PMID- 34311531 OWN - NLM STAT- MEDLINE DCOM- 20210803 LR - 20210803 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 138 DP - 2021 Jun TI - FTZ attenuates liver steatosis and fibrosis in the minipigs with type 2 diabetes by regulating the AMPK signaling pathway. PG - 111532 LID - S0753-3322(21)00317-6 [pii] LID - 10.1016/j.biopha.2021.111532 [doi] AB - Fufang Zhenzhu Tiaozhi formula (FTZ), a preparation of Chinese herbal medicine, has various pharmacological properties, such as hypoglycemic, hypolipidemic, anticoagulant, and anti-inflammatory activities. Hepatocyte apoptosis is a marker of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. Given the multiple effects of FTZ, we investigated whether FTZ can be a therapeutic agent for NASH and its mechanism. In the present study, we observed that FTZ treatment had an obviously favorable influence on hepatic steatosis and fibrosis in the histopathologic features of type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) with NASH minipigs. In addition, immunohistochemical analysis showed increased expression of the fibrotic marker alpha-smooth muscle actin (alpha-SMA), and a TUNEL assay revealed increased apoptotic positive hepatic cells in the liver tissues of the model group. Furthermore, FTZ administration reduced the increased expression of alpha-SMA, and FTZ inhibited apoptosis by affecting Bcl-2/Bax and cleaved caspase-3 expression. Mechanistically, our data suggested that FTZ treatment attenuated hepatic steatosis and fibrosis via the adenosine monophosphate-activated protein kinase (AMPK) pathway. In vitro studies showed that FTZ also attenuated intracellular lipid accumulation in HepG2 cells exposed to palmitic acid (PA) and oleic acid (OA). FTZ upregulated the expression levels of P-AMPK and BCL-2 and downregulated BAX. The changes induced by FTZ were reversed by Compound C, an inhibitor of AMPK. In conclusion, FTZ attenuated NASH by ameliorating steatosis and hepatocyte apoptosis, which is attributable to the regulation of the AMPK pathway. CI - Copyright (c) 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Wang, Hong AU - Wang H AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Huang, Minyi AU - Huang M AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Bei, Weijian AU - Bei W AD - Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Yang, Yiqi AU - Yang Y AD - Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China; Guangdong TCM Key Laboratory against Metabolic Diseases, China. FAU - Song, Lixia AU - Song L AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Zhang, Dongxing AU - Zhang D AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Zhan, Wenjing AU - Zhan W AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Zhang, Yuzhen AU - Zhang Y AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Chen, Xu AU - Chen X AD - Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China. FAU - Wang, Weixuan AU - Wang W AD - Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China; Guangdong TCM Key Laboratory against Metabolic Diseases, China. FAU - Wang, Lexun AU - Wang L AD - Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China; Guangdong TCM Key Laboratory against Metabolic Diseases, China. FAU - Guo, Jiao AU - Guo J AD - Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, China; Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), China; Institute of Chinese Medicinal Sciences, Guangdong Pharmaceutical University, China; Guangdong TCM Key Laboratory against Metabolic Diseases, China. Electronic address: gyguoyz@163.com. LA - eng PT - Journal Article DEP - 20210403 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Biomarkers) RN - 0 (Blood Glucose) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Lipids) RN - 0 (fufang-zhenzhu-tiaozhi) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Apoptosis/drug effects MH - Apoptosis Regulatory Proteins/metabolism MH - Biomarkers/blood MH - Blood Glucose/drug effects/metabolism MH - Coronary Disease/enzymology/etiology/prevention & control MH - Diabetes Mellitus, Type 2/complications/*drug therapy/enzymology MH - Drugs, Chinese Herbal/*pharmacology MH - Hep G2 Cells MH - Humans MH - Lipid Metabolism/*drug effects MH - Lipids/blood MH - Liver/*drug effects/enzymology/pathology MH - Liver Cirrhosis/enzymology/etiology/pathology/*prevention & control MH - Male MH - Non-alcoholic Fatty Liver Disease/enzymology/etiology/pathology/*prevention & control MH - Phosphorylation MH - Signal Transduction/drug effects MH - Swine MH - Swine, Miniature OTO - NOTNLM OT - AMPK OT - Apoptosis OT - Fibrosis OT - Fufang Zhenzhu Tiaozhi OT - Nonalcoholic steatohepatitis OT - Steatosis EDAT- 2021/07/28 06:00 MHDA- 2021/08/04 06:00 CRDT- 2021/07/27 01:01 PHST- 2020/11/17 00:00 [received] PHST- 2021/03/19 00:00 [revised] PHST- 2021/03/21 00:00 [accepted] PHST- 2021/07/27 01:01 [entrez] PHST- 2021/07/28 06:00 [pubmed] PHST- 2021/08/04 06:00 [medline] AID - S0753-3322(21)00317-6 [pii] AID - 10.1016/j.biopha.2021.111532 [doi] PST - ppublish SO - Biomed Pharmacother. 2021 Jun;138:111532. doi: 10.1016/j.biopha.2021.111532. Epub 2021 Apr 3.