Comparative transcriptomic analysis reveals an association of gibel carp fatty liver with ferroptosis pathway

Abstract

Background Fatty liver has become a main problem that causes huge economic losses in many aquaculture modes. It is a common physiological or pathological phenomenon in aquaculture, but the causes and occurring mechanism are remaining enigmatic. Methods Each three liver samples from the control group of allogynogenetic gibel carp with normal liver and the overfeeding group with fatty liver were collected randomly for the detailed comparison of histological structure, lipid accumulation, transcriptomic profile, latent pathway identification analysis (LPIA), marker gene expression, and hepatocyte mitochondria analyses. Results Compared to normal liver, larger hepatocytes and more lipid accumulation were observed in fatty liver. Transcriptomic analysis between fatty liver and normal liver showed a totally different transcriptional trajectory. GO terms and KEGG pathways analyses revealed several enriched pathways in fatty liver, such as lipid biosynthesis, degradation accumulation, peroxidation, or metabolism and redox balance activities. LPIA identified an activated ferroptosis pathway in the fatty liver. qPCR analysis confirmed that gpx4, a negative regulator of ferroptosis, was significantly downregulated while the other three positively regulated marker genes, such as acsl4, tfr1 and gcl, were upregulated in fatty liver. Moreover, the hepatocytes of fatty liver had more condensed mitochondria and some of their outer membranes were almost ruptured. Conclusions We reveal an association between ferroptosis and fish fatty liver for the first time, suggesting that ferroptosis might be activated in liver fatty. Therefore, the current study provides a clue for future studies on fish fatty liver problems.

Acyl-CoA synthase ACSL4: an essential target in ferroptosis and fatty acid metabolism

“…Similarly, emerging evidence has revealed a close relationship between liver diseases and ACSL4. ACSL4 was upregulated in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) [167,168] . The hypomethylated CpG site of ACSL4 was associated with an increased risk of NAFLD and NASH [169] .…”

“…ACSL4 was upregulated in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). [ 167 , 168 ] The hypomethylated CpG site of ACSL4 was associated with an increased risk of NAFLD and NASH. [ 169 ] In addition, the suppression of ACSL4 by ROSI or siRNA significantly alleviated arsenic-induced NASH and ferroptosis by diminishing the 5-HETE content.…”

Cadmium aggravates liver injury by activating ferroptosis and neutrophil extracellular traps formation in Nile tilapia (Oreochromis niloticus)

“…14 A study on Gibel carp fatty liver associated with ferroptosis reported that the positive regulator ACSL4 is significantly upregulated in fatty liver, implying the importance of ACSL4 in the regulation ferroptosis. 62 Our data show that SLC7A11 expression was downregulated, while ACSL4 expression was significantly upregulated. In our study, we established an association between ferroptosis and Cd-triggered liver injury through marker gene expression and relevant ferroptosis indicators.…”

“…ACSL4 is an essential driver of ferroptosis, which can ligate long‐chain polyunsaturated fatty acids with coenzyme A, and the products are re‐esterified into phospholipids by other enzymes 14 . A study on Gibel carp fatty liver associated with ferroptosis reported that the positive regulator ACSL4 is significantly upregulated in fatty liver, implying the importance of ACSL4 in the regulation ferroptosis 62 . Our data show that SLC7A11 expression was downregulated, while ACSL4 expression was significantly upregulated.…”

Effects of Curcumin on Oxidative Stress and Ferroptosis in Acute Ammonia Stress-Induced Liver Injury in Gibel Carp (Carassius gibelio)

“…In addition to autophagy and apoptosis, oxidative stress pathways can also lead to cellular ferroptosis, a non-apoptosis-regulated form of cell death [ 13 ]. It has been reported that ferroptosis was associated with a fatty liver, where the outer mitochondrial membrane was broken and shrunken in gibel carp [ 30 ]. In the present study, ferroptosis was induced in the TAN group as reflected by mitochondrial atrophy, reduction or disappearance of cristae, and increased membrane density.…”