Altered lipid metabolism could drive the bone marrow failure in fanconi anaemia

Ravera, Silvia; Degan, Paolo; Sabatini, Federica; Columbaro, Marta; Dufour, Carlo; Cappelli, Enrico

doi:10.1111/bjh.15171

Cited by 17 publications

(19 citation statements)

References 11 publications

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“…5D). This alteration in the expression of a fatty acid regulating transcription factor in livers of Fancd2 Ϫ/Ϫ mice fed the Paigen diet is consistent with previously reported altered fatty acid metabolism in FA lymphoblasts and lymphocytes (20). Stearoyl-CoA desaturase is a rate-limiting enzyme that catalyzes the synthesis of monounsaturated fatty acids that are important for hepatic VLDL export and cholesterol esterification (44).…”

Section: Male Fancd2 ؊/؊ Mice Have Impaired Cholesterol and Lipid Regsupporting

confidence: 89%

“…Furthermore, the specific DNA lesions and cellular aberrations that arise and contribute to disease phenotypes in the absence of an intact FA pathway are incompletely characterized. Recent work suggests the FA pathway regulates multiple components of cellular metabolism, including energy and lipid metabolism, in addition to its canonical functions in DNA repair (14,15,(17)(18)(19)(20)(21). In this study, we tested the in vivo sensitivity of FA-deficient mice to challenge with a high-lipid HFD or the high-fat, high-cholesterol cholic acidenriched Paigen diet to probe whether FA deficiency would result in increased DNA damage accumulation and/or altered cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…lipid metabolism (16). FA deficiency has been reported to impact the abundance of lipids and other metabolites in multiple cancer types, as well as FA cell lines and lymphoblasts (17)(18)(19)(20). Abnormal production of glycerophospholipids by FA bone marrow mesenchymal stromal cells may contribute to altered hematopoietic cell physiology (21).…”

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confidence: 99%

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Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge

Moore

Daugherity

Karambizi

et al. 2019

Journal of Biological Chemistry

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Edited by John M. Denu Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2 ؊/؊ and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2 ؊/؊ mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2 ؊/؊ mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1. Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA. Fanconi anemia (FA) 2 is a human genetic disorder characterized by developmental defects, sterility, hematopoietic failure, cancer predisposition, and metabolic disease. FA is caused by biallelic mutation of any of the 22 genes encoding components of the FA pathway. Canonically, the FA pathway responds to replicative stress, particularly to DNA interstrand cross-links. FA-deficient cells are hypersensitive to genotoxins, such as DNA cross-linking agents, irradiation, alkylating agents, and oxidative stress. Endocrine and metabolic abnormalities are also components of the FA phenotype (1-3). Close to 80% of FA patients have at least one endocrine abnormality (2). Dyslipidemia has been reported in 55% of FA patients (3) and impaired glucose tolerance in 27-68% of FA patients (2-5). The endogenous agents contributing to DNA damage and the etiologic connection between FA deficiency and the development of metabolic disease remain incompletely characterized. FA phenotypes may be the direct result of DNA damage arising from endogenous sources normally counteracted by the FA pathway's DNA repair functions. This is thought to be the mechanism underlying the hypersensitivity of FA-deficient cells to aldehydes and formaldehyde by-products generated as a result of cellular ...

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Section: Male Fancd2 ؊/؊ Mice Have Impaired Cholesterol and Lipid Regsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge

Moore

Daugherity

Karambizi

et al. 2019

Journal of Biological Chemistry

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“…Very recently, the first genotype-phenotype correlation of FA endocrine defects has been studied in a cohort of 24 patients homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG [72]. Defects usually observed in FA patients are related to glucose and insulin metabolism as well as to lipid dysregulation [73]. Mice deficient for the Fanca or Fancc gene seem to be diabetes-and obesity-prone [74].…”

Section: Endocrinopathiesmentioning

confidence: 99%

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Milletti

Strocchio

Pagliara

et al. 2020

Cancers

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Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.

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“…At the cellular level, metabolome analysis of mesenchymal stromal cells from FA-knockout mice revealed abnormal lipid profiles, especially in glycerophospholipid biosynthesis [24]. FA-deficient human cells also show accumulation of lipid droplets (LDs) [25], which are nuclear and cytoplasmic organelles that store neutral lipids and are important for energy metabolism. Recently, it has been suggested that LDs may serve as a biomarker for metabolic diseases [26].…”

Section: Lipid Peroxidation-derived Aldehydesmentioning

confidence: 99%

Importance of finding the bona fide target of the Fanconi anemia pathway

Sakai

Sugasawa

2019

Genes and Environ

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Fanconi anemia (FA) is a rare genetic disease characterized by the deficiency of the cellular response and repair pathway for DNA interstrand crosslink (ICL) damage. Although recent studies have revealed the detailed molecular functions of FA proteins encoded by 22 genes, the mechanism of occurrence of endogenous ICLs in the human body remains poorly understood. In this short review, we summarize the potential endogenous sources of ICLs counteracted by FA proteins, and provide perspectives on the unanswered questions regarding FA.

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Altered lipid metabolism could drive the bone marrow failure in fanconi anaemia

Cited by 17 publications

References 11 publications

Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge

Sex-specific hepatic lipid and bile acid metabolism alterations in Fancd2-deficient mice following dietary challenge

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Importance of finding the bona fide target of the Fanconi anemia pathway

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