scholarly journals Effects of Caffeine and Chlorogenic Acid on Nonalcoholic Steatohepatitis in Mice Induced by Choline-Deficient, L-Amino Acid-Defined, High-Fat Diet

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3886
Author(s):  
Erdenetsogt Dungubat ◽  
Shiori Watabe ◽  
Arisa Togashi-Kumagai ◽  
Masato Watanabe ◽  
Yasuyuki Kobayashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chlorogenic Acid ◽  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
Cell Injury ◽  
Control Diet ◽  
Experimental Studies ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression

Several recent experimental studies have investigated the effects of caffeine and chlorogenic acid (CGA), representative ingredients of coffee, on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the results are conflicting, and their effects are yet to be clarified. In the present study, we examined the effects of caffeine and CGA on choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, relatively new model mice of NASH. Seven-week-old male C57BL/6J mice were divided into the following groups: Control diet (control), CDAHFD (CDAHFD), CDAHFD supplemented with 0.05% (w/w) caffeine (caffeine), and CDAHFD supplemented with 0.1% (w/w) CGA (CGA). After seven weeks, the mice were killed and serum biochemical, histopathological, and molecular analyses were performed. Serum alanine aminotransferase (ALT) levels were significantly higher in the caffeine and CGA groups than in the CDAHFD group. On image analysis, the prevalence of Oil red O-positive areas (reflecting steatosis) was significantly higher in the caffeine group than in the CDAHFD group, and that of CD45R-positive areas (reflecting lymphocytic infiltration) in the hepatic lobule was significantly higher in the caffeine and CGA groups than in the CDAHFD group. Hepatic expression of interleukin (IL)-6 mRNA was higher in the caffeine and CGA groups than in the CDAHFD group, and the difference was statistically significant for the caffeine group. In conclusion, in the present study, caffeine and CGA significantly worsened the markers of liver cell injury, inflammation, and/or steatosis in NASH lesions in mice.

scholarly journals Effects of Caffeine and Chlorogenic Acid on Nonalcoholic Steatohepatitis in Mice Induced by Choline-Deficient, L-Amino Acid-Defined, High-Fat Diet

2021 ◽  
Author(s):  
Erdenetsogt Dungubat Shiori Watabe ◽  
Arisa Togashi-Kumagai ◽  
Masato Watanabe ◽  
Yasuyuki Kobayashi ◽  
Naoki Harada ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chlorogenic Acid ◽  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
High Fat

scholarly journals Deficiency of the Purinergic Receptor 2X7 Attenuates Nonalcoholic Steatohepatitis Induced by High-Fat Diet: Possible Role of the NLRP3 Inflammasome

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Claudia Blasetti Fantauzzi ◽  
Stefano Menini ◽  
Carla Iacobini ◽  
Chiara Rossi ◽  
Eleonora Santini ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Purinergic Receptor ◽  
High Fat ◽  
Liver Sinusoidal Endothelial Cells ◽  
Nonalcoholic Fatty Liver ◽  
Markers Of Inflammation

Molecular mechanisms driving transition from simple steatosis to nonalcoholic steatohepatitis (NASH), a critical step in the progression of nonalcoholic fatty liver disease (NAFLD) to cirrhosis, are poorly defined. This study aimed at investigating the role of the purinergic receptor 2X7 (PR2X7), through the NLRP3 inflammasome, in the development of NASH. To this end, mice knockout for the Pr2x7 gene (Pr2x7−/−) and coeval wild-type (WT) mice were fed a high-fat diet (HFD) or normal-fat diet for 16 weeks. NAFLD grade and stage were lower in Pr2x7−/− than WT mice, and only 1/7 Pr2x7−/− animals showed evidence of NASH, as compared with 4/7 WT mice. Molecular markers of inflammation, oxidative stress, and fibrosis were markedly increased in WT-HFD mice, whereas no or significantly reduced increments were detected in Pr2x7−/− animals, which showed also decreased modulation of genes of lipid metabolism. Deletion of Pr2x7 gene was associated with blunted or abolished activation of NLRP3 inflammasome and expression of its components, which were induced in liver sinusoidal endothelial cells challenged with appropriate stimuli. These data show that Pr2x7 gene deletion protects mice from HFD-induced NASH, possibly through blunted activation of NLRP3 inflammasome, suggesting that PR2X7 and NLRP3 may represent novel therapeutic targets.

scholarly journals Hepatocyte X-box binding protein 1 deficiency increases liver injury in mice fed a high-fat/sugar diet

2015 ◽  
Vol 309 (12) ◽  
pp. G965-G974 ◽  
Author(s):  
Xiaoying Liu ◽  
Anne S. Henkel ◽  
Brian E. LeCuyer ◽  
Matthew J. Schipma ◽  
Kristy A. Anderson ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fatty Liver ◽  
Cell Injury ◽  
Binding Protein ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Huh7 Cells

Fatty liver is associated with endoplasmic reticulum stress and activation of the hepatic unfolded protein response (UPR). Reduced hepatic expression of the UPR regulator X-box binding protein 1 spliced (XBP1s) is associated with human nonalcoholic steatohepatitis (NASH), and feeding mice a high-fat diet with fructose/sucrose causes progressive, fibrosing steatohepatitis. This study examines the role of XBP1 in nonalcoholic fatty liver injury and fatty acid-induced cell injury. Hepatocyte-specific Xbp1-deficient ( Xbp1−/−) mice were fed a high-fat/sugar (HFS) diet for up to 16 wk. HFS-fed Xbp1−/− mice exhibited higher serum alanine aminotransferase levels compared with Xbp1fl/fl controls. RNA sequencing and Gene Ontogeny pathway analysis of hepatic mRNA revealed that apoptotic process, inflammatory response, and extracellular matrix structural constituent pathways had enhanced activation in HFS-fed Xbp1−/− mice. Liver histology demonstrated enhanced injury and fibrosis but less steatosis in the HFS-fed Xbp1−/− mice. Hepatic Col1a1 and Tgfβ1 gene expression, as well as Chop and phosphorylated JNK (p-JNK), were increased in Xbp1−/− compared with Xbp1fl/fl mice after HFS feeding. In vitro, stable XBP1-knockdown Huh7 cells (Huh7-KD) and scramble control cells (Huh7-SCR) were generated and treated with palmitic acid (PA) for 24 h. PA-treated Huh7-KD cells had increased cytotoxicity measured by lactate dehydrogenase release, apoptotic nuclei, and caspase3/7 activity assays compared with Huh7-SCR cells. CHOP and p-JNK expression was also increased in Huh7-KD cells following PA treatment. In conclusion, loss of XBP1 enhances injury in both in vivo and in vitro models of fatty liver injury. We speculate that hepatic XBP1 plays an important protective role in pathogenesis of NASH.

Lipid droplets are both highly oxidized and Plin2-covered in hepatocytes of diet-induced obese mice

2020 ◽  
Vol 45 (12) ◽  
pp. 1368-1376
Author(s):  
Diego Nocetti ◽  
Alejandra Espinosa ◽  
Francisco Pino-De la Fuente ◽  
Camila Sacristán ◽  
José Luis Bucarey ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
High Fat Diet ◽  
Lipid Droplets ◽  
Control Diet ◽  
Isolated Hepatocytes ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Adult Mice ◽  
Obesity Status ◽  
Intrahepatic Lipid

Chronic high-fat diet feeding is associated with obesity and accumulation of fat in the liver, leading to the development of insulin resistance and nonalcoholic fatty liver disease. This condition is characterized by the presence of a high number of intrahepatic lipid droplets (LDs), with changes in the perilipin pattern covering them. This work aimed to describe the distribution of perilipin (Plin) 2, an LD-associated protein involved in neutral lipid storage, and Plin5, which favors lipid oxidation in LD, and to evaluate lipid peroxidation through live-cell visualization using the lipophilic fluorescent probe C11-BODIPY581/591 in fresh hepatocytes isolated from mice fed a high-fat diet (HFD). Male C57BL/6J adult mice were divided into control and HFD groups and fed with a control diet (10% fat, 20% protein, and 70% carbohydrates) or an HFD (60% fat, 20% protein, and 20% carbohydrates) for 8 weeks. The animals fed the HFD showed a significant increase of Plin2 in LD of hepatocytes. LD from HFD-fed mice have a stronger lipid peroxidation level than control hepatocytes. These data provide evidence that obesity status is accompanied by a higher degree of lipid peroxidation in hepatocytes, both in the cytoplasm and in the fats stored inside the LD. Novelty Our study shows that lipid droplets from isolated hepatocytes in HFD-fed mice have a stronger lipid peroxidation level than control hepatocytes. C11-BODIPY581/591 is a useful tool to measure the initial level of intracellular lipid peroxidation in single isolated hepatocytes. Perilipins pattern changes with HFD feeding, showing an increase of Plin2 covering lipid droplets.

scholarly journals Triclosan leads to dysregulation of the metabolic regulator FGF21 exacerbating high fat diet-induced nonalcoholic fatty liver disease

2020 ◽  
Vol 117 (49) ◽  
pp. 31259-31266
Author(s):  
Mei-Fei Yueh ◽  
Feng He ◽  
Chen Chen ◽  
Catherine Vu ◽  
Anupriya Tripathi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Consumer Products ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Aberrant Expression ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression

Triclosan (TCS), employed as an antiseptic and disinfectant, comes into direct contact with humans through a plethora of consumer products and its rising environmental release. We have demonstrated that TCS promotes liver tumorigenesis in mice, yet the biological and molecular mechanisms by which TCS exerts its toxicity, especially in early stages of liver disease, are largely unexplored. When mice were fed a high-fat diet (HFD), we found that fatty liver and dyslipidemia are prominent early signs of liver abnormality induced by TCS. The presumably protective HFD-induced hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21) was blunted by TCS. TCS-alteredFgf21expression aligned with aberrant expression of genes encoding metabolic enzymes manifested as profound systemic metabolic changes that disturb homeostasis of amino acids, fatty acids, and glucose. Using a type 1 diabetic animal model, TCS potentiates and accelerates the development of steatohepatitis and fibrosis, accompanied by increased levels of hepatic lipid droplets and oxidative stress. Analysis of fecal samples revealed that HFD-fed mice exhibited a reduction in fecal species richness, and that TCS further diminished microbial diversity and shifted the bacterial community toward lower Bacteriodetes and higher Firmicutes, resembling changes in microbiota composition in nonalcoholic steatohepatitis (NASH) patients. Using reverse-genetic approaches, we demonstrate that, along with HFD, TCS induces hepatic steatosis and steatohepatitis jointly regulated by the transcription factor ATF4 and the nuclear receptor PPARα, which participate in the transcriptional regulation of theFgf21gene. This study provides evidence linking nutritional imbalance and exposure to TCS with the progression of NASH.

scholarly journals Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease

2010 ◽  
Vol 298 (5) ◽  
pp. G634-G642 ◽  
Author(s):  
Zhigang Wang ◽  
Tong Yao ◽  
Maria Pini ◽  
Zhanxiang Zhou ◽  
Giamila Fantuzzi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Control Diet ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Betaine Supplementation

Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 ± 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet-induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH2-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function.

scholarly journals Attenuation of High-Fat Diet-Induced Rat Liver Oxidative Stress and Steatosis by Combined Hydroxytyrosol- (HT-) Eicosapentaenoic Acid Supplementation Mainly Relies on HT

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Francisca Echeverría ◽  
Rodrigo Valenzuela ◽  
Andrés Bustamante ◽  
Daniela Álvarez ◽  
Macarena Ortiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Eicosapentaenoic Acid ◽  
High Fat Diet ◽  
Control Diet ◽  
Liver Steatosis ◽  
Pharmacological Therapy ◽  
High Fat ◽  
Total Recovery ◽  
Nonalcoholic Fatty Liver ◽  
The Impact

Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.

scholarly journals Composition of a maternal high fat diet rich in satured fats and omega 3 in gestation and lactation for studies with rodents

2019 ◽  
Vol 32 ◽  
Author(s):  
Laura Mata de Lima SILVA ◽  
Aline Maria Nunes de Lira Gomes BLOISE ◽  
Danilo Augusto Ferreira FONTES ◽  
Katarynna Santos de ARAÚJO ◽  
Mariana Oliveira BARBOSA ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Body Mass ◽  
High Fat Diet ◽  
Control Diet ◽  
Saturated Fatty Acids ◽  
Experimental Studies ◽  
Abdominal Circumference ◽  
Lactation Period ◽  
Omega 3 ◽  
High Fat

ABSTRACT Objective To prepare a high fat diet rich in satured fatty acids and supplemented with omega 3 for experimental studies in rodents. Methods Purified industrial ingredients and flaxseed oil as a source of omega 3 at a concentration of 3.5% (v/w) were used in the elaboration of the diets. Centesimal and nutritional compositions, fatty acids profile and dietary intake were evaluated. Serum levels of total protein, albumin, cholesterol and glucose in pregnant rats were verified. The offspring were assessed with regard to body mass and waist circumference. Statistical analysis was performed using the Kolmogorov-Smirnov, Anova One-Way test and Bonferroni post-test. Results High fat and high fat with omega 3 diets presented, respectively, 37% and 36% saturated fat, and the lipid amount was 80% higher than the American Institute of Nutrition 93G control diet. The omega 3 content was 50% higher in the high fat with omega 3 diet. There was no difference in consumption of diet types in weight (grams). The dams that received the High fat diet developed hypercholesterolemia and their High fat offspring exhibited higher body mass on the 1st day of life and increased abdominal circumference on the 30th day of life compared to the control and the high fat with omega 3 offspring. Conclusion The formulated diets with a higher amount of saturated fatty acids meet the nutritional requirements of the gestation and lactation period. The high fat diet with omega 3 was able to attenuate the changes observed in dams and their offspring.

scholarly journals A Trans Fatty Acid Substitute Aggravates Nonalcoholic Steatohepatitis Induced in Mice by Feeding a Choline-Deficient, Methionine-Lowered, L-Amino Acid-Defined, High-Fat Diet

2020 ◽  
Author(s):  
Noriko Suzuki-Kemuriyama ◽  
Akari Abe ◽  
Kinuko Uno ◽  
Shuji Ogawa ◽  
Atsushi Watanabe ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Amino Acid ◽  
Nonalcoholic Steatohepatitis ◽  
High Fat Diet ◽  
Saturated Fatty Acids ◽  
Elevated Serum ◽  
High Fat ◽  
Hepatocellular Apoptosis ◽  
Liver Changes

Abstract Background: Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Trans fatty acid (TFA) is hazardous for human health and a risk factor of NASH; thus, efforts have focused on reducing its intake. However, the health benefits of reducing dietary TFA are not fully elucidated. We investigated effects of TFA and its substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF). Methods: Mice were fed CDAA-HF containing shortening with TFA (CDAA-HF-T(+)), CDAA-HF containing shortening with a TFA substitute (CDAA-HF-T(−)), or a control chow for 13/26 weeks. Results: CDAA-HF-T(+) contained TFA, whereas CDAA-HF-T(−) contained no TFA and much saturated fatty acids. CDAA-HF-T(+) and CDAA-HF-T(−) induced NASH in mice, evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(−) induced more hepatocellular apoptosis and proliferative (preneoplastic and non-neoplastic) nodular lesions than CDAA-HF-T(+). Conclusions: Thus, replacement of dietary TFA with its substitute does not prevent but aggravates nutritionally induced NASH in mice, at least under the present conditions. Attention should be paid regarding future TFA substitute use in humans, and a fatty acid balance is likely more important than the particular types of fatty acids.

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