Chronic hyperglycemia induces hepatocyte pyroptosis via Gα12/Gα13-associated endoplasmic reticulum stress: Effect of pharmacological intervention

• Published in: Life sciences (1973) 2025-01, Vol.360, p.123180, Article 123180
• Main Authors: Khan, Muhammad Sohaib, Tak, Jihoon, Kim, Yun Seok, Lee, Sang Gil, Lee, Eun Byul, Kim, Sang Geon
• Format: Article
• Language: English
• Subjects: ER stress; Fibrogenesis; Gα12/Gα13; Pyroptosis; VEGF
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2024.123180

Hyperglycemia induces pathophysiological changes. Endoplasmic reticulum (ER) stress with Gα12 overexpression may promote hepatocyte death. This study investigated whether sustained hyperglycemia triggers ER stress-associated pyroptosis and fibrosis in the liver alongside an overexpression of Gα12, and examined the potential link with VEGF-A levels. Mice were subjected to a high-fat diet (60 kcal% fat) with streptozotocin (50 mg/kg body weight, three consecutive times, between 12‐13th weeks). AZ2 (a functional Gα12 inhibitor) was treated at 10 mg/kg body weight (5 times/week, 3 weeks). Immunoblotting and immunohistochemistry analyses were performed. Hepatic Gα12/Gα13 were overexpressed in the diabetic mice. The following proteins downstream from the Gα12 axis were upregulated: PGC1α, PPARα, and SIRT1. Sustained hyperglycemia promoted ER stress marker levels. Histopathological and biochemical assays showed large-sized lipid droplet accumulation, hepatocyte degeneration, and damage as blood transaminase activities increased. Moreover, the diabetic condition increased IL-1β, caspase-1, and NLRP3 levels, which were supportive of pyroptosis. Consistently, the intensities of Masson's trichrome, collagen-1A1, α-SMA, vimentin, and fibronectin all increased. VEGF-A and VEGFR2 levels also increased in the liver and/or sera. The levels of hepatic pigment epithelial-derived factor (PEDF), a physiological antagonist of VEGF-A, decreased with its reciprocal increase in serum. These events were reversed by AZ2 treatment, supporting the role of Gα12 in hyperglycemic stress in the liver. Chronic hyperglycemia causes hepatic pyroptosis and fibrosis related to ER stress with Gα12/Gα13 and VEGF overexpression, which may be overcome by AZ2 treatments.