Serpina3c protects against high-fat diet-induced pancreatic dysfunction through the JNK-related pathway

Serpina3 is a member of the serine protease inhibitor family and is involved in the inflammatory response. In this study, we investigated the effect of Serpina3c on pancreatic function in hypercholesterolemic mice. To investigate the role of Serpina3c in hyperlipidaemia, Serpina3c knockout mice were bred with Apoe-knockout mice (on a C57BL/6 background) to generate heterozygous Serpina3c-Apoe double knockout (Serpina3c+/−/Apoe+/−) mice and were then bred to obtain homozygotes. C57BL/6, Serpina3c−/−, Apoe−/−, and Apoe−/-Serpina3c−/− mice were fed normal chow, and Apoe−/− and Apoe−/-Serpina3c−/− mice were fed a high-fat diet (HFD). After feeding for 3 months, the mice were monitored for body weight, blood glucose, glucose tolerance, and insulin tolerance test (ITT). ELISA and immunohistochemistry were used to detect insulin levels and glucagon expression. Immunohistochemical staining for macrophages in the pancreas was also performed. Western blot analysis was performed on pancreatic tissues to detect the protein levels of insulin-associated molecules, the metalloproteinase MMP2, the tissue inhibitor TIMP2 and components of the JNK-related pathway. Blood glucose levels, glucose tolerance, and ITT were not significantly different among the groups. Serpina3c knockout resulted in blood lipid abnormalities in mice under HFD conditions. Insulin secretion was decreased in Apoe−/-Serpina3c−/− mice compared with Apoe−/− mice under normal chow conditions. In addition, Apoe−/-Serpina3c−/− mice exhibited increased insulin and glucagon secretion and expression after three months of HFD feeding, but insulin secretion was decreased in Apoe−/-Serpina3c−/− mice compared with Apoe−/− mice after the fifth month of HFD feeding. Serpina3c knockout increased MMP2 protein levels, whereas TIMP2 levels in the pancreas were decreased. Furthermore, Serpina3c knockout significantly upregulated the number of macrophages in the pancreas under HFD conditions. The JNK/AKT/FOXO1/PDX-1 axis was found to be involved in Serpina3c-regulated insulin secretion. These novel findings show that Serpina3c could play a protective role in insulin secretion partly through the JNK-related pathway under HFD conditions.