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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F21%3A00075207" target="_blank" >RIV/00159816:_____/21:00075207 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S1388198121000469?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S1388198121000469?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbalip.2021.158920" target="_blank" >10.1016/j.bbalip.2021.158920</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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-beta 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-beta 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 &quot;omics&quot; 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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-beta 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-beta 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 &quot;omics&quot; 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Mapování molekulární podstaty procesů stárnutí pro vývoj nových léčebných metod</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

ISSN

1388-1981

e-ISSN

—

Svazek periodika

1866

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

15

Strana od-do

—

Kód UT WoS článku

000636044800011

EID výsledku v databázi Scopus

—