Global and mitochondrial choline dehydrogenase contribute to goose fatty liver formation by differentially regulating energy metabolism, autophagy and oxidative stress related pathways.

The liver of geese has a strong ability to deposit fat and also has the ability to resist inflammation. Goose fatty liver represents a unique physiological model that exhibits no or low-level inflammation despite severe steatosis. Mitochondria and their proteins play a crucial role in the regulation of hepatic inflammation. However, it remains unclear whether choline dehydrogenase (CHDH), a mitochondrial protein, is involved in fat deposition and inflammation resistance in goose fatty liver formation. Here, we observed distinct expression patterns of mitochondrial CHDH (mCHDH) other than global CHDH (gCHDH) in goose versus mouse fatty livers, highlighting the unique role of mCHDH in goose fatty liver formation. Overexpression of gCHDH in goose primary hepatocytes led to increased cellular lipid accumulation, mitochondrial membrane potential (MMP) and respiratory chain complex II activity, alongside activation of immune response, apoptosis, cell adhesion, and lipid metabolism-related pathways. Moreover, overexpression studies in HepG2 cells revealed that both gCHDH and a mitochondrial targeting sequence-mutant CHDH (Δ1-38CHDH) elevated MMP, but they differentially regulated reactive oxygen species (ROS) level (Δ1-38CHDH slightly reduced intracellular ROS level) and the abundance of mitochondria-related proteins (gCHDH selectively increased tAMPK and decreased LC3B in mitochondrial lysates, whereas Δ1-38CHDH mainly reduced tAMPK and pAMPK in whole-cell lysates). Furthermore, transcriptome sequencing and mass spectrometry analyses revealed that CHDH may participate in processes such as immune response, ubiquitin-mediated degradation, autophagy, signal transduction and lipid metabolism. In summary, gCHDH and mCHDH contribute to the formation of goose fatty liver by affecting mitochondrial protein composition (AMPK, LC3B), mitochondrial function and related biological processes, though their effects exhibit certain differences. These findings provide new insights into the mechanism underlying the uniqueness of goose fatty liver.