Dataset Information

Spontaneous nonsense mutation in Tuft1 (tuftelin 1) gene is associated with abnormal hair appearance and amelioration of glucose and lipid metabolism in the rat

ABSTRACT: A new spontaneous mutation, abnormal hair appearance in the rat, has been identified as a non-functional Tuft1 (tuftelin 1) gene. The pleiotropic effects of this mutation regulate glucose and lipid metabolism. Analysis of the liver proteome revealed possible molecular mechanisms for the metabolic effects of the Tuft1 gene. Recently, we identified a recessive mutation, an abnormal coat appearance, in BXH6 strain, a member of the HXB/BXH set of recombinant inbred strains derived from the SHR (spontaneously hypertensive rat) and BN-Lx (Brown Norway rat) progenitors. Whole genome sequencing of the mutant rats identified the 195875980 G/A mutation in the Tuft1 (tuftelin 1) gene on chromosome 2, which resulted in a premature stop codon. Compared to wild-type BXH6 rats, BXH6-Tuft1 mutant rats exhibited lower body weight due to reduced visceral fat and ectopic fat accumulation in the liver and heart. Reduced adiposity was associated with decreased serum glucose and insulin, and increased insulin-stimulated glycogenesis in skeletal muscle. In addition, mutant rats had lower serum MCP-1 and leptin levels, indicative of reduced inflammation. Analysis of the liver proteome identified differentially expressed proteins from fatty acid metabolism and beta oxidation, peroxisomes, carbohydrate metabolism, inflammation, and proteasome pathways. These results provide evidence for an important role of Tuft1 gene in the regulation of lipid and glucose metabolism and suggest underlying molecular mechanisms.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Liver

SUBMITTER: Marek Vrbacky

LAB HEAD: Michal Pravenec

PROVIDER: PXD045880 | Pride | 2024-03-12

REPOSITORIES: Pride

ACCESS DATA

Publications

Spontaneous nonsense mutation in the tuftelin 1 gene is associated with abnormal hair appearance and amelioration of glucose and lipid metabolism in the rat.

Šilhavý Jan J Mlejnek Petr P Šimáková Miroslava M Liška František F Malínská Hana H Marková Irena I Hüttl Martina M Miklánková Denisa D Mušálková Dita D Stránecký Viktor V Kmoch Stanislav S Sticová Eva E Vrbacký Marek M Mráček Tomáš T Pravenec Michal M

Physiological genomics 20231113 1

Recently, we have identified a recessive mutation, an abnormal coat appearance in the BXH6 strain, a member of the HXB/BXH set of recombinant inbred (RI) strains. The RI strains were derived from the spontaneously hypertensive rat (SHR) and Brown Norway rat (BN-<i>Lx</i>) progenitors. Whole genome sequencing of the mutant rats identified the 195875980 G/A mutation in the tuftelin 1 (<i>Tuft1</i>) gene on chromosome 2, which resulted in a premature stop codon. Compared with wild-type BXH6 rats, B ...[more]

PMID: 37955133

Similar Datasets

Project description:Hypertension and kidney disease, two related, common, and severe disease entities have been repeatedly associated with genomic variants and metabolic alterations of lysine metabolism. Here, we developed a stable isotope labeling strategy compatible with untargeted metabolomics acquisition to investigate the physiology and molecular spectrum of lysine’s metabolic fate in vivo. Mice received 13C6 labeled lysine through the diet over two months to track more than 100 lysine metabolites across various organs and body fluids. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, as opposed to slow or incorporation into proteins and metabolization into acylcarnitines. Lysine metabolism is accelerated in the rat model of the Dahl salt-sensitive hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Here, lysine administration completely diminished the development of salt-sensitive hypertension and kidney injury. Administration of lysine leads to diuresis, even further acceleration of 13C6 lysine conjugate formation, and inhibition of albumin uptake, thereby protecting from nephron injury and metabolic stress. Lysine conjugates with malonyl-CoA to form a novel metabolite N-malonyl-lysine, to deplete malonyl-CoA from fatty acid synthesis. This process occurs at the expense of protein malonylation. In hypertensive rats with kidney damage, lysine molecules were excreted as fructoselysine, saccharopine and Nε-acetyllysine, via the urine, leading to an overall depletion of central carbon metabolites from the organism and kidney. Consistent with findings in the salt-sensitive rat, lysine challenge of patients with mild kidney damage inhibited tubular albumin uptake, increased lysine conjugate formation in the urine, and reduced TCA cycle metabolites, in contrast to kidney-healthy volunteers. In conclusion, comprehensive lysine isotope tracing mapped an accelerated lysine metabolism in hypertension, and further, lysine administration induced kidney protection in kidney disease.

Dataset Information

Spontaneous nonsense mutation in Tuft1 (tuftelin 1) gene is associated with abnormal hair appearance and amelioration of glucose and lipid metabolism in the rat

Publications

Spontaneous nonsense mutation in the tuftelin 1 gene is associated with abnormal hair appearance and amelioration of glucose and lipid metabolism in the rat.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure