scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals The effects of B1344, a novel fibroblast growth factor 21 analog, on nonalcoholic steatohepatitis in nonhuman primates

2020 ◽  
Author(s):  
Ada Admin ◽  
Aoyuan Cui ◽  
Jian Li ◽  
Shaohui Ji ◽  
Fengguang Ma ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Primate Species ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Long Acting ◽  
Hepatocyte Death

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting PEGylated FGF21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy, and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease, administration of B1344 via subcutaneous injection for eleven weeks caused a profound reduction of hepatic steatosis, inflammation and fibrosis, and amelioration of liver injury and hepatocyte death as evidenced by liver biopsy and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkey, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, administration of B1344 were performed in mice fed with methionine and choline deficiency diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis at a dose-dependent manner. These results provide preclinical validation for an innovative therapeutics to NAFLD, and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

scholarly journals ATF4- and CHOP-Dependent Induction of FGF21 through Endoplasmic Reticulum Stress

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-shan Wan ◽  
Xiang-hong Lu ◽  
Ye-cheng Xiao ◽  
Yuan Lin ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Glucose And Lipid Metabolism ◽  
Fgf21 Expression

Fibroblast growth factor 21 (FGF21) is an important endogenous regulator involved in the regulation of glucose and lipid metabolism. FGF21 expression is strongly induced in animal and human subjects with metabolic diseases, but little is known about the molecular mechanism. Endoplasmic reticulum (ER) stress plays an essential role in metabolic homeostasis and is observed in numerous pathological processes, including type 2 diabetes, overweight, nonalcoholic fatty liver disease (NAFLD). In this study, we investigate the correlation between the expression of FGF21 and ER stress. We demonstrated that TG-induced ER stress directly regulated the expression and secretion of FGF21 in a dose- and time-dependent manner. FGF21 is the target gene for activating transcription factor 4 (ATF4) and CCAAT enhancer binding protein homologous protein (CHOP). Suppression of CHOP impaired the transcriptional activation of FGF21 by TG-induced ER stress in CHOP−/− mouse primary hepatocytes (MPH), and overexpression of ATF4 and CHOP resulted in FGF21 promoter activation to initiate the transcriptional programme. In mRNA stability assay, we indicated that ER stress increased the half-life of mRNA of FGF21 significantly. In conclusion, FGF21 expression is regulated by ER stress via ATF- and CHOP-dependent transcriptional mechanism and posttranscriptional mechanism, respectively.

The Role of Neuropeptide Y and Peptide YY in the Development of Obesity via Gut-brain Axis

2019 ◽  
Vol 20 (7) ◽  
pp. 750-758 ◽  
Author(s):  
Yi Wu ◽  
Hengxun He ◽  
Zhibin Cheng ◽  
Yueyu Bai ◽  
Xi Ma
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuropeptide Y ◽  
Metabolic Diseases ◽  
Peptide Yy ◽  
Vital Role ◽  
Gut Peptides ◽  
Nonalcoholic Fatty Liver ◽  
The Central Nervous System

Obesity is one of the main challenges of public health in the 21st century. Obesity can induce a series of chronic metabolic diseases, such as diabetes, dyslipidemia, hypertension and nonalcoholic fatty liver, which seriously affect human health. Gut-brain axis, the two-direction pathway formed between enteric nervous system and central nervous system, plays a vital role in the occurrence and development of obesity. Gastrointestinal signals are projected through the gut-brain axis to nervous system, and respond to various gastrointestinal stimulation. The central nervous system regulates visceral activity through the gut-brain axis. Brain-gut peptides have important regulatory roles in the gut-brain axis. The brain-gut peptides of the gastrointestinal system and the nervous system regulate the gastrointestinal movement, feeling, secretion, absorption and other complex functions through endocrine, neurosecretion and paracrine to secrete peptides. Both neuropeptide Y and peptide YY belong to the pancreatic polypeptide family and are important brain-gut peptides. Neuropeptide Y and peptide YY have functions that are closely related to appetite regulation and obesity formation. This review describes the role of the gutbrain axis in regulating appetite and maintaining energy balance, and the functions of brain-gut peptides neuropeptide Y and peptide YY in obesity. The relationship between NPY and PYY and the interaction between the NPY-PYY signaling with the gut microbiota are also described in this review.

scholarly journals The Role of Vitamin E in the Treatment of NAFLD

Diseases ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 86 ◽  
Author(s):  
Brandon Perumpail ◽  
Andrew Li ◽  
Nimy John ◽  
Sandy Sallam ◽  
Neha Shah ◽  
...  
Keyword(s):  
Vitamin E ◽  
Nonalcoholic Steatohepatitis ◽  
Medical Literature ◽  
Ease Of Use ◽  
Alpha Tocopherol ◽  
Diabetic Patients ◽  
Nonalcoholic Fatty Liver ◽  
Therapeutic Choice ◽  
The Impact

There has been a growing interest in the role of vitamin E supplementation in the treatment and/or prevention of nonalcoholic fatty liver (NAFLD). We performed a systematic review of the medical literature from inception through 15 June 2018 by utilizing PubMed and searching for key terms such as NAFLD, vitamin E, alpha-tocopherol, and nonalcoholic steatohepatitis (NASH). Data from studies and medical literature focusing on the role of vitamin E therapy in patients with NAFLD and nonalcoholic steatohepatitis (NASH) were reviewed. Most studies assessing the impact of vitamin E in NAFLD were designed to evaluate patients with NASH with documented biochemical and histological abnormalities. These studies demonstrated improvement in biochemical profiles, with a decline in or normalization of liver enzymes. Furthermore, histological assessment showed favorable outcomes in lobular inflammation and hepatic steatosis following treatment with vitamin E. Current guidelines regarding the use of vitamin E in the setting of NAFLD recommend that vitamin E-based treatment be restricted to biopsy-proven nondiabetic patients with NASH only. However, some concerns have been raised regarding the use of vitamin E in patients with NASH due to its adverse effects profile and lack of significant improvement in hepatic fibrosis. In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic properties of vitamin E accompanied by ease-of-use and exceptional tolerability have made vitamin E a pragmatic therapeutic choice in non-diabetic patients with histologic evidence of NASH. Future clinical trials with study design to assess vitamin E in combination with other anti-fibrotic agents may yield an additive or synergistic therapeutic effect.

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 Nonalcoholic Steatohepatitis: An Evolving Diagnosis

2000 ◽  
Vol 14 (4) ◽  
pp. 321-326 ◽  
Author(s):  
Brent A Neuschwander-Tetri
Keyword(s):  
Alcohol Abuse ◽  
Liver Biopsy ◽  
Nonalcoholic Steatohepatitis ◽  
Aminotransferase Level ◽  
Obese Patients ◽  
Imaging Studies ◽  
Liver Transplants ◽  
Pathophysiological Role ◽  
Alanine Aminotransferase Level

Nonalcoholic steatohepatitis (NASH) is a histological diagnosis applied to a constellation of liver biopsy findings that develop in the absence of alcohol abuse. Steatosis, a mixed cellular inflammatory infiltrate across the lobule, evidence of hepatocyte injury and fibrosis are the findings that can be seen. This entity is often identified during evaluation of elevated aminotransferases after exclusion of viral, metabolic and other causes of liver disease. Obesity is a major risk factor for NASH. The role of diabetes is less certain, although evidence is accumulating that hyperinsulinism may play an important pathophysiological role. Patients sometimes suffer from right upper quadrant abdominal pain and fatigue; examination may reveal centripetal obesity and hepatomegaly. Although patients are often discovered because of persistent aminotransferase elevations, these enzymes can be normal in NASH. When they are elevated, the alanine aminotransferase level is typically significantly greater than the aspartate aminotransferase level. This can be particularly helpful for excluding occult alcohol abuse. Imaging studies identify hepatic steatosis when the amount of fat in the liver is significant; however, imaging does not distinguish benign steatosis from NASH. Ultimately a liver biopsy is needed to diagnose NASH. The biopsy may be useful for establishing prognosis based on the presence or absence of fibrosis and for excluding other unexpected causes of liver enzyme elevations. Weight loss is the mainstay of treatment for obese patients. About 15% to 40% of NASH patients develop fibrosis; how many of these cases progress to cirrhosis is unknown, but about 1% of liver transplants are performed with a pretransplant diagnosis of NASH.

scholarly journals Fibroblast growth factor 21: a regulator of metabolic disease and health span

2017 ◽  
Vol 313 (3) ◽  
pp. E292-E302 ◽  
Author(s):  
Ting Xie ◽  
Po Sing Leung
Keyword(s):  
Lipid Metabolism ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Metabolic Diseases ◽  
Scientific Basis ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Glucose And Lipid Metabolism ◽  
Care Guidelines

Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule.

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