Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease

Title:Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease

Volume: 16 Issue: 1

Author(s): Vishal Patel, Amit Joharapurkar*, Samadhan Kshirsagar, Brijesh Sutariya, Maulik Patel, Hiren Patel, Dheerendra Pandey, Dipam Patel, Ramchandra Ranvir, Shekhar Kadam, Rajesh Bahekar and Mukul Jain

Affiliation:

• Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad, 382210,India

Keywords: Coagonist, GLP-1/glucagon, NAFLD, high fat diet, glucagon receptor, fibrosis.

Abstract: Background: Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like- Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity. Glucagon treatment reduces lipids after acute and chronic treatment.

Objective: In this study, we have investigated the effect of co-agonist on the prevention of NAFLD induced by long-term feeding of High Fat Diet (HFD).

Method: We have used HFD to induce NAFLD after chronic feeding in mice. Co-agonist treatment (150 µg.kg-1, s.c.) was initiated with induction of HFD, which was continued for 40 weeks. Body weight, food intake, glucose homeostasis, lipid profile, inflammatory and fibrotic markers were assessed at the end of treatment.

Results: Co-agonist treatment prevented body weight gain, glucose intolerance and insulin resistance. Treatment with co-agonist reduced NEFA, increased FGF21 and adiponectin levels. Co-agonist increased glycerol release and energy expenditure, while decreased respiratory quotient. Co-agonist reduced lipids in circulation and liver. Expression of SREBP-1C, SCD-1, ACC and FAS were decreased, while ACOX1 and CPT1 were increased after co-agonist treatment. Inflammatory cytokine TNF-α and IL-6 in plasma and expression of MCP-1, TGF-ß, MMP-9, TNF-α, TIMP-1, α-SMA, and COL1A1 were decreased after co-agonist treatment. Plasma transaminases, hepatic TBARS, hepatic hydroxyproline and relative liver weight were suppressed after co-agonist treatment. Fat accumulation, inflammation and fibrosis were reduced in histological assessment of liver in co-agonist treated animals.

Conclusion: Co-agonist prevented development of HFD-induced NAFLD by ameliorating obesity, diabetes, inflammation and fibrosis.

Cite this article as:

Patel Vishal , Joharapurkar Amit*, Kshirsagar Samadhan, Sutariya Brijesh, Patel Maulik , Patel Hiren, Pandey Dheerendra, Patel Dipam , Ranvir Ramchandra, Kadam Shekhar , Bahekar Rajesh and Jain Mukul , Coagonist of GLP-1 and Glucagon Receptor Ameliorates Development of Non-Alcoholic Fatty Liver Disease, Cardiovascular & Hematological Agents in Medicinal Chemistry 2018; 16 (1) . https://dx.doi.org/10.2174/1871525716666180118152158