Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male m...Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.展开更多
基金National Key Research and Development Program of China,Grant/Award Number:2021YFF0702200Science and Technology Projects in Guangzhou,Grant/Award Number:202206010084,202206010197 and 202206060002+1 种基金Guangdong S&T programme,Grant/Award Number:2009A081000002 and 2023B0303040004Technology Planning Project of Linzhi,Grant/Award Number:2023-YZ-01。
文摘Background:The aim of the study was to develop a non-human primate model of metabolic dysfunction in Macaca fascicularis using chronic high-fat diet(HFD)to mimic clinical disease progression.Methods:Thirty-five male macaques aged 10-15 years underwent an 18-month HFD intervention.Physiological parameters(BMI,BP,hematology),liver fat fraction(evaluated by ultrasound/MRI),cardiac function(assessed by echocardiography),and histopathology(using liver biopsy)were measured before and after the intervention.Serum proteomics with KEGG/STRING analyses identified molecular mechanisms.Results:Within 6 months,HFD induced dyslipidemia(elevated TG,TCHO,HDL-C,LDL-C).After 18 months,metabolic dysfunction-associated steatohepatitis(MASH)was confirmed by histopathology in 57.14%(16/28)of macaques,diabetes(elevated FPG/HbA1c)in 17.86%(5/28),and myocardial hypertrophy(elevated LVMass/LAD)in 46.43%(13/28).Proteomics identified Bile acid-CoA:amino acid N-acyltransferase(BAAT)as a MASH hallmark protein,the level of which was inversely correlated with the degree of fibrosis.For diabetes,citrate synthase(CS)and malate dehydrogenase 1(MDH1)impaired glucose oxidation via the TCA cycle,while hexose-6-phosphate de-hydrogenase(H6PD)disrupted gluconeogenesis.Myocardial hypertrophy was associ-ated with the downregulation of SRC proto-oncogene,non-receptor tyrosine kinase(SRC),mitogen-activated protein kinase 14(MAPK14),emerin(EMD),and integrin subunit beta 1(ITGB1).Conclusions:An 18-month HFD successfully established a translational M.fascicula-ris model replicating key metabolic disorders(MASH,diabetes,cardiac hypertrophy).BAAT,CS/MDH1/H6PD,and SRC/MAPK14/EMD/ITGB1 were identified as mecha-nistic biomarkers for these conditions.
