Role of AMPK/ACC/SREBP-1 and MAPK Pathways in Glucose Intolerance and Liver Dysfunction of Largemouth Bass

Background and Objectives Largemouth bass ( Micropterus salmoides ), a carnivorous fish, struggles to process dietary carbohydrates, often resulting in energy metabolism issues and fatty liver disease. This study explored the liver glycolipid accumulation and mitochondrial dysfunction in both largemouth bass and primary hepatocytes treated with high glucose. Methods An 8-week feeding experiment was conducted to evaluated the effects of high carbohydrate (HC) diet on liver morphology, fatty acid metabolism, bile acid metabolism, and MAPK signaling pathways in largemouth bass. Primary hepatocytes were treated with high-glucose (HG) medium to simulate the conditions of high carbohydrate feeding to further evaluated the effects of high-glucose treatment on cell growth, ROS production, antioxidant capacity, mitochondrial fusion, fission, mitophagy and mitochondrial apoptosis. Results The results showed that the HC diet significantly increased the hepatosomatic and visceral somatic indices, causing liver enlargement, mitochondrial damage, and glycolipid buildup. Compared to a control diet, the HC diet enhanced lipid synthesis through the AMPK/ACC/SREBP-1 pathway and increased the phosphorylation levels of ERK, JNK and p38 MAPK, while it decreased bile acid synthesis by downregulating cholesterol 7-hydroxylase ( CYP7A1 ) and sterol 12-hydroxylase ( CYP8B1 ). In vitro experiments showed that high glucose (HG) treatment in primary hepatocytes inhibited cell growth, promoted apoptosis, increased reactive oxygen species (ROS), and reduced antioxidant capacity. Mechanistically, HG treatment led to mitochondrial fission and damage. Damaged mitochondria bind to autophagosomes for lysosomal degradation, resulting in mitochondrion-dependent apoptosis by regulating p38 MAPK/BCL-2/CAS3 signaling pathway. Conclusions High glucose could not only induce accumulation of lipid and glycogen mediated by the AMPK/ACC/SREBP-1 signaling pathway, but could activate p38MAPK-mediated signaling to induce mitochondrial apoptosis.