Fig. 6: The murine CD model shows evidence of an ISR that may underly and aggravate urea cycle dysfunction.
From: Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency
a–c, Differentially expressed hepatic genes shown in volcano plots for slc25a13−/− mice versus wild type (a), slc25a13−/−gpd2−/− mice versus wild type (b) and slc25a13−/−gpd2−/− glycerol-exposed mice versus wild-type water-exposed (c). d, Mitochondrial generation of Asp and the role of Slc25a13 in providing Asp to hepatocyte cytosol are depicted. Asp is consumed by Asn synthetase (Asns) to make Asn, is used in protein synthesis and is ligated to citrulline by argininosuccinate synthetase 1 (Ass1) in the urea cycle. e, An ISR is proposed to be initiated by shortage of cytosolic Asp and the consequent accumulation of uncharged tRNA Asp and/or tRNA Asn, which activate Gcn2 kinase activity on eIF2α. Subsequent induction of Atf5 and Atf5 target genes could aggravate the urea cycle dysfunction because Fgf21 drives protein ingestion, Slc3a2 increases amino acid uptake, Asns consumes Asp, further limiting the availability of Asp for nitrogen disposal, and Cth produces ammonia which may exacerbate the nitrogen disposal problem. FC, fold change; n.s., not significant; OAA, oxaloacetic acid. Panels d and e created with BioRender.com.
