Citrin deficiency: Does the reactivation of liver aralar-1 come into play and promote HCC development?

Autor: Mention K; Univ. Lille, RADEME - Maladies RAres Du Développement et Du Métabolisme: Du Phénotype au Génotype et à La Fonction, Lille, EA, 7364, France; Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre Hospital, CHRU, Lille, France., Joncquel Chevalier Curt M; CHU Lille, Centre de Biologie Pathologie Génétique, UF Métabolisme Général et Maladies Rares, F-59000, Lille, France., Dessein AF; CHU Lille, Centre de Biologie Pathologie Génétique, UF Métabolisme Général et Maladies Rares, F-59000, Lille, France., Douillard C; Endocrinology-Diabetology-Metabolism Department and Medical Reference Center for Inherited Metabolic Diseases Jeanne de Flandre Hospital, CHRU Lille, Lille, France., Dobbelaere D; Univ. Lille, RADEME - Maladies RAres Du Développement et Du Métabolisme: Du Phénotype au Génotype et à La Fonction, Lille, EA, 7364, France; Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre Hospital, CHRU, Lille, France., Vamecq J; Inserm, Univ. Lille EA 7364 RADEME, CHU Lille, Centre de Biologie Pathologie Génétique, UF Métabolisme Général et Maladies Rares, F-59000, Lille, France. Electronic address: joseph.vamecq@inserm.fr.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2021 Nov; Vol. 190, pp. 20-23. Date of Electronic Publication: 2021 Jul 03.
DOI: 10.1016/j.biochi.2021.06.018
Abstrakt: Hepatocellular carcinoma (HCC) is a longstanding issue in clinical practice and metabolic research. New clues in better understanding the pathogenesis of HCC might relate to the metabolic context in patients with citrin (aspartate-glutamate carrier 1) deficiency (CD). Because citrin-deficient liver (CDL) is subject to HCC, it represents a unique metabolic model to highlight the mechanisms of HCC promotion, offering different angles of study than the classical metabolic syndrome/obesity/non-alcoholic fatty liver disease (NAFLD)/HCC study axis. In turn, the metabolic features of HCC could shed light on the pathogenesis of CDL. Among these, HCC-induced re-activation of aralar-1 (aspartate-glutamate carrier 2), physiologically not expressed in the adult liver, might take place in CDL, so gene redundancy for mitochondrial aspartate-glutamate carriers would be exploited by the CDL. This proposed (aralar-1 re-activation) and known (citrate/malate cycle) adaptive mechanisms may substitute for the impaired function in CD and are consistent with the clinical remission stage of CD and CD improvement by medium-chain triglycerides (MCT). However, these metabolic adaptive benefits could also promote HCC development. In CD, as a result of PPARα down-regulation, liver mitochondrial fatty acid-derived acetyl-CoA would, like glucose-derived acetyl-CoA, be used for lipid anabolism and fuel nuclear acetylation events which might trigger aralar-1 re-activation as seen in non-CD HCC. A brief account of these metabolic events which might lead to aralar-1 re-activation in CDL is here given. Consistency of this account for CDL events further relies on the protective roles of PPARα and inhibition of mitochondrial and plasma membrane citrate transporters in non-CD HCC.
Competing Interests: Declaration of competing interest None.
(Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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