BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is one of the main chronic liver diseases.However,the roles of mitochondrial carnitine palmitoyl transferase-II(CPT-II)downregulation and liver can...BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is one of the main chronic liver diseases.However,the roles of mitochondrial carnitine palmitoyl transferase-II(CPT-II)downregulation and liver cancer stem cell(LCSC)activation remain to be identified.AIM To investigate the dynamic alterations in CPT-II inactivity and LCSC activation during the malignant progression of MAFLD.METHODS Dynamic models of mouse MAFLD were generated via the consumption of a high-fat diet or the addition of 2-fluorenylacetamide for hepatocarcinogenesis.The mice were divided into groups on the basis of hematoxylin and eosin staining.Biochemistries,CPT-II,intrahepatic T cells,and LCSCs were determined and confirmed in clinical samples.The mitochondrial membrane potential(MMP)was analyzed.Differentially expressed genes were screened via RNA sequencing and enriched in KEGG pathways or GO functions.RESULTS Dynamic models of MAFLD malignant transformation were successfully generated on the basis of pathological examination.Hepatic lipid accumulation was associated with the loss of mitochondrial CPT-II activity and alterations in the MMP,with decreases in liver CD3+or CD4+T cells and increased AFP levels.In the lipid accumulation microenvironment,mitochondrial CPT-II was inactivated,followed by aberrant activation of CD44+or CD24+LCSCs,as validated in MAFLD or hepatocellular carcinoma patient samples.In terms of mechanism,the biological process category focused mainly on the metabolic regulation of cells in response to external stimuli.The enriched molecular functions included protein binding,cell apoptosis,and cell proliferation.CONCLUSION CPT-II inactivity promotes the malignant progression of MAFLD via the loss of innate immune function and abnormal LCSC activation.展开更多
Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseas...Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world.The complex mechanisms of NAFLD formation are still under identification.Carnitine palmitoyltransferase-Ⅱ(CPT-Ⅱ)on inner mitochondrial membrane(IMM)regulates long chain fatty acidβ-oxidation,and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD.The sequences of its peptide chain and DNA nucleotides have been identified,and the catalytic activity of CPT-Ⅱ is affected on its gene mutations,deficiency,enzymatic thermal instability,circulating carnitine level and so on.Recently,the CPT-Ⅱ dysfunction has been discovered in models of liver lipid accumulation.Meanwhile,the malignant transformation of hepatocyte-related CD44^(+) stem T cell activation,high levels of tumor-related biomarkers(AFP,GPC3)and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology.This review focuses on some of the progress of CPT-Ⅱ inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.展开更多
基金Supported by the National Natural Science Foundation of China,No.32470985 and No.81673241.
文摘BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is one of the main chronic liver diseases.However,the roles of mitochondrial carnitine palmitoyl transferase-II(CPT-II)downregulation and liver cancer stem cell(LCSC)activation remain to be identified.AIM To investigate the dynamic alterations in CPT-II inactivity and LCSC activation during the malignant progression of MAFLD.METHODS Dynamic models of mouse MAFLD were generated via the consumption of a high-fat diet or the addition of 2-fluorenylacetamide for hepatocarcinogenesis.The mice were divided into groups on the basis of hematoxylin and eosin staining.Biochemistries,CPT-II,intrahepatic T cells,and LCSCs were determined and confirmed in clinical samples.The mitochondrial membrane potential(MMP)was analyzed.Differentially expressed genes were screened via RNA sequencing and enriched in KEGG pathways or GO functions.RESULTS Dynamic models of MAFLD malignant transformation were successfully generated on the basis of pathological examination.Hepatic lipid accumulation was associated with the loss of mitochondrial CPT-II activity and alterations in the MMP,with decreases in liver CD3+or CD4+T cells and increased AFP levels.In the lipid accumulation microenvironment,mitochondrial CPT-II was inactivated,followed by aberrant activation of CD44+or CD24+LCSCs,as validated in MAFLD or hepatocellular carcinoma patient samples.In terms of mechanism,the biological process category focused mainly on the metabolic regulation of cells in response to external stimuli.The enriched molecular functions included protein binding,cell apoptosis,and cell proliferation.CONCLUSION CPT-II inactivity promotes the malignant progression of MAFLD via the loss of innate immune function and abnormal LCSC activation.
基金Supported by the National Natural Science Foundation of China,No.81873915 and No.31872738the Key Plan of Nantong S&T Development,No.MS12020021the S&T Program of Medical School of Nantong University,No.TDYX2021010.
文摘Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world.The complex mechanisms of NAFLD formation are still under identification.Carnitine palmitoyltransferase-Ⅱ(CPT-Ⅱ)on inner mitochondrial membrane(IMM)regulates long chain fatty acidβ-oxidation,and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD.The sequences of its peptide chain and DNA nucleotides have been identified,and the catalytic activity of CPT-Ⅱ is affected on its gene mutations,deficiency,enzymatic thermal instability,circulating carnitine level and so on.Recently,the CPT-Ⅱ dysfunction has been discovered in models of liver lipid accumulation.Meanwhile,the malignant transformation of hepatocyte-related CD44^(+) stem T cell activation,high levels of tumor-related biomarkers(AFP,GPC3)and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology.This review focuses on some of the progress of CPT-Ⅱ inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.
