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Updated: Dec 1, 2025
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular
Sharik Hernandez1, Arturo Simoni-Nieves1,2, Monserrat Gerardo-Ramírez1,2
1Posgrado en Biología Experimental, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico.
Abstract:
Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor-suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor-suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma-derived cell lines were exposed to GDF11 (50 ng/ml), RNA-seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum-related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real-time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.
Insights
Growth Differentiation Factor 11 (GDF11) suppresses liver cancer by impairing cancer cell metabolism. GDF11 targets lipid homeostasis, glycolysis, and mitochondria, reducing cancer aggressiveness and stemness features.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Metabolism
Background:
- Growth Differentiation Factor 11 (GDF11) regulates cell differentiation and stemness.
- GDF11 exhibits tumor-suppressive properties in hepatocellular carcinoma (HCC) by reducing cancer stemness and aggressiveness.
- The precise mechanisms underlying GDF11's tumor-suppressive effects in liver cancer require further elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which GDF11 exerts its tumor-suppressive effects in liver cancer cells.
- To identify the key metabolic pathways and cellular functions targeted by GDF11 in hepatocellular carcinoma.
Main Methods:
- Hepatocellular carcinoma cell lines (Huh7, Hep3B) were treated with GDF11.
- RNA-sequencing (RNA-seq) was performed on Huh7 cells to analyze transcriptomic changes.
- Lipid content (cholesterol, triglycerides), mTOR signaling, mevalonate pathway proteins, and real-time cellular metabolism (glycolysis, oxygen consumption, ATP production) were assessed.
- Transmission electron microscopy (TEM) was used to examine mitochondrial morphology.
Main Results:
- GDF11 treatment significantly impacted gene expression, particularly in cholesterol and steroid metabolic processes, and endoplasmic reticulum-related functions.
- GDF11 significantly reduced cholesterol and triglyceride levels in HCC cells.
- The mTOR signaling pathway and key mevalonate pathway proteins were downregulated by GDF11.
- GDF11 impaired glycolysis, glycolytic capacity, oxygen consumption rate, and ATP production.
- TEM revealed mitochondrial abnormalities, including cristae disarrangement, in GDF11-treated cells.
Conclusions:
- GDF11 inhibits hepatocellular carcinoma progression by disrupting cancer cell metabolism.
- GDF11 targets lipid homeostasis, glycolysis, and mitochondrial function, leading to reduced cancer aggressiveness.
- These findings highlight GDF11 as a potential therapeutic target for liver cancer treatment.
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