Effect of Phenolic Compounds from Elderflowers on Glucose- and Fatty Acid Uptake in Human Myotubes and HepG2-Cells

Abstract Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating HepG2 cells with 400 µM oleic acid (OA) overnight. Further treatment with 200nM Ex-4 for 3 hours significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Furthermore, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake via FABP1 downregulation.

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Chitobiose alleviates oleic acid-induced lipid accumulation by decreasing fatty acid uptake and triglyceride synthesis in HepG2 cells

Journal of Functional Foods ◽

10.1016/j.jff.2018.04.058 ◽

2018 ◽

Vol 46 ◽

pp. 202-211 ◽

Cited By ~ 16

Author(s):

Xiaodan Li ◽

Mengyao Zhao ◽

Liqiang Fan ◽

Xuni Cao ◽

Liehuan Chen ◽

...

Keyword(s):

Oleic Acid ◽

Fatty Acid ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Triglyceride Synthesis

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Picroside II attenuates fatty acid accumulation in HepG2 cells via modulation of fatty acid uptake and synthesis

Clinical and Molecular Hepatology ◽

10.3350/cmh.2017.0039 ◽

2018 ◽

Vol 24 (1) ◽

pp. 77-87 ◽

Cited By ~ 5

Author(s):

Hiteshi Dhami-Shah ◽

Rama Vaidya ◽

Shobha Udipi ◽

Srividhya Raghavan ◽

Shiny Abhijit ◽

...

Keyword(s):

Fatty Acid ◽

Hepg2 Cells ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Picroside Ii ◽

Fatty Acid Accumulation ◽

Acid Accumulation

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Ethanol up-regulates fatty acid uptake and plasma membrane expression and export of mitochondrial aspartate aminotransferase in HepG2 cells

Hepatology ◽

10.1002/hep.510270423 ◽

1998 ◽

Vol 27 (4) ◽

pp. 1064-1074 ◽

Cited By ~ 49

Author(s):

Sheng-Li Zhou ◽

Ronald E. Gordon ◽

Michael Bradbury ◽

Decherd Stump ◽

Chih-Li Kiang ◽

...

Keyword(s):

Plasma Membrane ◽

Fatty Acid ◽

Aspartate Aminotransferase ◽

Hepg2 Cells ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Membrane Expression ◽

Plasma Membrane Expression ◽

Mitochondrial Aspartate Aminotransferase

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Fatty acid transport and metabolism in HepG2 cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00386.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. G528-G534 ◽

Cited By ~ 31

Author(s):

Wen Guo ◽

Nasi Huang ◽

Jun Cai ◽

Weisheng Xie ◽

James A. Hamilton

Keyword(s):

Fatty Acids ◽

Plasma Membrane ◽

Fatty Acid ◽

Hepg2 Cells ◽

Fatty Acid Uptake ◽

Metabolic Inhibitors ◽

Fatty Acid Transport ◽

Acid Uptake ◽

Triacsin C ◽

Membrane Bound

The mechanism(s) of fatty acid uptake by liver cells is not fully understood. We applied new approaches to address long-standing controversies of fatty acid uptake and to distinguish diffusion and protein-based mechanisms. Using HepG2 cells containing an entrapped pH-sensing fluorescence dye, we showed that the addition of oleate (unbound or bound to cyclodextrin) to the external buffer caused a rapid (seconds) and dose-dependent decrease in intracellular pH (pHin), indicating diffusion of fatty acids across the plasma membrane. pHin returned to its initial value with a time course (in min) that paralleled the metabolism of radiolabeled oleate. Preincubation of cells with the inhibitors phloretin or triacsin C had no effect on the rapid pHin drop after the addition of oleate but greatly suppressed pHin recovery. Using radiolabeled oleate, we showed that its esterification was almost completely inhibited by phloretin or triacsin C, supporting the correlation between pHin recovery and metabolism. We then used a dual-fluorescence assay to study the interaction between HepG2 cells and cis-parinaric acid (PA), a naturally fluorescent but slowly metabolized fatty acid. The fluorescence of PA increased rapidly upon its addition to cells, indicating rapid binding to the plasma membrane; pHin decreased rapidly and simultaneously but did not recover within 5 min. Phloretin had no effect on the PA-mediated pHin drop or its slow recovery but decreased the absolute fluorescence of membrane-bound PA. Our results show that natural fatty acids rapidly bind to, and diffuse through, the plasma membrane without hindrance by metabolic inhibitors or by an inhibitor of putative membrane-bound fatty acid transporters.

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

Planta Medica ◽

10.1055/a-0901-1307 ◽

2019 ◽

Vol 85 (09/10) ◽

pp. 719-728 ◽

Cited By ~ 1

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.

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A STUDY ON CLASSIFICATION OF INHIBITORS OF FATTY ACID TRANSPORT PROTEIN-2 IN CELL

10.36106/ijsr/4725187 ◽

2021 ◽

pp. 58-60

Author(s):

Anand Shanker Singh ◽

G . Radhika ◽

R . Praveen Kumar ◽

Debarshi Jana

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

High Throughput ◽

Hepg2 Cells ◽

High Throughput Screening ◽

Atypical Antipsychotics ◽

Fatty Acid Uptake ◽

Fatty Acid Transport ◽

Acid Uptake ◽

Acid Transport

Inhibition of uptake of fatty acids in non-adipose tissues seems an attractive mechanism for treatment of lipotoxicity, dyslipidemia and other elements related to metabolic syndrome and obesity. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterication with coenzyme A. To date, only inhibitors specic to FATP1 and FATP4 have been identied. Here we characterize a FATP2-specic fatty acid uptake inhibitor, CB5. Identied in a high throughput screening in yeast transformed with humanFATP2, CB5 is effective in inhibiting the uptake of fatty acid at low micro-molar ranges in cell lines that are models for intestines, liver, muscle, pancreas and adipose tissue with varying potencies. Inhibition was also specic for long and very-long chain fatty acids and not for medium chain fatty acids, which are transported by diffusion. Finally, CB5 was effective in protecting the cell lines that are models for liver and pancreas and primary liver cells from lipotoxic effects of saturated fatty acid, palmitic acid. High throughput screening also identied clozapine and chlorpromazine, atypical antipsychotics drugs, as inhibitors of FATP2-mediated fatty acid uptake in yeast system. However, atypical antipsychotics were ineffective in inhibiting the uptake of FAanalog C1-BODIPY-C12 in HepG2 cells. They were also ineffective in protecting HepG2 cells from the lipotoxic effects generated by saturated fatty acid compared to CB5 that exhibited protection to the cells, demonstrating that they are not effective inhibitors of fatty acid transport compared with CB5.

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