LO2 cells function and decreased the cells inflammation. However, over the concentration of 200μM in TMAO, cells inflammation was increased and function was declined apparently. In addition, TMAO promoted lipid accumulation. Mechanistically, this change was accompanied by the activation of NF-κB signaling pathway. Furthermore, blocking NF-κB by SN50 was significantly increased in lipid accumulation and apoptosis. SN50 was markedly decreased the protein expression stimulating by TMAO.ConclusionsOverall, the result suggested that TMAO promotes cells inflammation and lipid accumulation in hepatocytes and it might be associated with NF-κB signaling pathway.

scholarly journals E3 ubiquitin ligase Grail promotes hepatic steatosis through Sirt1 inhibition

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Pei-Yao Liu ◽  
Cheng-Cheung Chen ◽  
Chia-Ying Chin ◽  
Te-Jung Liu ◽  
Wen-Chiuan Tsai ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Acid Synthesis ◽  
Sirtuin 1 ◽  
Nonalcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Hepatic Fat ◽  
Underlying Mechanisms

AbstractIn obese adults, nonalcoholic fatty liver disease (NAFLD) is accompanied by multiple metabolic dysfunctions. Although upregulated hepatic fatty acid synthesis has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are yet to be elucidated. In this study, we reported upregulated expression of gene related to anergy in lymphocytes (GRAIL) in the livers of humans and mice with hepatic steatosis. Grail ablation markedly alleviated the high-fat diet-induced hepatic fat accumulation and expression of genes related to the lipid metabolism, in vitro and in vivo. Conversely, overexpression of GRAIL exacerbated lipid accumulation and enhanced the expression of lipid metabolic genes in mice and liver cells. Our results demonstrated that Grail regulated the lipid accumulation in hepatic steatosis via interaction with sirtuin 1. Thus, Grail poses as a significant molecular regulator in the development of NAFLD.

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