Mechanisms of high-glucose-induced mitochondrial damage and glycolipid accumulation in largemouth bass

Abstract

The carnivorous fish, largemouth bass (Micropterus salmoides), has difficulty metabolizing dietary carbohydrates, frequently resulting in issues with energy metabolism and fatty liver disease. Nevertheless, the molecular mechanisms involved are still not fully understood. The results of high-carbohydrate (HC) diets and high-glucose (HG) treatments in largemouth bass hepatocytes showed that high-glucose causes liver damage and glycolipid accumulation. High-glucose promoted the lipogenesis process by activating AMPK/ACC/SREBP-1 pathway and reduced bile acid synthesis by downregulating cholesterol 7-hydroxylase (cyp7a1) and sterol 12-hydroxylase (cyp8b1). Concurrently, HG treatments also caused mitochondrial fission and damage by increasing the expression of dynamin-related protein 1 (Drp1), leading to impaired mitochondria accumulation and mitochondria-dependent apoptosis via the p38 MAPK/Bcl-2/Casp3 pathway. Additionally, HG treatments decreased Sirt1 expression and relocated it from the nucleus to the cytoplasm, where it interacts with autophagosomes and lysosomes, inhibiting Pink1/Parkin-mediated mitophagy. This also led to the cytoplasmic translocation of Pink1 and its co-localization with Sirt1, indicating that Sirt1 regulates high glucose-induced metabolic stress by inhibiting the Pink1/Parkin mitophagy pathway. In summary, HG treatment induces mitochondrial damage and glycolipid accumulation in largemouth bass through mechanisms involving AMPK/SREBP1/ACC1-mediated lipogenesis, bile acid metabolism, Sirt-mediated mitophagy, and p38 MAPK/Bcl-2/Casp3-activated apoptosis.