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

التفاصيل البيبلوغرافية
العنوان: Elevated Kallistatin promotes the occurrence and progression of non-alcoholic fatty liver disease
المؤلفون: 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
المصدر: Signal Transduction and Targeted Therapy, Vol 9, Iss 1, Pp 1-15 (2024)
بيانات النشر: Nature Publishing Group, 2024.
سنة النشر: 2024
المجموعة: LCC:Medicine
LCC:Biology (General)
مصطلحات موضوعية: Medicine, Biology (General), QH301-705.5
الوصف: Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic 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 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2059-3635
Relation: https://doaj.org/toc/2059-3635
DOI: 10.1038/s41392-024-01781-9
URL الوصول: https://doaj.org/article/f3063c2bca26431aa1f8b5268563ee6f
رقم الأكسشن: edsdoj.f3063c2bca26431aa1f8b5268563ee6f
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20593635
DOI:10.1038/s41392-024-01781-9