IMR Press / FBL / Volume 7 / Issue 4 / DOI: 10.2741/okuno

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.

Retinoids in liver fibrosis and cancer
Show Less
1 First Department of the Internal Medicine, Gifu University School of Medicine, Gifu, Japan
2 Laboratory of Molecular Cell Sciences, Tsukuba Institute, RIKEN, Tsukuba, Japan
3 Department of Pathobiochemistry, Gifu University School of Medicine, Gifu, Japan
4 Nikken Pharmaceutical Co., Tokyo, Japan
5 Sugiyama Jogakuen University, Nagoya, Japan
Front. Biosci. (Landmark Ed) 2002, 7(4), 204–218;
Published: 1 January 2002

Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-β (TGF-β), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-β activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally.

HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-α (RXRα) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive α-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of "clonal deletion" therapy for cancer chemoprevention, a new category of cancer chemotherapy.

Hepatocellular Carcinoma
Retinoic Acid
Retinol-Binding Protein
Cellular Retinol-Binding Protein
Cellular Retinoic Acid-Binding Protein
Retinoic Acid Receptor
Retinoid X Receptor
Ra Response Element
Response Element
Hepatic Parenchymal Cell
Hepatic Stellate Cell
Extracellular Matrix
Transforming Growth Factor-Beta
Plasminogen Activator
Fibroblast Growth Factor
Smooth Muscle Actin
Pa Inhibitor-1
Hepatitis B Virus
Hepatitis C Virus
Mitogen-Activated Protein Kinase
Acute Promyelocyte Leukemia
Cholangiocellular Carcinoma
Lectin-Reactive alpha-Fetoprotein Fraction
Alcohol Dehydrogenase
Aldehyde Dehydrogenase
High Performance Liquid Chromatography
Back to top