Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic damage.Hyperlipidemia(HLP)is the lea...Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic damage.Hyperlipidemia(HLP)is the leading risk factor for NAFLD.This study aims to illuminate the causative contributor and potential mechanism of Kallistatin(KAL)mediating HLP to NAFLD.221 healthy control and 253 HLP subjects,62 healthy control and 44 NAFLD subjects were enrolled.The plasma KAL was significantly elevated in HLP subjects,especially in hypertriglyceridemia(HTG)subjects,and positively correlated with liver injury.Further,KAL levels of NAFLD patients were significantly up-regulated.KAL transgenic mice induced hepatic steatosis,inflammation,and fibrosis with time and accelerated inflammation development in high-fat diet(HFD)mice.In contrast,KAL knockout ameliorated steatosis and inflammation in high-fructose diet(HFruD)and methionine and choline-deficient(MCD)diet-induced NAFLD rats.Mechanistically,KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase(ATGL)and comparative gene identification 58(CGl-58)by LRP6/Gas/PKA/GSK3βpathway through down-regulating peroxisome proliferator-activated receptor(PPARy)and up-regulating kruppel-like factor four(KLF4),respectively.CGl-58 is bound to NF-kB p65 in the cytoplasm,and diminishing CGl-58 facilitated p65 nuclear translocation and TNFa induction.Meanwhile,hepatic CGl-58-overexpress reverses NASH in KAL transgenic mice.Further,free fatty acids up-regulated KAL against thyroid hormone in hepatocytes.Moreover,Fenofibrate,one triglyceride-lowering drug,could reverse hepatic steatosis by down-regulating KAL.These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.展开更多
Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regu...Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.展开更多
Backgroud and aim:Non-alcoholic fatty liver disease(NAFLD)is a worldwide health problem,which associated with systemic health problems and causes a higher risk of all-cause mortality.The leading causes of death in NAF...Backgroud and aim:Non-alcoholic fatty liver disease(NAFLD)is a worldwide health problem,which associated with systemic health problems and causes a higher risk of all-cause mortality.The leading causes of death in NAFLD patients are cardiac complications followed by NAFLD-related liver complications.This study aimed to quantitatively measure the contents of liver and cardiac fat with varying degrees of NAFLD in an obese group and a type 2 diabetes mellitus(T2DM)group to explore differences and correlations.Materials and methods:This study included 170 patients who underwent echo asymmetry and least square estimation-iron quantification sequencing at 3.0 T magnetic resonance imaging.Fat fraction values were quantitatively measured in regions of interest of the liver,myocardium,and periapical adipose tissue.Results:In both the obese and T2DM groups,cardiac fat content was correlated with liver fat content using linear regression(P<0.01).For both the obese and T2DM groups,myocardial fat was higher in the T2DM group than that in the obese group(ventricular septum,3.33%±1.40%vs.2.51%±0.88%;the left ventricle,3.38%±1.43%vs.2.26%±0.87%).For the T2DM group,the different myocardial fat contents and myocardial enzymes were positively correlated with fatty liver severity by multiple comparisons of different degrees of NAFLD(P<0.05).Periapical fat was statistically significant only between mild fatty and normal liver(obese group,P<0.01;T2DM group,P¼0.01).Conclusion:T2DM patients with fatty liver had higher myocardial fat content than obese patients with fatty liver,and both had a linear relationship.Periapical fat is an index for liver fat deposition in patients.The myocardial fat contents in T2DM patients with an increase in the liver fat content,which would influence cardiac function,should be given more attention in clinic.展开更多
基金supported by The National Natural Science Foundation of China (Grants 82070888,82100917,82070882,82273116,and 82203661)National Key R&D Program of China (Grant 2018YFA0800403)+5 种基金Guangdong Special Support Program for Young Top Scientist (Grant 201629046)Guangdong Natural Science Fund (Grant 2021A1515010434,2022A1515012423,2022A1515012513 and 2023A1515010316)Key Sci-Tech Research Project of Guangzhou Municipality (202201010820)China Postdoctoral Science Foundation (Grant 2021M703679)Guangzhou Key Laboratory for Metabolic Diseases (202102100004)2019 Milstein Medical Asian American Partnership Foundation Research Project Award in Translational Medicine.
文摘Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease worldwide,and the development of nonalcoholic steatohepatitis(NASH)might cause irreversible hepatic damage.Hyperlipidemia(HLP)is the leading risk factor for NAFLD.This study aims to illuminate the causative contributor and potential mechanism of Kallistatin(KAL)mediating HLP to NAFLD.221 healthy control and 253 HLP subjects,62 healthy control and 44 NAFLD subjects were enrolled.The plasma KAL was significantly elevated in HLP subjects,especially in hypertriglyceridemia(HTG)subjects,and positively correlated with liver injury.Further,KAL levels of NAFLD patients were significantly up-regulated.KAL transgenic mice induced hepatic steatosis,inflammation,and fibrosis with time and accelerated inflammation development in high-fat diet(HFD)mice.In contrast,KAL knockout ameliorated steatosis and inflammation in high-fructose diet(HFruD)and methionine and choline-deficient(MCD)diet-induced NAFLD rats.Mechanistically,KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase(ATGL)and comparative gene identification 58(CGl-58)by LRP6/Gas/PKA/GSK3βpathway through down-regulating peroxisome proliferator-activated receptor(PPARy)and up-regulating kruppel-like factor four(KLF4),respectively.CGl-58 is bound to NF-kB p65 in the cytoplasm,and diminishing CGl-58 facilitated p65 nuclear translocation and TNFa induction.Meanwhile,hepatic CGl-58-overexpress reverses NASH in KAL transgenic mice.Further,free fatty acids up-regulated KAL against thyroid hormone in hepatocytes.Moreover,Fenofibrate,one triglyceride-lowering drug,could reverse hepatic steatosis by down-regulating KAL.These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.
基金This work was supported in part by the Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University and the Indiana University Health e Indiana University School of Medicine Strategic Research Initiative,the Research Career Scientist to Dr.Alpini from the United States Department of Veteran’s Affairs,Biomedical Laboratory Research and Development Service and National Institutes of Health(NIH)grants DK054811,DK110035,and DK076898 to Drs.G.Alpini and S.Glaser.In addition,this work was supported in whole or in part by grants from the American Diabetes Association(ADA)(1-10-BS-76 to C.Wu)the National Institutes of Health(DK095828 and DK124854 to C.Wu).
文摘Background and objectives:Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease(NAFLD).However,whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated.Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(Pfkfb3/iPfk2)dissociates fat deposition and inflammation,the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.Methods:Pfkfb3-disrupted(Pfkfb3^(+/-))mice and wild-type(WT)littermates were fed a high-fat diet(HFD)and examined for NAFLD phenotype.Also,bone marrow cells isolated from Pfkfb3^(+/-)mice andWT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation(BMT)to generate chimeric(WT/BMT-Pfkfb3^(+/-))mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric(WT/BMT-WT)mice.The latter were also fed an HFD and examined for NAFLD phenotype.In vitro,hepatocytes were co-cultured with bone marrowderived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.Results:After the feeding period,HFD-fed Pfkfb3^(+/-)mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice.When inflammatory activation was analyzed,Pfkfb3^(+/-)macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation.When NAFLD phenotype was analyzed in the chimeric mice,WT/BMT-Pfkfb3^(+/-) mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice.At the cellular level,hepatocytes co-cultured with Pfkfb3^(+/-) macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.Conclusions:Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis.As such,the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.
基金grants from the National Natural Science Foundation of China(No.81801757)Guangdong Basic and Applied Basic Research Foundation(No.2019A1515012051,2022A1515010369)to R.-M.Guo.
文摘Backgroud and aim:Non-alcoholic fatty liver disease(NAFLD)is a worldwide health problem,which associated with systemic health problems and causes a higher risk of all-cause mortality.The leading causes of death in NAFLD patients are cardiac complications followed by NAFLD-related liver complications.This study aimed to quantitatively measure the contents of liver and cardiac fat with varying degrees of NAFLD in an obese group and a type 2 diabetes mellitus(T2DM)group to explore differences and correlations.Materials and methods:This study included 170 patients who underwent echo asymmetry and least square estimation-iron quantification sequencing at 3.0 T magnetic resonance imaging.Fat fraction values were quantitatively measured in regions of interest of the liver,myocardium,and periapical adipose tissue.Results:In both the obese and T2DM groups,cardiac fat content was correlated with liver fat content using linear regression(P<0.01).For both the obese and T2DM groups,myocardial fat was higher in the T2DM group than that in the obese group(ventricular septum,3.33%±1.40%vs.2.51%±0.88%;the left ventricle,3.38%±1.43%vs.2.26%±0.87%).For the T2DM group,the different myocardial fat contents and myocardial enzymes were positively correlated with fatty liver severity by multiple comparisons of different degrees of NAFLD(P<0.05).Periapical fat was statistically significant only between mild fatty and normal liver(obese group,P<0.01;T2DM group,P¼0.01).Conclusion:T2DM patients with fatty liver had higher myocardial fat content than obese patients with fatty liver,and both had a linear relationship.Periapical fat is an index for liver fat deposition in patients.The myocardial fat contents in T2DM patients with an increase in the liver fat content,which would influence cardiac function,should be given more attention in clinic.
