Mitochondrial membrane protein mitofusin 2 as a potential therapeutic target for treating free fatty acid induced hepatic inflammation in dairy cows during early lactation

摘要

Inflammation is critical in the progression from benignhepatic lipidosis to pathological hepatic steatosis. Theobjective of this study was to examine the potential roleof the outer mitochondrial membrane protein mitofusin2 (MFN2) in the etiology of hepatic steatosis in dairycows during early lactation. Using a nested case–controldesign, we compared blood and liver samples from 10healthy cows and 10 age-matched cows with moderatefatty liver. Cows with moderate fatty liver had highliver triacylglycerols, elevated plasma concentrationsof free fatty acids (FFA) and β-hydroxybutyrate, andlow concentrations of glucose. Cows with moderatefatty liver had overactivated inflammatory pathwaysin the liver, as indicated by increased abundance ofphosphorylated nuclear factor κB (NF-κB) p65, NLRfamily pyrin domain containing 3 (NLRP3) and caspase-1 inflammasome protein, and elevated plasmaconcentrations and hepatic mRNA abundance of theirmolecular targets IL-1β, IL-6, and tumor necrosis factorα (TNF-α). In the cell culture model, we were ableto replicate our findings in cows with moderate fattyliver: 1.2 mM exogenous FFA decreased the abundanceof MFN2 and upregulated phosphorylation levels ofthe inhibitor of NF-κB (IκB) α and NF-κB p65, theIκB kinase β activity, and the abundance of NLRP3,caspase-1, IL-1β, IL-6, and TNF-α. Whereas MFN2knockdown potentiated the FFA-induced activation ofthese inflammatory pathways, overexpression of MFN2attenuated the detrimental effect of excess exogenousFFA by improving mitochondrial function and decreasingthe release of reactive oxygen species, suggestingthat MFN2 may be a potential therapeutic target forFFA-induced hepatic inflammation in dairy cows duringearly lactation.