GDF11 rapidly increases lipid accumulation in liver cancer cells through ALK5-dependent signaling

Jan Frohlich; Tommaso Mazza; Cyril Sobolewski; Michelangelo Foti; Manlio Vinciguerra

doi:10.1016/j.bbalip.2021.158920

GDF11 rapidly increases lipid accumulation in liver cancer cells through ALK5-dependent signaling

Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jun;1866(6):158920. doi: 10.1016/j.bbalip.2021.158920. Epub 2021 Mar 6.

Authors

Jan Frohlich¹, Tommaso Mazza², Cyril Sobolewski³, Michelangelo Foti³, Manlio Vinciguerra⁴

Affiliations

¹ International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
² Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
³ Department of Cell Physiology & Metabolism and Translational Research Centre in Onco-haematology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁴ International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic; Department of Translational Stem Cell Biology, Medical University of Varna, Varna, Bulgaria; Institute of Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom. Electronic address: manlio.vinciguerra@fnusa.cz.

PMID: 33684566
DOI: 10.1016/j.bbalip.2021.158920

Abstract

Hepatocellular carcinoma (HCC) is one of the fastest-growing causes of cancer-related mortalities worldwide and this trend is mimicked by the surge of non-alcoholic fatty liver disease (NAFLD). Altered hepatic lipid metabolism promotes HCC development through inflammation and activation of oncogenes. GDF11 is a member of the TGF-β superfamily and recent data have implicated GDF11 as an anti-aging factor that can alleviate high-fat diet induced obesity, hyperglycemia, insulin resistance and NAFLD. However, its role in hepatic lipid metabolism is still not fully delineated. The aim of the present study was to characterize the role of GDF11 in hepatic and HCC cells lipid accumulation. To achieve this, we performed imaging, biochemical, lipidomic, and transcriptomic analyses in primary hepatocytes and in HCC cells treated with GDF11 to study the GDF11-activated signaling pathways. GDF11 treatment rapidly triggered ALK5-dependent SMAD2/3 nuclear translocation and elevated lipid droplets in HCC cells, but not in primary hepatocytes. In HCC cells, ALK5 inhibition hampered GDF11-mediated SMAD2/3 signaling and attenuated lipid accumulation. Using ultra-high-performance liquid chromatography/mass spectrometry, we detected increased accumulation of longer acyl-chain di/tri-acylglycerols and glycerophospholipids. Unbiased transcriptomic analysis identified TGF-β and PI3K-AKT signaling among the top pathways/cellular processes activated in GDF11 treated HCC cells. In summary, GDF11 supplementation promotes pro-lipogenic gene expression and lipid accumulation in HCC cells. Integration of our "omics" data pointed to a GDF11-induced upregulation of de novo lipogenesis through activation of ALK5/SMAD2/3/PI3K-AKT pathways. Thus, GDF11 could contribute to metabolic reprogramming and dysregulation of lipid metabolism in HCC cells, without effects on healthy hepatocytes.

Keywords: BMP11; GDF11; Growth differentiation factor 11; Lipid accumulation; Liver; NAFLD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Morphogenetic Proteins / metabolism*
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Growth Differentiation Factors / metabolism*
Hepatocytes / metabolism
Humans
Lipid Metabolism*
Lipogenesis
Liver Neoplasms / pathology*
Receptor, Transforming Growth Factor-beta Type I / metabolism*
Signal Transduction*
Smad2 Protein / metabolism
Up-Regulation

Substances

Bone Morphogenetic Proteins
GDF11 protein, human
Growth Differentiation Factors
SMAD2 protein, human
Smad2 Protein
Receptor, Transforming Growth Factor-beta Type I
TGFBR1 protein, human