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Currently, there remains no approved therapy. Ramulus mori (Sangzhi) alkaloids (SZ-As), a novel natural medicine, have achieved comprehensive benefits in the treatment of type 2 diabetes; however, few studies have focused on its role in ameliorating hepatic lipid metabolic disturbance. Herein, the therapeutic effect and mechanism of SZ-As on a high-fat diet (HFD) combined with streptozotocin (STZ)-induced NAFLD mice were investigated via incorporating transcriptomics and lipidomics. SZ-As reduced body weight and hepatic lipid levels, restored pathological alternation and converted the blood biochemistry perturbations. SZ-A treatment also remarkedly inhibited lipogenesis and enhanced lipolysis, fatty acid oxidation and thermogenesis. Transcriptomics analysis confirmed that SZ-As mainly altered fatty acid oxidative metabolism and the TNF signaling pathway. SZ-As were further demonstrated to downregulate inflammatory factors and effectively ameliorate hepatic inflammation. Lipidomics analysis also suggested that SZ-As affected differential lipids including triglyceride (TG) and phosphatidylcholine (PC) expression, and the main metabolic pathways included glycerophospholipid, sphingomyelins and choline metabolism. Collectively, combined with transcriptomics and metabolomics data, it is suggested that SZ-As exert their therapeutic effect on NAFLD possibly through regulating lipid metabolism pathways (glycerophospholipid metabolism and choline metabolism) and increasing levels of PC and lysophosphatidylcholine (LPC) metabolites. This study provides the basis for more widespread clinical applications of SZ-As.<\/jats:p>","DOI":"10.3390\/nu15183914","type":"journal-article","created":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T09:09:21Z","timestamp":1694423361000},"page":"3914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet\/Streptozotocin-Induced Diabetic Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Fan","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sai-Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-7842","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Plant Development, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100193, China"},{"name":"Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China"},{"name":"Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing 100193, China"},{"name":"Key Laboratory of Efficacy Evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing 100193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1801585","DOI":"10.1002\/advs.201801585","article-title":"Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases","volume":"6","author":"Yu","year":"2019","journal-title":"Adv. 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