Glucagon Like Peptide-1 Receptor Agonists Alter Pancreatic and Hepatic Histology and Regulation of Endoplasmic Reticulum Stress in High-fat Diet Mouse Model

Abstract

Background Obesity is a major health problem worldwide, and non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty liver disease (NAFLD) are obesity-associated complications. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been approved for treatment of obesity. We aimed to evaluate the therapeutic effects of liraglutide on the complications through its regulation of endoplasmic reticulum (ER) stress.

Methods A high-fat diet mouse model was established in C57BL/6J mice. Two groups of mice were fed a high-fat diet with 60% fat for 16 weeks and control mice were fed standard chow. A four-week 0.6 mg/kg/day liraglutide treatment was started in one high-fat diet group after 12 weeks of the high-fat diet. After sacrificing the mice, pancreatic and hepatic tissues were prepared for western blot and immunohistochemistry for ER stress proteins, including activating transcription factor 4 (ATF4), caspase 12, C/EBP homologous protein (CHOP) eukaryotic initiation factor 2 α (eIF2α), glucose regulated protein (GRP) 78 and protein kinase RNA-like endoplasmic reticulum kinase (PERK).

Results Liraglutide significantly decreased body weight gained by mice consuming a high-fat diet (27.6 g vs. 34.5 g, P<0.001), and levels of all ER proteins increased significantly in both the pancreas and liver (all P<0.05). Expression of most ER stress proteins in pancreatic tissue correlated with disease scores of NAFLD (all P<0.05). However, no significant differences were found in pancreatic ATF 4 expression between mice without NAFLD, and those with early non-alcoholic steatohepatitis (NASH) and fibrotic NASH (P=0.122).

Conclusion Liraglutide may reduce the severity of NAFPD and NAFLD through regulating the ER stress pathway and downstream apoptosis signaling.

Key words

non-alcoholic fatty pancreas disease - non-alcoholic fatty liver disease - endoplasmic reticulum stress - glucagon-like peptide-1 receptor agonist

Publikationsverlauf

Eingereicht: 13. März 2020
Eingereicht: 04. August 2020

Angenommen: 10. August 2020

Artikel online veröffentlicht:
22. September 2020

• References

• 1 Finucane MM, Stevens GA, Cowan MJ. et al. National, regional, and global trends in body-mass index since 1980: Systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet (London, England) 2011; 377: 557-567 doi:10.1016/S0140-6736(10)62037-5
• 2 WHO. Obesity and Overweight: Fact Sheet. World Health Organisation In:; 2018
• 3 Della Corte C, Mosca A, Majo F. et al. Nonalcoholic fatty pancreas disease and Nonalcoholic fatty liver disease: more than ectopic fat. Clin Endocrinol (Oxf) 2015; 83: 656-662 doi:10.1111/cen.12862
• 4 Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008; 94: 206-218 DOI: 10.1016/j.physbeh.2007.10.010
• 5 Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-887 DOI: 10.1038/nature05488
• 6 van Geenen EJ, Smits MM, Schreuder TC. et al. Nonalcoholic fatty liver disease is related to nonalcoholic fatty pancreas disease. Pancreas 2010; 39: 1185-1190 doi:10.1097/MPA.0b013e3181f6fce2
• 7 van der Zijl NJ, Goossens GH, Moors CC. et al. Ectopic fat storage in the pancreas, liver, and abdominal fat depots: Impact on beta-cell function in individuals with impaired glucose metabolism. The Journal of Clinical Endocrinology and Metabolism 2011; 96: 459-467 doi:10.1210/jc.2010-1722
• 8 Dhir G, Cusi K. Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: A novel therapeutic option. Journal of investigative medicine : The Official Publication of the American Federation for Clinical Research 2018; 66: 7-10 DOI: 10.1136/jim-2017-000554
• 9 Armstrong MJ, Gaunt P, Aithal GP. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679-690 doi:10.1016/s0140-6736(15)00803-x
• 10 Jiang Y, Wang Z, Ma B. et al. GLP-1 Improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Frontiers in pharmacology 2018; 9: 1168 doi:10.3389/fphar.2018.01168
• 11 Ao N, Yang J, Wang X. et al. Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway. Hepatology research : The Official Journal of the Japan Society of Hepatology 2016; 46: 343-353 doi:10.1111/hepr.12551
• 12 Ozcan U, Cao Q, Yilmaz E. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (New York, NY) 2004; 306: 457-461 doi:10.1126/science.1103160
• 13 Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nature Reviews Drug Discovery 2013; 12: 703-719 DOI: 10.1038/nrd3976
• 14 Soeda J, Mouralidarane A, Cordero P. et al. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. Journal of Physiology and Biochemistry 2016; 72: 281-291 doi:10.1007/s13105-016-0476-6
• 15 Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C. et al. A Mouse Model of Metabolic Syndrome: Insulin Resistance, Fatty Liver and Non-Alcoholic Fatty Pancreas Disease (NAFPD) in C57BL/6 Mice Fed a High Fat Diet. J Clin Biochem Nutr 2010; 46: 212-223 doi:10.3164/jcbn.09-83
• 16 Gao H, Zeng Z, Zhang H. et al. The Glucagon-Like Peptide-1 Analogue Liraglutide Inhibits Oxidative Stress and Inflammatory Response in the Liver of Rats with Diet-Induced Non-alcoholic Fatty Liver Disease. Biological & Pharmaceutical Bulletin 2015; 38: 694-702 doi:10.1248/bpb.b14-00505
• 17 Bedossa P, Poitou C, Veyrie N. et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012; 56: 1751-1759 doi:10.1002/hep.25889
• 18 Kleiner DE, Brunt EM, Van Natta M. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-1321 doi:10.1002/hep.20701
• 19 van Geenen EJ, Smits MM, Schreuder TC. et al. Smoking is related to pancreatic fibrosis in humans. The American Journal of Gastroenterology 2011; 106: 1161-1166. quiz 1167. doi:10.1038/ajg.2011.43
• 20 Tang A, Rabasa-Lhoret R, Castel H. et al. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial. Diabetes Care 2015; 38: 1339-1346 doi:10.2337/dc14-2548
• 21 Cuthbertson DJ, Irwin A, Gardner CJ. et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One 2012; 7: e50117 doi:10.1371/journal.pone.0050117
• 22 Petit JM, Cercueil JP, Loffroy R. et al. Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study. The. Journal of Clinical Endocrinology and Metabolism 2017; 102: 407-415 doi:10.1210/jc.2016-2775
• 23 Banhegyi G, Baumeister P, Benedetti A. et al. Endoplasmic reticulum stress. Annals of the New York Academy of Sciences 2007; 1113: 58-71 doi:10.1196/annals.1391.007
• 24 Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147: 943-951 DOI: 10.1210/en.2005-0570
• 25 Rahman SM, Schroeder-Gloeckler JM, Janssen RC. et al. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 2007; 45: 1108-1117 doi:10.1002/hep.21614
• 26 Puri P, Mirshahi F, Cheung O. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008; 134: 568-576 doi:10.1053/j.gastro.2007.10.039
• 27 Lauressergues E, Bert E, Duriez P. et al. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?. Neuropharmacology 2012; 62: 784-796 doi:10.1016/j.neuropharm.2011.08.048
• 28 Cao J, Dai DL, Yao L. et al. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Molecular and cellular biochemistry 2012; 364: 115-129 doi:10.1007/s11010-011-1211-9
• 29 Deutsch G, Jung J, Zheng M. et al. A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development (Cambridge, England) 2001; 128: 871-881
• 30 Harding HP, Zhang Y, Zeng H. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular cell 2003; 11: 619-633
• 31 Cullinan SB, Zhang D, Hannink M. et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Molecular and Cellular Biology 2003; 23: 7198-7209 doi:10.1128/mcb.23.20.7198-7209.2003
• 32 Averous J, Bruhat A, Jousse C. et al. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. The. Journal of Biological Chemistry 2004; 279: 5288-5297 doi:10.1074/jbc.M311862200
• 33 Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. The Journal of Biological Chemistry 2003; 278: 34864-34873 10.1074/jbc.M301107200
• 34 Wang CY, Ou HY, Chen MF. et al. Enigmatic ectopic fat: prevalence of nonalcoholic fatty pancreas disease and its associated factors in a Chinese population. Journal of the American Heart Association 2014; 3: e000297 doi:10.1161/jaha.113.000297
• 35 Patel NS, Peterson MR, Lin GY. et al. Insulin resistance increases MRI-estimated pancreatic fat in nonalcoholic fatty liver disease and normal controls. Gastroenterology Research and Practice 2013; 2013: 498296 doi:10.1155/2013/498296
• 36 Schwenzer NF, Machann J, Martirosian P. et al. Quantification of pancreatic lipomatosis and liver steatosis by MRI: comparison of in/opposed-phase and spectral-spatial excitation techniques. Investigative Radiology 2008; 43: 330-337 doi:10.1097/RLI.0b013e31816a88c6
• 37 Heni M, Machann J, Staiger H. et al. Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: A nuclear magnetic resonance study. Diabetes/metabolism Research and Reviews 2010; 26: 200-205 doi:10.1002/dmrr.1073