scholarly journals Aqueous Extract of Pepino Leaves Ameliorates Palmitic Acid-Induced Hepatocellular Lipotoxicity via Inhibition of Endoplasmic Reticulum Stress and Apoptosis

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 903
Author(s):  
Jen-Ying Hsu ◽  
Hui-Hsuan Lin ◽  
Charng-Cherng Chyau ◽  
Zhi-Hong Wang ◽  
Jing-Hsien Chen
Keyword(s):  
Fatty Acid ◽  
Palmitic Acid ◽  
Er Stress ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Liver Lipid ◽  
Antioxidant Response ◽  
Long Chain Fatty Acid ◽  
Nrf2 Expression

Saturated fatty acid is one of the important nutrients, but contributes to lipotoxicity in the liver, causing hepatic steatosis. Aqueous pepino leaf extract (AEPL) in the previous study revealed alleviated liver lipid accumulation in metabolic syndrome mice. The study aimed to investigate the mechanism of AEPL on saturated long-chain fatty acid-induced lipotoxicity in HepG2 cells. Moreover, the phytochemical composition of AEPL was identified in the present study. HepG2 cells treated with palmitic acid (PA) were used for exploring the effect of AEPL on lipid accumulation, apoptosis, ER stress, and antioxidant response. The chemical composition of AEPL was analyzed by HPLC-ESI-MS/MS. AEPL treatment reduced PA-induced ROS production and lipid accumulation. Further molecular results revealed that AEPL restored cytochrome c in mitochondria and decreased caspase 3 activity to cease apoptosis. In addition, AEPL in PA-stressed HepG2 cells significantly reduced the ER stress and suppressed SREBP-1 activation for decreasing lipogenesis. For defending PA-induced oxidative stress, AEPL promoted Nrf2 expression and its target genes, SOD1 and GPX3, expressions. The present study suggested that AEPL protected from PA-induced lipotoxicity through reducing ER stress, increasing antioxidant ability, and inhibiting apoptosis. The efficacy of AEPL on lipotoxicity was probably concerned with kaempferol and isorhamnetin derived compounds.

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

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.

scholarly journals Catalpol Attenuates Hepatic Steatosis by Regulating Lipid Metabolism via AMP-Activated Protein Kinase Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Xiang Tian ◽  
Qin Ru ◽  
Qi Xiong ◽  
Ruojian Wen ◽  
Yong Chen
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Fatty Acid Synthase ◽  
Target Genes ◽  
Dependent Manner ◽  
Compound C ◽  
Amp Activated Protein Kinase

The increased prevalence of nonalcoholic fatty liver disease (NAFLD), which develops from hepatic steatosis, represents a public health challenge. Catalpol, a natural component extracted from the roots of Radix Rehmanniae, has several pharmacological activities. The present study is aimed at examining whether catalpol prevents hepatic steatosis in cell and animal experiments and elucidating the possible mechanisms. HepG2 cells were treated with 300 μM palmitate (PA) and/or catalpol for 24 h in vitro, and male C57BL/6J mice fed a high-fat diet (HFD) were administered catalpol for 18 weeks in vivo. The results revealed that catalpol significantly decreased lipid accumulation in PA-treated HepG2 cells. Moreover, catalpol drastically reduced body weight and lipid accumulation in the liver, whereas it ameliorated hepatocyte steatosis in HFD-fed mice. Notably, catalpol remarkably promoted the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, catalpol repressed the expressions of lipogenesis-associated genes such as sterol regulatory element-binding protein 1c and fatty acid synthase but promoted the expressions of genes associated with fatty acid β-oxidation such as peroxisome proliferator-activated receptor α together with its target genes carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 (ACOX1). However, the preincubation of the HepG2 cells with compound C (10 μM), an AMPK inhibitor, prevented catalpol-mediated beneficial effects. These findings suggest that catalpol ameliorates hepatic steatosis by suppressing lipogenesis and enhancing fatty acid β-oxidation in an AMPK-dependent manner. Therefore, catalpol has potential as a novel agent in the treatment of NAFLD.

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo

Planta Medica ◽  
2019 ◽  
Vol 85 (09/10) ◽  
pp. 719-728 ◽  
Author(s):  
Wonseok Lee ◽  
Hye Ryoung Koo ◽  
You-Jin Choi ◽  
Jin Gyu Choi ◽  
Myung Sook Oh ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Fatty Acid ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Regulatory Element ◽  
Fatty Acid Uptake ◽  
Acid Uptake

AbstractAbnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet–induced hepatic steatosis in mice as well as oleic acid–induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid–induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.

scholarly journals Exendin-4 improves ER stress-induced lipid accumulation and regulates lipin-1 signaling in HepG2 cells

2018 ◽  
Vol 23 (4) ◽  
pp. 629-638 ◽  
Author(s):  
Jinmi Lee ◽  
Seok-Woo Hong ◽  
Hyemi Kwon ◽  
Se Eun Park ◽  
Eun-Jung Rhee ◽  
...  
Keyword(s):  
Er Stress ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Lipin 1

scholarly journals Diosgenin ameliorates palmitic acid-induced lipid accumulation via AMPK/ACC/CPT-1A and SREBP-1c/FAS signaling pathways in LO2 cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Ke Fang ◽  
Fan Wu ◽  
Guang Chen ◽  
Hui Dong ◽  
Jingbin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Palmitic Acid ◽  
Mitochondrial Function ◽  
Lipid Accumulation ◽  
Lipid Synthesis ◽  
Underlying Mechanism ◽  
Intracellular Lipid

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is characterized by excessive hepatic lipid accumulation. Many studies have suggested that lipid overload is the key initial factor that contributes to hepatic steatosis. Our previous study indicated that diosgenin (DSG) has a beneficial effect on energy metabolism, but the underlying mechanism remains unclear. Methods Human normal hepatocytes (LO2 cells) were incubated with palmitic acid to establish the cell model of nonalcoholic fatty liver. The effects of DSG on lipid metabolism, glucose uptake and mitochondrial function were evaluated. Furthermore, the mechanism of DSG on oxidative stress, lipid consumption and lipid synthesis in LO2 cells was investigated. Results The results indicated that palmitic acid induced obvious lipid accumulation in LO2 cells and that DSG treatment significantly reduced the intracellular lipid content. DSG treatment upregulated expression of lipolysis proteins, including phospho-AMP activated protein kinase (p-AMPK), phospho-acetyl-coA carboxylase (p-ACC) and carnitine acyl transferase 1A (CPT-1A), and inhibited expression of lipid synthesis-related proteins, including sterol regulatory element-binding protein 1c (SREBP-1c) and fatty acid synthase (FAS). Additionally, DSG-treated cells displayed a marked improvement in mitochondrial function, with less production of reactive oxygen species and a higher mitochondrial membrane potential compared with the model group. Conclusion This study suggests that DSG can reduce intracellular lipid accumulation in LO2 cells and that the underlying mechanism may be related to the improving oxidative stress, increasing fatty acid β-oxidation and decreasing lipid synthesis. The above changes might be mediated by the activation of the AMPK/ACC/CPT-1A pathway and inhibition of the SREBP-1c/FAS pathway.

Evaluation of anti-adipogenic active homoisoflavonoids from Portulaca oleracea

2019 ◽  
Vol 74 (9-10) ◽  
pp. 265-273 ◽  
Author(s):  
Jung Im Lee ◽  
Jung Hwan Oh ◽  
Chang-Suk Kong ◽  
Youngwan Seo
Keyword(s):  
Fatty Acid ◽  
Crude Extract ◽  
Lipid Accumulation ◽  
Target Genes ◽  
Adipogenic Differentiation ◽  
Portulaca Oleracea ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding

Abstract This study was performed to isolate antiobesity components from the crude extract of Portulaca oleracea. The crude extract was partitioned into n-hexane, 85% aqueous methanol, n-butanol, and water fractions. Their effects on adipogenic differentiation were evaluated in 3T3-L1 cells. Among the solvent fractions from P. olearacea, the 85% aq. MeOH effectively reduced the levels of lipid accumulation. Further purification of 85% aq. MeOH led to the isolation of the known homoisoflavonoids 1–4, as the active substances. The administration of homoisoflavonoids to adipocyte cells decreased the lipid accumulation and glucose consumption and increased the release of glycerol into culture medium. In particular, homoisoflavonoid 3 effectively down-regulated the adipogenic transcription genes such as peroxisome proliferator activated receptor-γ (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPα), and adipogenic target genes such as fatty acid binding protein 4 (FABP4), fatty acid transport protein 1 (FATP1), and acyl-CoA synthase 1 (ACS1).

A Dipeptidyl Peptidase IV Inhibitory Peptide Relieves Palmitic Acid-Induced Endoplasmic Reticulum Stress in HepG2 Cells Independently of Inhibiting Dipeptidyl Peptidase IV Activity

2021 ◽  
Author(s):  
Ritian Jin ◽  
Haowei Ren ◽  
Minhe Liao ◽  
Jiaqi Shang ◽  
Dangfeng Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Palmitic Acid ◽  
Er Stress ◽  
Hepg2 Cells ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Inhibitory Peptide ◽  
Dpp Iv

The peptide VLATSGPG (VLA) is known to inhibit dipeptidyl peptidase IV (DPP-IV), although its mechanism in relieving endoplasmic reticulum (ER) stress is unclear. In this study, we found that treating...

scholarly journals Differential Lipotoxic Effects of Palmitate and Oleate in Activated Human Hepatic Stellate Cells and Epithelial Hepatoma Cells

2016 ◽  
Vol 39 (4) ◽  
pp. 1648-1662 ◽  
Author(s):  
Alexandra M. Hetherington ◽  
Cynthia G. Sawyez ◽  
Emma Zilberman ◽  
Alexandra M. Stoianov ◽  
Debra L. Robson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Er Stress ◽  
Hepatic Stellate Cells ◽  
Hepg2 Cells ◽  
Stellate Cells ◽  
Hepatoma Cells ◽  
Surrounding Tissue ◽  
High Oleate ◽  
Activated Hepatic Stellate Cells

Background/Aims: Nonalcoholic fatty liver disease (NAFLD) progression to fibrosis, cirrhosis and hepatocellular carcinoma, alters the cellular composition of this organ. During late-stage NAFLD, fibrotic and possibly cancerous cells can proliferate and, like normal hepatocytes, are exposed to high concentrations of fatty acids from both surrounding tissue and circulating lipid sources. We hypothesized that primary human activated hepatic stellate cells and epithelial hepatoma (HepG2) cells respond differently to lipotoxic conditions, and investigated the mechanisms involved. Methods: Primary activated hepatic stellate cells and HepG2 cells were exposed to pathophysiological concentrations of fatty acids and comparative studies of lipid metabolic and stress response pathways were performed. Results: Both cell types remained proliferative during exposure to a combination of palmitate plus oleate reflective of the general saturated versus unsaturated fatty acid composition of western diets. However, exposure to either high palmitate or high oleate alone induced cytotoxicity in activated stellate cells, while only palmitate caused cytotoxicity in HepG2 cells. mRNA microarray and biochemical comparisons revealed that stellate cells stored markedly less fatty acids as neutral lipids, and had reduced capacity for beta-oxidation. Similar to previous observations in HepG2 cells, palmitate, but not oleate, induced ER stress and actin stress fiber formation in activated stellate cells. In contrast, oleate, but not palmitate, induced the inflammatory signal TXNIP, decreased cytoskeleton proteins, and decreased cell polarity preceding cell death in activated stellate cells. Conclusions: Palmitate-induced lipotoxicity was associated with ER stress pathways in both primary activated hepatic stellate cells and epithelial hepatoma cells, whereas high oleate caused lipotoxicity only in activated stellate cells, possibly through a distinct mechanism involving disruption of cytoskeleton components. This may have implications for optimal dietary fatty acid compositions during various stages of NAFLD.

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