Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component ...Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.展开更多
Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without co...Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.展开更多
Although primary vesical calculi is an ancient disease,the mechanism of calculi formation remains unclear.In this study,we established a novel primary vesical calculi model with D,L-choline tartrate in mice.Compared w...Although primary vesical calculi is an ancient disease,the mechanism of calculi formation remains unclear.In this study,we established a novel primary vesical calculi model with D,L-choline tartrate in mice.Compared with commonly used melamine and ethylene glycol models,our model was the only approach that induced vesical calculi without causing kidney injury.Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi,yet the effect of fat is overlooked.To assay the relationship of dietary fat with the formation of primary vesical calculi,D,L-choline tartrate-treated mice were fed a high-fat,low-fat,or normal-fat diet.Genetic changes in the mouse bladder were detected with transcriptome analysis.A high-fat diet remarkably reduced the morbidity of primary vesical calculi.Higher fatty acid levels in serum and urine were observed in the high-fat diet group,and more intact epithelia in bladder were observed in the same group compared with the normal-and low-fat diet groups,suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure.Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14(Cxcl14)was upregulated in the bladders of high-fat diet-fed mice compared with those of normal-or low-fat diet-fed mice,which was consistent with histological observations.The expression of CXCL14 significantly increased in the bladder in the high-fat diet group.CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages,which led to phagocytosis of budding crystals and prevented accumulation of calculi.In human bladder epithelia(HCV-29)cells,high fatty acid supplementation significantly increased the expression of CXCL14.Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi,which provides new ideas for the reduction of morbidity of primary vesical calculi.展开更多
基金financially supported by grants from the National Natural Science Foundation of China(8217087381871095)+1 种基金the National Key R&D Program of China(2018YFC2000304)the Tsinghua University Spring Breeze Fund(20211080005).
文摘Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.
基金supported by the National Natural Science Foundation of China (81871095 and 82170873)the National Key R&D Program of China (2018YFC2000304)+1 种基金the Tsinghua Precision Medicine Foundation (10001020132, China)the Tsinghua University Spring Breeze Fund (20211080005, China)。
文摘Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.
基金supported by grants from the National Natural Science Foundation of China(81974503 and 81871095)the National Key R&D Program of China(2018YFC2000304)+3 种基金the Key International S&T Cooperation Program of China(2016YFE0113700)the European Union’s Horizon 2020 Research and Innovation Program(633589)the Natural Science Foundation of Beijing,China(7202096)the Tsinghua University independent research program(7191007,China)。
文摘Although primary vesical calculi is an ancient disease,the mechanism of calculi formation remains unclear.In this study,we established a novel primary vesical calculi model with D,L-choline tartrate in mice.Compared with commonly used melamine and ethylene glycol models,our model was the only approach that induced vesical calculi without causing kidney injury.Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi,yet the effect of fat is overlooked.To assay the relationship of dietary fat with the formation of primary vesical calculi,D,L-choline tartrate-treated mice were fed a high-fat,low-fat,or normal-fat diet.Genetic changes in the mouse bladder were detected with transcriptome analysis.A high-fat diet remarkably reduced the morbidity of primary vesical calculi.Higher fatty acid levels in serum and urine were observed in the high-fat diet group,and more intact epithelia in bladder were observed in the same group compared with the normal-and low-fat diet groups,suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure.Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14(Cxcl14)was upregulated in the bladders of high-fat diet-fed mice compared with those of normal-or low-fat diet-fed mice,which was consistent with histological observations.The expression of CXCL14 significantly increased in the bladder in the high-fat diet group.CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages,which led to phagocytosis of budding crystals and prevented accumulation of calculi.In human bladder epithelia(HCV-29)cells,high fatty acid supplementation significantly increased the expression of CXCL14.Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi,which provides new ideas for the reduction of morbidity of primary vesical calculi.