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Glyphosate implications on Metabolic-associated Fatty Liver Desease in mice: role of NFR2, p65, SREBP1 transcription factors

Grant number: 21/07954-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2021
Effective date (End): September 30, 2022
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal researcher:Guilherme Ribeiro Romualdo
Grantee:Ana Carolina Sprocatti dos Santos
Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

The metabolic-associated fatty liver disease (MAFLD) is closely associated with diabetes and obesity, affecting 25% of the global population. MAFLD is also related to the high intake of saturated fatty acids and simple carbohydrates. MAFLD pathogenesis involves an imbalance in hepatic lipid metabolism, increased inflammation, and oxidative stress, that is associated with deregulation of SREBP1, NF-ºB (p65), and Nrf2 transcription factors. respectively. The herbicide glyphosate (N-(phosphonomethyl) glycine) is widely used in agriculture and its residues are frequently identified in foods. This herbicide has already demonstrated hepatic pro-oxidant, lipogenic, and/or inflammatory effects in preclinical studies, at doses below the toxicological limits adopted by regulatory agencies. Thus, the project will evaluate whether the administration of the herbicide glyphosate promotes MAFLD in an in vivo nutritional model. In detail, we will evaluate the implications of this herbicide on NF-ºB (p65), Nrf2, and SREBP1 transcription factors, directly related to the pathogenesis of MAFLD. C57BL/6J male mice (n=10/group) will receive a high-fat diet (30% lard and 0.2% cholesterol), containing 20% sucrose and high sugar solution (23.1 g/L of fructose and 18.9 g/L of glucose) for 6 months. Concomitantly, the animals will receive glyphosate [0.05, 5 or 50 mg/kg/day by gavage (5x/week)]. The doses were based on the Acceptable Daily Intake (ADI) or the No Observed Adverse Effect Level (NOAEL) values from European/American regulatory agencies. The glucose tolerance test will be calculated (after 3 and 6 months) and serum will be sampled for biochemical analysis (alanine aminotransferase, triglycerides, and cholesterol). Liver samples will be collected for histological analysis, including MAFLD grade (H&E), collagen (Sirius red) and lipid (Oil red) morphometry, and immunohistochemistry for Ki-67 (i.e., proliferation), CD68 (i.e., macrophage marker), and ±-SMA (i.e., active stellate cell marker). Other liver samples will be obtained for immunoblotting (p65, Nrf2, and SREBP1) the determination lipid hydroperoxide levels, catalase, superoxide dismutase, glutathione peroxidase, and glutathione-S transferase activities. (AU)

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