Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

• DOI: 10.1002/ctm2.1325
• Publication Date: 2023-07-07T05:50:15Z
• Authors: Tingting Lv; Xiaofeng Xiong; Wei Yan; Mei Liu; Hongwei Xu; Qin He
• Keywords: Steatohepatitis

Abstract Background Mitochondria play central roles in metabolic diseases including nonalcoholic steatohepatitis (NASH). However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with metabolism. Nevertheless, the GCN5L1 are unclear. Aims and methods The expression was detected fatty livers patients animals. Hepatocyte‐specific deficiency or overexpression mice were used to induce models by feeding a high‐fat/high‐cholesterol methionine‐choline deficient diet. molecular mechanisms underlying GCN5L1‐regulated further explored verified mice. Results conclusions increased patients. Upregulated level also illustrated Mice hepatocyte‐specific conditional knockout improved inflammatory response compared flox/flox augmented response. Mechanically, acetylated CypD enhanced its binding ATP5B, which induced opening permeability transition pores release ROS into cytoplasm. promoted ferroptosis hepatocytes accumulation high mobility group box microenvironment, recruited neutrophils generation neutrophil extracellular traps (NETs). NETs block impaired GCN5L1‐induced progression. Furthermore, upregulation contributed lipid overload‐induced endoplasmic reticulum stress. Together, has vital function promoting regulating oxidative metabolism hepatic microenvironment. Thus, might be potential intervention target treatment.