Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease  

作　　者：Zhenzhen Fang Gang Shen Yina Wang Fuyan Hong Xiumei Tang Yongcheng Zeng Ting Zhang Huanyi Liu Yanmei Li Jinhong Wang Jing Zhang Anton Gao Weiwei Qi Xia Yang Ti Zhou Guoquan Gao 

机构地区：[1]Department of Biochemistry,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,China [2]Department of VIP Medical Center,the Third Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China [3]Physical Examination Center,the Third Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China [4]Department of Clinical Laboratory,Guangzhou First People's Hospital,Guangzhou 510080,China [5]Guangdong Key Laboratory of Liver Disease Research,the Third Affiliated Hospital of Sun Yat-Sen University,Guangzhou 51008,China [6]Department of Health Sciences,College of Health Solutions,Arizona State University,Tempe,USA [7]Guangdong Engineering&Technology Research Center for Gene Manipulation and Biomacromolecular Products,Sun Yat-Sen University,Guangzhou 510080,China [8]Guangdong Province Key Laboratory of Diabetology,Guangzhou 510o80,China [9]Guangdong Province Key Laboratory of Brain Function and Disease,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第4期1730-1744,共15页信号转导与靶向治疗（英文）

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);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.

摘　　要：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.

关 键 词：GSK3Β inflammation ELEVATED 

分 类 号：R575.5[医药卫生—消化系统]