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

Taiyong Fang; Siying Huang; Yongpeng Chen; Zongchi Chen; Jiangmu Chen; Weitao Hu

doi:10.1055/a-1240-4936

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2021; 129(09): 625-633
DOI: 10.1055/a-1240-4936

Article

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

Taiyong Fang‡

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

,

Siying Huang‡

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

,

Yongpeng Chen

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

,

Zongchi Chen

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

,

Jiangmu Chen

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

,

Weitao Hu

Department of Gastroenterology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China

› Institutsangaben

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

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