scholarly journals Prolonged Lipid Accumulation in Cultured Primary Human Hepatocytes Rather Leads to ER Stress than Oxidative Stress

2020 ◽  
Vol 21 (19) ◽  
pp. 7097
Author(s):  
Christiane Rennert ◽  
Theresa Heil ◽  
Gerda Schicht ◽  
Anna Stilkerich ◽  
Lena Seidemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Lipid Accumulation ◽  
Expression Profiles ◽  
Redox Homeostasis ◽  
Protein Translation ◽  
Human Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Primary Human Hepatocytes ◽  
Cellular Defenses

Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.

Continuous lipid treatment of primary human hepatocytes leads to an elevation of oxidative stress

2013 ◽  
Vol 51 (01) ◽  
Author(s):  
T Schulz ◽  
V Kegel ◽  
B Burkhardt ◽  
D Seehofer ◽  
M Glanemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes

scholarly journals N-Acetyl Cysteine Targets Hepatic Lipid Accumulation to Curb Oxidative Stress and Inflammation in NAFLD: A Comprehensive Analysis of the Literature

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1283
Author(s):  
Phiwayinkosi V. Dludla ◽  
Bongani B. Nkambule ◽  
Sithandiwe E. Mazibuko-Mbeje ◽  
Tawanda M. Nyambuya ◽  
Fabio Marcheggiani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Accumulation ◽  
Randomized Clinical Trials ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Metabolic Complications ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation ◽  
Acetyl Cysteine

Impaired adipose tissue function and insulin resistance remain instrumental in promoting hepatic lipid accumulation in conditions of metabolic syndrome. In fact, enhanced lipid accumulation together with oxidative stress and an abnormal inflammatory response underpin the development and severity of non-alcoholic fatty liver disease (NAFLD). There are currently no specific protective drugs against NAFLD, and effective interventions involving regular exercise and healthy diets have proved difficult to achieve and maintain. Alternatively, due to its antioxidant and anti-inflammatory properties, there has been growing interest in understanding the therapeutic effects of N-acetyl cysteine (NAC) against metabolic complications, including NAFLD. Here, reviewed evidence suggests that NAC blocks hepatic lipid accumulation in preclinical models of NAFLD. This is in part through the effective regulation of a fatty acid scavenger molecule (CD36) and transcriptional factors such as sterol regulatory element-binding protein (SREBP)-1c/-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Importantly, NAC appears effective in improving liver function by reducing pro-inflammatory markers such as interleukin (IL)-6 IL-1β, tumour necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This was primarily through the attenuation of lipid peroxidation and enhancements in intracellular response antioxidants, particularly glutathione. Very few clinical studies support the beneficial effects of NAC against NAFLD-related complications, thus well-organized randomized clinical trials are still necessary to confirm its therapeutic potential.

Long-term functional maintenance of primary human hepatocytes in vitro

Science ◽  
2019 ◽  
Vol 364 (6438) ◽  
pp. 399-402 ◽  
Author(s):  
Chengang Xiang ◽  
Yuanyuan Du ◽  
Gaofan Meng ◽  
Liew Soon Yi ◽  
Shicheng Sun ◽  
...  
Keyword(s):  
Cell Biology ◽  
Expression Profiles ◽  
Antiviral Drug ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Human Hepatocytes ◽  
Hbv Infection ◽  
Primary Human Hepatocytes

The maintenance of terminally differentiated cells, especially hepatocytes, in vitro has proven challenging. Here we demonstrated the long-term in vitro maintenance of primary human hepatocytes (PHHs) by modulating cell signaling pathways with a combination of five chemicals (5C). 5C-cultured PHHs showed global gene expression profiles and hepatocyte-specific functions resembling those of freshly isolated counterparts. Furthermore, these cells efficiently recapitulated the entire course of hepatitis B virus (HBV) infection over 4 weeks with the production of infectious viral particles and formation of HBV covalently closed circular DNA. Our study demonstrates that, with a chemical approach, functional maintenance of PHHs supports long-term HBV infection in vitro, providing an efficient platform for investigating HBV cell biology and antiviral drug screening.

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

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 382 ◽  
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.

Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes

2011 ◽  
Vol 1811 (10) ◽  
pp. 626-633 ◽  
Author(s):  
Josef Wanninger ◽  
Markus Neumeier ◽  
Claus Hellerbrand ◽  
Doris Schacherer ◽  
Sabrina Bauer ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Activin A ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes

scholarly journals Kaempferol-3-O-Glucuronide Ameliorates Non-Alcoholic Steatohepatitis in High-Cholesterol-Diet-Induced Larval Zebrafish and HepG2 Cell Models via Regulating Oxidation Stress

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 445
Author(s):  
Yang Deng ◽  
Ji Ma ◽  
Xin Weng ◽  
Yuqin Wang ◽  
Maoru Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
Zebrafish Model ◽  
Alcoholic Fatty Liver ◽  
Larval Zebrafish

NAFLD (non-alcoholic fatty liver disease) is one of the most prominent liver diseases in the world. As a metabolic-related disease, the development of NAFLD is closely associated with various degrees of lipid accumulation, oxidation, inflammation, and fibrosis. Ilex chinensis Sims is a form of traditional Chinese medicine which is used to treat bronchitis, burns, pneumonia, ulceration, and chilblains. Kaempferol-3-O-glucuronide (K3O) is a natural chemical present in Ilex chinensis Sims. This study was designed to investigate the antioxidative, fat metabolism-regulating, and anti-inflammatory potential of K3O. A high-cholesterol diet (HCD) was used to establish steatosis in larval zebrafish, whereby 1mM free fatty acid (FFA) was used to induce lipid accumulation in HepG2 cells, while H2O2 was used to induce oxidative stress in HepG2. The results of this experiment showed that K3O reduced lipid accumulation and the level of reactive oxygen species (ROS) both in vivo (K3O, 40μM) and in vitro (K3O, 20μM). Additionally, K3O (40μM) reduced neutrophil aggregation in vivo. K3O (20μM) also decreased the level of malondialdehyde (MDA) and significantly increased the level of glutathione peroxidase (GSH-px) in both the HCD-induced larval zebrafish model and H2O2-exposed HepG2 cells. In the mechanism study, keap1, nrf2, tnf-α, and il-6 mRNA were all significantly reversed by K3O (20μM) in zebrafish. Changes in Keap1 and Nrf2 mRNA expression were also detected in H2O2-exposed HepG2 cells after they were treated with K3O (20μM). In conclusion, K3O exhibited a reduction in oxidative stress and lipid peroxidation, and this may be related to the Nrf2/Keap1 pathway in the NAFLD larval zebrafish model.

scholarly journals Ethyl Acetate Fraction of Amomum villosum var. xanthioides Attenuates Hepatic Endoplasmic Reticulum Stress-Induced Non-Alcoholic Steatohepatitis via Improvement of Antioxidant Capacities

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 998
Author(s):  
Jung-Hyo Cho ◽  
Jong-Suk Lee ◽  
Hyeong-Geug Kim ◽  
Hye Won Lee ◽  
Zhigang Fang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Liver ◽  
Ethyl Acetate ◽  
Er Stress ◽  
Antioxidant Properties ◽  
Ethyl Acetate Fraction ◽  
Hepatic Tissue ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Amomum Villosum

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), affects 25% of the global population. Despite the prevalence of NAFLD worldwide, effective therapeutics are currently lacking. Amomum villosum var. xanthioides (Wall. ex Baker) T.L.Wu & S.J.Chen (AX) is a medicinal herb traditionally used for treating digestive tract disorders in countries across Asia. We aimed to examine the pharmacological effects of the ethyl acetate fraction of AX (AXEF) against tunicamycin (TM)-induced ER stress in a NASH mouse model using C57/BL6J male mice. Following TM injections (2 mg/kg), the mice were orally administrated AXEF (12.5, 25, or 50 mg/kg), silymarin (50 mg/kg), or distilled water daily for 5 days, and the outcomes for fatty liver, inflammation, and oxidative stress were measured in serum or liver tissue levels. AXEF drastically attenuated hepatic ER stress-induced NASH as indicated by decreases in lipid droplet accumulations, serum liver enzymes, hepatic inflammations, and cell death signals in the hepatic tissue and/or serum levels. Interestingly, AXEF showed potent antioxidant effects by quenching reactive oxidative stress and its final product lipid peroxide in the hepatic tissue, specifically an increase in metallothionein (MT). To confirm the underlying actions of AXEF, we observed that AXEF increases MT1 gene promoter activities in the physiological levels. Collectively, AXEF showed antioxidant properties on TM-induced ER stress in a NASH mice model through the improvement of MTs.

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