Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabe...Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evi-dence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipo-genesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transform-ing growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription fac-tors, namely peroxisome proliferator-activated receptor(PPAR)-α. Recent studies have proposed downregula-tion of PPAR-α in cases of hepatic steatosis. This re-view discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.展开更多
The Ca 2+-binding protein of the EF-hand type,S100B,exerts both intracellular and extracellular regulatory activities.As an intracellular regulator,S100B is involved in the regulation of energy metabolism,transcriptio...The Ca 2+-binding protein of the EF-hand type,S100B,exerts both intracellular and extracellular regulatory activities.As an intracellular regulator,S100B is involved in the regulation of energy metabolism,transcription,protein phosphorylation,cell proliferation,survival,differentiation and motility,and Ca 2+ homeostasis,by interacting with a wide array of proteins(i.e.,enzymes,enzyme substrates,cytoskeletal subunits,scaffold/adaptor proteins,transcription factors,ubiquitin E3 ligases,ion channels) in a restricted number of cell types.As an extracellular signal,S100B engages the pattern recognition receptor,receptor for advanced glycation end-products(RAGE),on immune cells as well as on neuronal,astrocytic and microglial cells,vascular smooth muscle cells,skeletal myoblasts and cardiomyocytes.However,RAGE may not be the sole receptor activated by S100B,the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types.Moreover,extracellular effects of S100B vary depending on its local concentration.Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury,which is up to a few nM levels,S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis.The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development,repair and regeneration.展开更多
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of...Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells.Macrophages are embryo-or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome,atherosclerosis,fibrosis or cancer.Macrophage metabolism has largely been studied in vitro.However,different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions.This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions.Here,we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.展开更多
Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most imp...Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor γ （PPARγ）, which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPAR7 agonists are therapeutic agents used in the treatment of type 2 diabetes. This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARγ in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARγ modulators.展开更多
Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic di...Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases.The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects,inducing insulin resistance through increased inflammation,impaired thermogenesis,and adipose tissue fibrosis.Meanwhile,adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis,facilitating the clearance of dead adipocytes,and promoting mitochondrial transfer.Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions.Recently,the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology.In this review,we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity,as well as explore the potential of drug delivery systems targeting macrophages,aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.展开更多
Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung adenocarcinomas.Tyrosine kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic ...Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung adenocarcinomas.Tyrosine kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage,but also a variety of adverse events.Skin toxicities,hematological deficiencies,nausea,vomiting,diarrhea,and headache are among the most common,with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently.In normal epithelia,RTKs regulate tissue homeostasis.For example,EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling.Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations.Mechanistically,blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK.This innate immune response within the tumor microenvironment(TME)involves increased antigen presentation and effector T cell recruitment that may participate in therapy response.This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy.However,early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events,especially pneumonitis,hepatitis,and pulmonary fibrosis.Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells,cancer cells,and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.展开更多
The mammalian carboxylesterase 1(Ces1/CES1)family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids.To investigate the pharmacological and physiological roles of Ces1/CES1,we gen...The mammalian carboxylesterase 1(Ces1/CES1)family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids.To investigate the pharmacological and physiological roles of Ces1/CES1,we generated Ces1 cluster knockout(Ces1^(-/-))mice,and a hepatic human CES1 transgenic model in the Ces1^(-/-)background(TgCES1).Ces1^(-/-)mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues.TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney.Ces1 and hCES1 activity increased irinotecan toxicity,likely by enhancing the formation of pharmacodynamically active SN-38.Ces1^(-/-)mice also showed markedly increased capecitabine plasma exposure,which was moderately decreased in TgCES1 mice.Ces1^(-/-)mice were overweight with increased adipose tissue,white adipose tissue inflammation(in males),a higher lipid load in brown adipose tissue,and impaired blood glucose tolerance(in males).These phenotypes were mostly reversed in TgCES1 mice.TgCES1 mice displayed increased triglyceride secretion from liver to plasma,together with higher triglyceride levels in the male liver.These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification.Ces1^(-/-)and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.展开更多
文摘Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evi-dence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipo-genesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transform-ing growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription fac-tors, namely peroxisome proliferator-activated receptor(PPAR)-α. Recent studies have proposed downregula-tion of PPAR-α in cases of hepatic steatosis. This re-view discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.
基金Supported by Ministero dell'Università e della Ricerca,No. PRIN 2007LNKSYS,No.2007AWZTHH_004 and No.2009WBFZYM_002Association Fran aise contre les Myopathies,No. Project 12992+1 种基金Associazione Italiana per la Ricerca sul Cancro,No. Project 6021Fondazione Cassa di Risparmio di Perugia,No. 2007.0218.020,No.2009.020.0021 and No.2012.0241.021
文摘The Ca 2+-binding protein of the EF-hand type,S100B,exerts both intracellular and extracellular regulatory activities.As an intracellular regulator,S100B is involved in the regulation of energy metabolism,transcription,protein phosphorylation,cell proliferation,survival,differentiation and motility,and Ca 2+ homeostasis,by interacting with a wide array of proteins(i.e.,enzymes,enzyme substrates,cytoskeletal subunits,scaffold/adaptor proteins,transcription factors,ubiquitin E3 ligases,ion channels) in a restricted number of cell types.As an extracellular signal,S100B engages the pattern recognition receptor,receptor for advanced glycation end-products(RAGE),on immune cells as well as on neuronal,astrocytic and microglial cells,vascular smooth muscle cells,skeletal myoblasts and cardiomyocytes.However,RAGE may not be the sole receptor activated by S100B,the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types.Moreover,extracellular effects of S100B vary depending on its local concentration.Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury,which is up to a few nM levels,S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis.The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development,repair and regeneration.
基金SKW and the project that gave rise to these results received support in the form of a fellowship from the La Caixa Foundation(ID 100010434)The fellowship code is LCF/BQ/PR20/11770008+5 种基金GD is supported by a European Molecular Biology Organization Long-term Fellowship(ALTF 379-2019)This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.892965IHM is supported by a La Caixa INPhINIT fellowship(ID 100010434,fellowship code:LCF/BQ/IN17/11620074)Work in the DS laboratory is funded by the CNIC,by the European Research Council(ERC-2016-Consolidator Grant 725091)by the Agencia Estatal de Investigación(PID2019-108157RB)by the Comunidad de Madrid(B2017/BMD-3733 Immunothercan-CM),by Atresmedia(Constantes y Vitales prize),by the Fondo Solidario Juntos(Banco Santander),and by the FundacióLa Maratóde TV3(201723).The CNIC is supported by the Instituto de Salud Carlos III(ISCIII),the MICINN and the Pro CNIC Foundation.
文摘Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells.Macrophages are embryo-or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome,atherosclerosis,fibrosis or cancer.Macrophage metabolism has largely been studied in vitro.However,different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions.This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions.Here,we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
基金supported by the Etat de Vaud and the Swiss National Science Foundation.
文摘Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor γ （PPARγ）, which is a fatty acid- and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPAR7 agonists are therapeutic agents used in the treatment of type 2 diabetes. This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARγ in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARγ modulators.
基金funded by the National Natural Science Foundation of China(32000525)Shanghai Municipal Science and Technology Major Project,Shanghai Municipal Science and Technology Major Project(TM202101H001)the Lingang Laboratory(LG202103-03-01).
文摘Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases.The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects,inducing insulin resistance through increased inflammation,impaired thermogenesis,and adipose tissue fibrosis.Meanwhile,adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis,facilitating the clearance of dead adipocytes,and promoting mitochondrial transfer.Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions.Recently,the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology.In this review,we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity,as well as explore the potential of drug delivery systems targeting macrophages,aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.
文摘Receptor tyrosine kinases(RTKs)bearing oncogenic mutations in EGFR,ALK and ROS1 occur in a significant subset of lung adenocarcinomas.Tyrosine kinase inhibitors(TKIs)targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage,but also a variety of adverse events.Skin toxicities,hematological deficiencies,nausea,vomiting,diarrhea,and headache are among the most common,with more acute and often fatal side effects such as liver failure and interstitial lung disease occurring less frequently.In normal epithelia,RTKs regulate tissue homeostasis.For example,EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling.Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations.Mechanistically,blockade of EGFR causes a Type I interferon response within keratinocytes and in carcinoma cells driven by this RTK.This innate immune response within the tumor microenvironment(TME)involves increased antigen presentation and effector T cell recruitment that may participate in therapy response.This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology agents that rely on T-cell inflammation for efficacy.However,early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events,especially pneumonitis,hepatitis,and pulmonary fibrosis.Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells,cancer cells,and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.
基金funded in part by the China Scholarship Council(CSC Scholarship No.201506240145 to Changpei Gan)。
文摘The mammalian carboxylesterase 1(Ces1/CES1)family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids.To investigate the pharmacological and physiological roles of Ces1/CES1,we generated Ces1 cluster knockout(Ces1^(-/-))mice,and a hepatic human CES1 transgenic model in the Ces1^(-/-)background(TgCES1).Ces1^(-/-)mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues.TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney.Ces1 and hCES1 activity increased irinotecan toxicity,likely by enhancing the formation of pharmacodynamically active SN-38.Ces1^(-/-)mice also showed markedly increased capecitabine plasma exposure,which was moderately decreased in TgCES1 mice.Ces1^(-/-)mice were overweight with increased adipose tissue,white adipose tissue inflammation(in males),a higher lipid load in brown adipose tissue,and impaired blood glucose tolerance(in males).These phenotypes were mostly reversed in TgCES1 mice.TgCES1 mice displayed increased triglyceride secretion from liver to plasma,together with higher triglyceride levels in the male liver.These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification.Ces1^(-/-)and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.
