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Article

Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC

1
Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
2
Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
3
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
4
Center Esther Koplowitz, Planta Cuarta, C/Rosselló 149, 08036 Barcelona, Spain
5
Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Matias A. Avila, Carmen Berasain and Andrea Casadei-Gardini
Cancers 2021, 13(16), 4091; https://doi.org/10.3390/cancers13164091
Received: 3 June 2021 / Revised: 5 August 2021 / Accepted: 6 August 2021 / Published: 13 August 2021
(This article belongs to the Special Issue Theranostic Advances in Hepatobiliary Tumors)
In the present study, which is part of the Special Issue “Theranostic Advances in Hepatobiliary Tumors”, we address whether hepatic steatosis per se or cholesterol sensitizes to NASH-driven HCC. This is a very important health issue, as the incidence of HCC derived from NASH is expected to keep rising due to the association of NASH with the obesity and type 2 diabetes epidemic. Using dietary and genetic models to generate hepatic steatosis with or without cholesterol accumulation, we provide evidence for the tumor promoter role of cholesterol in NASH-HCC associated with an increased expression of the genes involved in immune checkpoints, which suggests that cholesterol favors a milieu prone to T-cell exhaustion.
The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation of different lipid species, and cholesterol has emerged as an important player in NASH development, which has been shown to promote NASH-driven HCC. However, recent findings indicated a tumor suppressor role of cholesterol in liver carcinogenesis and HCC development. Thus, we examined the contribution of hepatic steatosis with or without cholesterol accumulation induced by dietary or genetic approaches in liver tumorigenesis and whether the role of cholesterol in NASH-driven HCC is species-dependent. While diethylnitrosamine (DEN) treatment to rats or mice fed a choline-deficient diet decreased the hepatic steatosis, feeding an atherogenic diet enriched in cholesterol potentiated the liver tumor markers. Similar effects were observed in DEN-treated transgenic SREBP-2 mice but not wild-type (WT) mice fed a regular chow diet. Remarkably, long-term feeding of a high-fat high-cholesterol diet (HFHC) but not a high-fat diet (HFD) to WT mice caused severe NASH with spontaneous progression to HCC. A similar outcome was observed in MUP-uPA transgenic mice fed a HFHC diet, which resulted in increased liver tumors and expression of the genes involved in the immune checkpoints. Ezetimibe treatment ameliorated chronic liver disease and, more importantly, tumor multiplicity in HFHC-fed MUP-uPA mice or DEN-treated WT mice. Thus, these results revealed a differential role of steatosis and cholesterol in NASH-driven HCC and indicated that the tumor-promoter role of cholesterol is species-independent and associated with impaired immunosurveillance. View Full-Text
Keywords: cholesterol; hepatocellular carcinoma; steatosis; NASH cholesterol; hepatocellular carcinoma; steatosis; NASH
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MDPI and ACS Style

Ribas, V.; Conde de la Rosa, L.; Robles, D.; Núñez, S.; Segalés, P.; Insausti-Urkia, N.; Solsona-Vilarrasa, E.; Fernández-Checa, J.C.; García-Ruiz, C. Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC. Cancers 2021, 13, 4091. https://doi.org/10.3390/cancers13164091

AMA Style

Ribas V, Conde de la Rosa L, Robles D, Núñez S, Segalés P, Insausti-Urkia N, Solsona-Vilarrasa E, Fernández-Checa JC, García-Ruiz C. Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC. Cancers. 2021; 13(16):4091. https://doi.org/10.3390/cancers13164091

Chicago/Turabian Style

Ribas, Vicent, Laura Conde de la Rosa, David Robles, Susana Núñez, Paula Segalés, Naroa Insausti-Urkia, Estel Solsona-Vilarrasa, José C. Fernández-Checa, and Carmen García-Ruiz. 2021. "Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC" Cancers 13, no. 16: 4091. https://doi.org/10.3390/cancers13164091

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