FPS-ZM1 attenuates the deposition of lipid in the liver of diabetic mice by sterol regulatory element binding protein-1c

• DOI: 10.1186/s12902-024-01705-2
• Publication Date: 2024-08-29T07:02:47Z
• Authors: Mengshu Zhang; Wanwan Zhao; Zhen Zhang; Mengting He; Ya Zhang; Bing Song; Jinlei Liu; Haoqiang Zhang
• Keywords: Male; Glycation End Products, Advanced; 0301 basic medicine; Research; Nonalcoholic fatty liver; Receptor for Advanced Glycation End Products; RC648-665; Lipid Metabolism; Diseases of the endocrine glands. Clinical endocrinology; Sterol regulatory element binding protein-1c; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease; Type 2 diabetes mellitus; Animals; Advanced glycation end products; Sterol Regulatory Element Binding Protein 1

Nonalcoholic fatty liver disease (NAFLD) shares common pathogenic mechanisms of type 2 diabetes mellitus (T2DM) with upregulated advanced glycation end products (AGEs). Here, we aim to investigate the effect of FPS-ZM1, an inhibitor for receptor for AGEs (RAGE), on lipid deposition in the liver of mice.KK-Ay mice were used as models of T2DM with NAFLD, while C57BL/6j mice were controls. Additionally, KK-Ay mice were treated with DMSO (with a concentration of 1%), with or without FPS-ZM1 (3 mg/kg/day, i.p). Lipid deposition in hepatocytes was observed using oil red O stain. Levels of AGEs and RAGE were measured. Sterol regulatory element-binding protein-1c (SREBP-1c), as well as nuclear factor κB p65 (p65 nfκb) and mitogen-activated protein kinase p38 (p38 MAPK), were also detected.Lipid deposition is increased in the hepatocytes of KK-Ay mice compared to C57BL/6j mice. In addition, not only were the levels of AGEs elevated in plasma, but also the levels of RAGE in liver tissue. Although total SREBP-1c levels did not change in the liver of diabetic mice, mature SREBP-1c increased in KK-Ay mice with diabetes mellitus. Moreover, diabetic mice showed increased levels of phosphorylated-p65 nfκb (p-p65 nfκb) and phosphorylated-p38 MAPK (p-p38 MAPK). On the contrary, FPS-ZM1 decreased lipid deposition in liver cells, as well as mature SREBP-1c, p-p65 nfκb and p-p38 MAPK levels in liver tissue.Generally, FPS-ZM1 may attenuate lipid deposition in hepatocytes of diabetic mice via SREBP-1c down-regulation. This may depend on the downregulation of p65 nfκb and p38 MAPK phosphorylation.