Ghrelin reduces TNF-α-induced human hepatocyte apoptosis, autophagy and pyroptosis: role in obesity-associated NAFLD

Ezquerro, Silvia; Mocha, F; Frühbeck, Gema; Guzmán‐Ruiz, Rocío; Valentí, Víctor; Mugueta, Carmen; Becerril, Sara; Catalán, Victoria; Gómez-Ambrosi, Javier; Silva, Camilo; Salvador, Javier; Colina, Inmaculada; Malagón, Marı́a M.; Rodrı́guez, Amaia

doi:10.1210/jc.2018-01171

Cited by 77 publications

(82 citation statements)

References 59 publications

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“…As a nonspecific PDE‐4 inhibitor, pentoxifylline has an ability to raise levels of cAMP and decrease tumor necrosis factor‐alpha (TNF‐α) gene transcription which could be beneficial in the treatment of many inflammatory diseases . Worth noted, hepatocyte cell death was reported to be induced by TNF‐alpha overexpression in hepatic cells of HFD‐fed rats and obese patients with NAFLD . Hence, suppression of NAFLD‐associated TNF‐α overexpression could have a potential role in ameliorating this disease.…”

Section: Introductionmentioning

confidence: 99%

Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

El-Deen

Heeba

Abdel‐latif

et al. 2020

Fundamemntal Clinical Pharma

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Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease linked to insulin resistance, oxidative stress, and cytokine imbalance. Phosphodiesterase (PDE) inhibitors have shown remarkable antioxidant and anti-inflammatory potential in different disease sets including liver diseases. This study aimed to compare the ameliorative effect of different PDE inhibitors on a high-fat diet (HFD)-induced NAFLD. Male Wistar rats were fed a HFD for 16 weeks to induce NAFLD, and then, oral treatments of a vehicle or different PDE inhibitors (pentoxifylline (50 mg/kg), cilostazol (20 mg/kg), or sildenafil (5 mg/kg)) were started in the last four weeks and given on a daily basis. Rats' body composition and liver indices were recorded. Serum levels of liver enzymes, glucose, insulin, bilirubin, total cholesterol, triglycerides, and nitric oxide were measured. Liver tissues were used for histopathological examination and detecting oxidative stress and inflammatory markers. Results showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD-induced NAFLD in rodents evident by different strength-ameliorated effects on the aforementioned parameters. Compared to cilostazol and sildenafil, insulin resistance, hepatic oxidative stress, and inflammatory markers were significantly reduced by pentoxifylline treatment. Furthermore, pentoxifylline nearly completely reversed hepatocyte steatosis and exhibited superior rectifying effect on the rats' liver status compared with other PDE inhibitors. This investigation highlighted the potential role of PDE inhibitors in NAFLD treatment. Pentoxifylline had the most remarkable ameliorative effects against NAFLD, while sildenafil was the least effective.

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Section: Introductionmentioning

confidence: 99%

Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

El-Deen

Heeba

Abdel‐latif

et al. 2020

Fundamemntal Clinical Pharma

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“…Recent in vitro studies have shown that UAG exhibits biological activities on cell proliferation and metabolism through combining their cell membranes [35,36]. In addition to its peripheral actions, which include cell senescence, inhibition of apoptosis, and fat metabolism [37], UAG may function in central feeding regulation via combining with other receptors (e. g., corticotropin releasing factor-2 [38], pre-opioid melanocyte corticosteroid [39]). In GHSR-deficient mice, the functional connection between UAG and the GHSR was revealed.…”

Section: Discussionmentioning

confidence: 99%

Unacylated Ghrelin Regulates Glucose-Sensitive Neurons Activity and Glycolipid Metabolism via Orexin-A Neurons in the Lateral Hypothalamic Area

Yan

Yao

et al. 2020

Horm Metab Res

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The objective of the study was to investigate the regulatory actions of unacylated ghrelin (UAG) on glucose-sensitive (GS) neurons and glycolipid metabolism in the lateral hypothalamus area (LHA) and its involvement with orexin-A-immunopositive neurons. The effects of UAG administered into the LHA on GS neurons discharges and glycolipid metabolism were detected by single neuron discharge recording, biochemical index analysis and quantitative real-time PCR; the level of c-fos protein in orexin-A-immunopositive neurons was observed using immunofluorescence staining. UAG microinjected into the LHA activated glucose-inhibited neurons, which were partially blocked by pre-administration of anti-orexin-A antibody in the LHA. Furthermore, UAG microinjected into the LHA significantly reduced serum triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol, blood glucose, insulin and hepatic TG levels, while elevated serum high-density lipoprotein cholesterol levels. UAG elevated the mRNA expression of carnitine palmitoyltransferase-1 and reduced the mRNA expression of acetyl-CoA carboxylase-1 in the liver. The above-mentioned effects of UAG were partially blocked by pre-administration of anti-orexin-A antibody. The expressions of orexin-A and c-fos were observed in the LHA. After UAG injection into the LHA, some neurons showed double labeling, and the percentage of double-labeled orexin-A/c-fos neurons in orexin-A-immunopositive neurons increased significantly. UAG in the LHA regulates glycolipid metabolism by activating orexin-A-immunopositive neurons in the LHA.

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“…Total cholesterol, HDL-cholesterol, LDL-cholesterol, and triacylglycerol concentrations (Roche) were calculated as previously described. 13 High sensitivity C-reactive protein (CRP) was measured using the Tinaquant CRP (Latex) ultrasensitive assay (Roche). Insulin was measured by an enzyme-amplified chemiluminescence assay (IMMULITE; Diagnostics Products Corp., Los Angeles, CA, USA).…”

Section: Human Study Cohort and Biological Analysismentioning

confidence: 99%

Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

et al. 2020

Self Cite

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The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high‐fat diet (HFD)‐induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno‐associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD‐induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9‐hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD‐induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.

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Ghrelin reduces TNF-α-induced human hepatocyte apoptosis, autophagy and pyroptosis: role in obesity-associated NAFLD

Abstract: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.

Cited by 77 publications

References 59 publications

Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

Unacylated Ghrelin Regulates Glucose-Sensitive Neurons Activity and Glycolipid Metabolism via Orexin-A Neurons in the Lateral Hypothalamic Area

Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

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