The Protective Effects Of MYDGF On Non-alcoholic Fatty Liver In Mice And Its Possible Mechanisms

Background and objectiveWhether bone marrow modulates systemic metabolism remains unknown.Our recent study suggested that myeloid-derived growth factor(MYDGF),which is secreted by bone marrow cells(BMCs),improves type 2 diabetes in mice insulin resistance(IR).Here,we explored whether MYDGF protects against non-alcoholic fatty liver disease(NAFLD)and serves as a factor in the crosstalk between bone marrow and the liver that regulates liver fat metabolism.Methods1.Myeloid cell specific MYDGF deficient(MYDGF-/-)mice and wide type(WT)mice on C57BL/6 background were fed with high-fat diet(HFD)to induce NAFLD.2.Liver MYDGF expression of adeno-associated viruses(AAV)-MYDGF,bone marrow transplantion(BMT)and in situ bone marrow MYDGF expression.Besides,inhibitor of kappa B kinase beta(IKK?)was silenced by siRNA in vivo.3.Hepatic lipid deposition in mice was detected by hematoxylin-eosin(HE)staining,oil red O staining and electron microscopy.Immunohistochemistry(IHC)and Sirius red staining were used to detect liver fibrosis in mice.IHC was used to detect the infiltration of liver macrophages.Reverse transcription-polymerise chain reaction(RT-PCR)was used to detect the expression of lipid synthesis genes and inflammatory factors in liver tissue,and the expressions of inflammatory proteins such as P-p65 and P-I?B? were detected by western blot.At the same time,the expressions of lipid proteins,such as pSREBP1c,nSREBP1c,FAS,ACC1 and SCD1 were detected by western blot.4.Primary mouse hepatocytes(PMHs)were treated with palmitic acid(PA),lipid deposition,lipogenesis and inflammation were measured in PMHs co-culture with bone marrow cells(BMCs),supplement with rMYDGF under PA-stimulated conditions or silenced by IKK? siRNA in vitro.5.The lipid deposition was detected by oil red O staining,and the P65 nuclear translocation was detected by immunofluorescence(IF).RT-PCR was used to detect the expression of lipid synthesis genes and inflammatory factors in PMHs.Western blot was used to detect the expression of inflammatory proteins such as P-p65 and P-IkB?.At the same time,the expression of lipogenesis proteins such as pSREBPlc,nSREBP1c,FAS,ACC1 and SCD1 were detected by western blot.Results1.Myeloid cell specific MYDGF deficiency aggravated inflammation,lipogenesis,hepatic steatosis,and fibrosis in vivo.2.MYDGF restoration by liver MYDGF expression,BMT and bone marrow MYDGF expression alleviated inflammation,lipogenesis,hepatic steatosis and fibrosis.3.Both the supplementation with rMYDGF and coculture of BMCs attenuated hepatocyte inflammation and fat deposition.4.Silencing IKK? in vivo and in vitro alleviated inflammation,lipogenesis and lipid deposition.5.Mechanistically,MYDGF protected NAFLD through IKK?/NF-?B signaling pathway.ConclusionThese results demonstrated that MYDGF plays a protective role in obesity-related NAFLD via IKK?/NF-?B signaling pathway,and serves as a crosstalk factor between bone marrow and liver.Bone marrow may serve as a therapeutic target for metabolic disorders such as NAFLD,obesity and diabetes.