Twisting of the spermatic cord: ischemia and reperfusion, toxicogenetic evaluation, and the effects of phosphatidylcholine in pre-clinical trials

Coelho, Henrique Rodrigues Scherer; Berno, Claudia Rodrigues; Falcão, Gustavo Ribeiro; Hildebrand, C R; Oliveira, Ricardo Jacó de; Antoniolli-Silva, Andréia Conceição Milan Brochado

doi:10.4238/gmr.15038529

Cited by 2 publications

(1 citation statement)

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“…Accumulation of CER and decrease of CL have been shown to promote cell death, oxidative stress, and inflammation ( 6 , 17 , 30 , 31 ). Since the accumulation of CER along with decreases of CL were found in NASH livers with I/R injury, the correlation between the aggressive hepatic injury and these dysregulated lipids was examined in terms of cell death and oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

Nonalcoholic steatohepatitis critically rewires the ischemia/reperfusion-induced dysregulation of cardiolipins and sphingolipids in mice

Yu¹,

Wang²,

Li³

et al. 2023

Hepatobiliary Surg Nutr

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Background Lipid dysregulation plays a fundamental role in nonalcoholic steatohepatitis (NASH), which is an emerging critical risk factor that aggravates hepatic ischemia/reperfusion (I/R) injury. However, the specific lipids that mediate the aggressive I/R injury in NASH livers have not yet been identified. Methods The mouse model of hepatic I/R injury on NASH was established on C56B/6J mice by first feeding the mice with a Western-style diet to induce NASH, then the NASH mice were subjected to surgical procedures to induce hepatic I/R injury. Untargeted lipidomics were performed to determine hepatic lipids in NASH livers with I/R injury through ultra-high performance liquid chromatography coupled with mass spectrometry. The pathology associated with the dysregulated lipids was examined. Results Lipidomics analyses identified cardiolipins (CL) and sphingolipids (SL), including ceramides (CER), glycosphingolipids, sphingosines, and sphingomyelins, as the most relevant lipid classes that characterized the lipid dysregulation in NASH livers with I/R injury. CER were increased in normal livers with I/R injury, and the I/R-induced increase of CER was further augmented in NASH livers. Metabolic pathway analysis revealed that the enzymes involved in the synthesis and degradation of CER were highly upregulated in NASH livers with I/R injury, including serine palmitoyltransferase 3 ( Sptlc3 ), ceramide synthase 2 ( Cers2 ), neutral sphingomyelinase 2 ( Smpd3 ), and glucosylceramidase beta 2 ( Gba2 ) that produced CER, and alkaline ceramidase 2 ( Acer2 ), alkaline ceramidase 3 ( Acer3 ), sphingosine kinase 1 ( Sphk1 ), sphingosine-1-phosphate lyase ( Sgpl1 ), and sphingosine-1-phosphate phosphatase 1 ( Sgpp1 ) that catalyzed the degradation of CER. CL were not affected by I/R challenge in normal livers, but CL was dramatically reduced in NASH livers with I/R injury. Consistently, metabolic pathway analyses revealed that the enzymes catalyzing the generation of CL were downregulated in NASH-I/R injury, including cardiolipin synthase ( Crls1 ) and tafazzin (Taz ). Notably, the I/R-induced oxidative stress and cell death were found to be aggravated in NASH livers, which were possibly mediated by the reduction of CL and accumulation of CER. Conclusions The I/R-induced dysregulation of CL and SL were critically rewired by NASH, which might potentially mediate the aggressive I/R injury in NASH livers.

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