Research Paper Volume 11, Issue 23 pp 11520—11540
Bone morphogenetic protein 4 (BMP4) alleviates hepatic steatosis by increasing hepatic lipid turnover and inhibiting the mTORC1 signaling axis in hepatocytes
- 1 Ministry of Education Key Laboratory of Diagnostic Medicine, and School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
- 2 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- 3 Clinical Epidemiology and Biostatistics Department, Department of Pediatric Research Institute, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
- 4 Key Laboratory of Molecular Biology for Infectious Diseases of The Ministry of Education of China, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Received: September 18, 2019 Accepted: November 19, 2019 Published: December 12, 2019
https://doi.org/10.18632/aging.102552How to Cite
Copyright © 2019 Peng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Liver has numerous critical metabolic functions including lipid metabolism, which is usually dysregulated in obesity, the metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates bone morphogenetic proteins (BMPs) play an important role in adipogenesis and thermogenic balance in adipogenic progenitors and adipose tissue. However, the direct impact of BMPs on hepatic steatosis and possible association with NAFLD are poorly understood. Here, we found that BMP4 was up-regulated in oleic acid-induced steatosis and during the development of high fat diet (HFD)-induced NAFLD. Exogenous BMP4 reduced lipid accumulation and up-regulated the genes involved in lipid synthesis, storage and breakdown in hepatocytes. Exogenous BMP4 inhibited hepatic steatosis, reduced serum triglyceride levels and body weight, and alleviated progression of NAFLD in vivo. Mechanistically, BMP4 overexpression in hepatocytes down-regulated most components of the mTORC1 signaling axis. Collectively, these findings strongly suggest that BMP4 may play an essential role in regulating hepatic lipid metabolism and the molecular pathogenesis of NAFLD. Manipulating BMP4 and/or mTORC1 signaling axis may lead to the development of novel therapeutics for obesity, metabolic syndrome, and NAFLD.
Abbreviations
NAFLD: non-alcoholic fatty liver disease; Bmp4: bone morphogenetic protein 4; Ad-B4: Adenovirus-overexpression of BMP4; Ad-GFP: Adenovirus-expression of Green fluorescent protein (GFP); TG: triglycerides; ORO: Oil red O; TqPCR: touchdown-quantitative real-time PCR; IHC: immunohistochemical; H&E: hematoxylin and eosin; TG: triglycerides; Gpam: glycerol-3-phosphate acyltransferase, mitochondrial; Mogat1: monoacylglycerol O-acyltransferase 1; Fasn: fatty acid synthase; Acaca: acetyl-CoA carboxylase alpha; Apoc3: apolipoprotein C3; Srebf1/Srebp: sterol regulatory element binding transcription factor 1; Plin2: perilipin 2; Plin3: perilipin 3; Scd1: stearoyl-Coenzyme A desaturase 1; Lipe: lipase E, hormone sensitive type; Ctnnb1: catenin beta 1; Ascl1: achaete-scute family bHLH transcription factor 1; Acat2: acetyl-CoA acetyltransferase 2; Cpt1b: carnitine palmitoyltransferase 1B; Ndufs4: NADH: ubiquinone oxidoreductase subunit S4; Pck2: phosphoenolpyruvate carboxykinase 2, mitochondrial; Cyp1a2: cytochrome P450 family 1 subfamily A member 2; Acads(Bcd-1): acyl-CoA dehydrogenase short chain; Acadm: acyl-CoA dehydrogenase medium chain; Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; Hadha: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; Deptor: DEP domain containing MTOR interacting protein; Pras40/Akt1s1: AKT1 substrate 1 (proline-rich); Rptor: regulatory associated protein of MTOR, complex 1; Mtor: mechanistic target of rapamycin kinase; Rps6kb1/S6k: ribosomal protein S6 kinase B1.